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Sample records for selectively inhibit positive

  1. Selective inhibition of distracting input.

    Science.gov (United States)

    Noonan, MaryAnn P; Crittenden, Ben M; Jensen, Ole; Stokes, Mark G

    2017-10-16

    We review a series of studies exploring distractor suppression. It is often assumed that preparatory distractor suppression is controlled via top-down mechanisms of attention akin to those that prepare brain areas for target enhancement. Here, we consider two alternative mechanisms: secondary inhibition and expectation suppression within a predictive coding framework. We draw on behavioural studies, evidence from neuroimaging and some animal studies. We conclude that there is very limited evidence for selective top-down control of preparatory inhibition. By contrast, we argue that distractor suppression often relies secondary inhibition of non-target items (relatively non-selective inhibition) and on statistical regularities of the environment, learned through direct experience. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  2. Glycogen synthase kinase-3 inhibitors suppress the AR-V7-mediated transcription and selectively inhibit cell growth in AR-V7-positive prostate cancer cells.

    Science.gov (United States)

    Nakata, Daisuke; Koyama, Ryokichi; Nakayama, Kazuhide; Kitazawa, Satoshi; Watanabe, Tatsuya; Hara, Takahito

    2017-06-01

    Recent evidence suggests that androgen receptor (AR) splice variants, including AR-V7, play a pivotal role in resistance to androgen blockade in prostate cancer treatment. The development of new therapeutic agents that can suppress the transcriptional activities of AR splice variants has been anticipated as the next generation treatment of castration-resistant prostate cancer. High-throughput screening of AR-V7 signaling inhibitors was performed using an AR-V7 reporter system. The effects of a glycogen synthase kinase-3 (GSK3) inhibitor, LY-2090314, on endogenous AR-V7 signaling were evaluated in an AR-V7-positive cell line, JDCaP-hr, by quantitative reverse transcription polymerase chain reaction. The relationship between AR-V7 signaling and β-catenin signaling was assessed using RNA interference. The effect of LY-2090314 on cell growth in various prostate cancer cell lines was also evaluated. We identified GSK3 inhibitors as transcriptional suppressors of AR-V7 using a high-throughput screen with an AR-V7 reporter system. LY-2090314 suppressed the reporter activity and endogenous AR-V7 activity in JDCaP-hr cells. Because silencing of β-catenin partly rescued the suppression, it was evident that the suppression was mediated, at least partially, via the activation of β-catenin signaling. AR-V7 signaling and β-catenin signaling reciprocally regulate each other in JDCaP-hr cells, and therefore, GSK3 inhibition can repress AR-V7 transcriptional activity by accumulating intracellular β-catenin. Notably, LY-2090314 selectively inhibited the growth of AR-V7-positive prostate cancer cells in vitro. Our findings demonstrate the potential of GSK3 inhibitors in treating advanced prostate cancer driven by AR splice variants. In vivo evaluation of AR splice variant-positive prostate cancer models will help illustrate the overall significance of GSK3 inhibitors in treating prostate cancer. © 2017 Wiley Periodicals, Inc.

  3. Regulation of spatial selectivity by crossover inhibition.

    Science.gov (United States)

    Cafaro, Jon; Rieke, Fred

    2013-04-10

    Signals throughout the nervous system diverge into parallel excitatory and inhibitory pathways that later converge on downstream neurons to control their spike output. Converging excitatory and inhibitory synaptic inputs can exhibit a variety of temporal relationships. A common motif is feedforward inhibition, in which an increase (decrease) in excitatory input precedes a corresponding increase (decrease) in inhibitory input. The delay of inhibitory input relative to excitatory input originates from an extra synapse in the circuit shaping inhibitory input. Another common motif is push-pull or "crossover" inhibition, in which increases (decreases) in excitatory input occur together with decreases (increases) in inhibitory input. Primate On midget ganglion cells receive primarily feedforward inhibition and On parasol cells receive primarily crossover inhibition; this difference provides an opportunity to study how each motif shapes the light responses of cell types that play a key role in visual perception. For full-field stimuli, feedforward inhibition abbreviated and attenuated responses of On midget cells, while crossover inhibition, though plentiful, had surprisingly little impact on the responses of On parasol cells. Spatially structured stimuli, however, could cause excitatory and inhibitory inputs to On parasol cells to increase together, adopting a temporal relation very much like that for feedforward inhibition. In this case, inhibitory inputs substantially abbreviated a cell's spike output. Thus inhibitory input shapes the temporal stimulus selectivity of both midget and parasol ganglion cells, but its impact on responses of parasol cells depends strongly on the spatial structure of the light inputs.

  4. Genes under positive selection in Escherichia coli

    DEFF Research Database (Denmark)

    Petersen, Lise; Bollback, Jonathan P; Dimmic, Matt

    2007-01-01

    We used a comparative genomics approach to identify genes that are under positive selection in six strains of Escherichia coli and Shigella flexneri, including five strains that are human pathogens. We find that positive selection targets a wide range of different functions in the E. coli genome......, including cell surface proteins such as beta barrel porins, presumably because of the involvement of these genes in evolutionary arms races with other bacteria, phages, and/or the host immune system. Structural mapping of positively selected sites on trans-membrane beta barrel porins reveals...... that the residues under positive selection occur almost exclusively in the extracellular region of the proteins that are enriched with sites known to be targets of phages, colicins, or the host immune system. More surprisingly, we also find a number of other categories of genes that show very strong evidence...

  5. Positive selection on the killer whale mitogenome

    DEFF Research Database (Denmark)

    Foote, Andrew David; Morin, Phillip A.; Durban, John W.

    2011-01-01

    Mitochondria produce up to 95 per cent of the eukaryotic cell's energy. The coding genes of the mitochondrial DNA may therefore evolve under selection owing to metabolic requirements. The killer whale, Orcinus orca, is polymorphic, has a global distribution and occupies a range of ecological niches....... It is therefore a suitable organism for testing this hypothesis. We compared a global dataset of the complete mitochondrial genomes of 139 individuals for amino acid changes that were associated with radical physico-chemical property changes and were influenced by positive selection. Two such selected non...

  6. Novel Antimicrobial Peptides That Inhibit Gram Positive Bacterial Exotoxin Synthesis

    Science.gov (United States)

    Merriman, Joseph A.; Nemeth, Kimberly A.; Schlievert, Patrick M.

    2014-01-01

    Gram-positive bacteria, such as Staphylococcus aureus, cause serious human illnesses through combinations of surface virulence factors and secretion of exotoxins. Our prior studies using the protein synthesis inhibitor clindamycin and signal transduction inhibitors glycerol monolaurate and α-globin and β-globin chains of hemoglobin indicate that their abilities to inhibit exotoxin production by S. aureus are separable from abilities to inhibit growth of the organism. Additionally, our previous studies suggest that inhibition of exotoxin production, in absence of ability to kill S. aureus and normal flora lactobacilli, will prevent colonization by pathogenic S. aureus, while not interfering with lactobacilli colonization. These disparate activities may be important in development of novel anti-infective agents that do not alter normal flora. We initiated studies to explore the exotoxin-synthesis-inhibition activity of hemoglobin peptides further to develop potential agents to prevent S. aureus infections. We tested synthesized α-globin chain peptides, synthetic variants of α-globin chain peptides, and two human defensins for ability to inhibit exotoxin production without significantly inhibiting S. aureus growth. All of these peptides were weakly or not inhibitory to bacterial growth. However, the peptides were inhibitory to exotoxin production with increasing activity dependent on increasing numbers of positively-charged amino acids. Additionally, the peptides could be immobilized on agarose beads or have amino acid sequences scrambled and still retain exotoxin-synthesis-inhibition. The peptides are not toxic to human vaginal epithelial cells and do not inhibit growth of normal flora L. crispatus. These peptides may interfere with plasma membrane signal transduction in S. aureus due to their positive charges. PMID:24748386

  7. Distractor Inhibition: Principles of Operation during Selective Attention

    Science.gov (United States)

    Wyatt, Natalie; Machado, Liana

    2013-01-01

    Research suggests that although target amplification acts as the main determinant of the efficacy of selective attention, distractor inhibition contributes under some circumstances. Here we aimed to gain insight into the operating principles that regulate the use of distractor inhibition during selective attention. The results suggest that, in…

  8. Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition

    Science.gov (United States)

    Limongelli, Vittorio; Bonomi, Massimiliano; Marinelli, Luciana; Gervasio, Francesco Luigi; Cavalli, Andrea; Novellino, Ettore; Parrinello, Michele

    2010-01-01

    The widely used nonsteroidal anti-inflammatory drugs block the cyclooxygenase enzymes (COXs) and are clinically used for the treatment of inflammation, pain, and cancers. A selective inhibition of the different isoforms, particularly COX-2, is desirable, and consequently a deeper understanding of the molecular basis of selective inhibition is of great demand. Using an advanced computational technique we have simulated the full dissociation process of a highly potent and selective inhibitor, SC-558, in both COX-1 and COX-2. We have found a previously unreported alternative binding mode in COX-2 explaining the time-dependent inhibition exhibited by this class of inhibitors and consequently their long residence time inside this isoform. Our metadynamics-based approach allows us to illuminate the highly dynamical character of the ligand/protein recognition process, thus explaining a wealth of experimental data and paving the way to an innovative strategy for designing new COX inhibitors with tuned selectivity. PMID:20215464

  9. Physicochemical evolution and positive selection of the ...

    Indian Academy of Sciences (India)

    2010-04-08

    Apr 8, 2010 ... It is not clear whether matK evolves under Darwinian selection. In this study, the gymnosperm Taxaceae, Cephalotaxaceae and Pinaceae were used to illustrate the physicochemical evolution, molecular adaptation and evolutionary dynamics of gene divergence in matKs. matK sequences were amplified ...

  10. The Neural Basis of Cognitive Control: Response Selection and Inhibition

    Science.gov (United States)

    Goghari, Vina M.; MacDonald, Angus W., III

    2009-01-01

    The functional neuroanatomy of tasks that recruit different forms of response selection and inhibition has to our knowledge, never been directly addressed in a single fMRI study using similar stimulus-response paradigms where differences between scanning time and sequence, stimuli, and experimenter instructions were minimized. Twelve right-handed…

  11. Inhibition spectrum studies of microthecin and other anhydrofructose derivatives using selected strains of Gram-positive and –negative bacteria, yeast and moulds, and investigation of the cytotoxicity of microthecin to malignant blood cell lines

    DEFF Research Database (Denmark)

    Fiskesund, R.; Thomas, L.V.; Schobert, M.

    2009-01-01

    Aims: To prepare 1,5-anhydro-d-fructose (AF) derivatives, test their microbial inhibition spectrum, and to further examine the most effective AF derivative against Pseudomonas aeruginosa and malignant blood cell lines. Methods and Results: Microthecin and nine other AF derivatives were synthesized...... both GP and GN bacteria, including Ps. aeruginosa. Further tests with three malignant blood cell lines (Mutu, Ramos, Raji) and one normal cell line indicated that microthecin was a cell toxin, with a cell mortality >85% at 50 ppm. The other nine AF derivatives demonstrated low or no antimicrobial...... activity. Conclusions: Microthecin was active 100–2000 ppm against GP and GN bacteria including Ps. aeruginosa, but was inactive against yeasts and moulds. Microthecin was also a cytotoxin to some mammalian cell lines. Significance and Impact of the Study: Microthecin might have potential for development...

  12. Selective inhibition of monoamine oxidase A by purpurin, an anthraquinone.

    Science.gov (United States)

    Lee, Hyun Woo; Ryu, Hyung Won; Kang, Myung-Gyun; Park, Daeui; Oh, Sei-Ryang; Kim, Hoon

    2017-03-01

    Monoamine oxidase (MAO) catalyzes the oxidation of monoamines that act as neurotransmitters. During a target-based screening of natural products using two isoforms of recombinant human MAO-A and MAO-B, purpurin (an anthraquinone derivative) was found to potently and selectively inhibit MAO-A, with an IC 50 value of 2.50μM, and not to inhibit MAO-B. Alizarin (also an anthraquinone) inhibited MAO-A less potently with an IC 50 value of 30.1μM. Furthermore, purpurin was a reversible and competitive inhibitor of MAO-A with a K i value of 0.422μM. A comparison of their chemical structures suggested the 4-hydroxy group of purpurin might play an important role in its inhibition of MAO-A. Molecular docking simulation showed that the binding affinity of purpurin for MAO-A (-40.0kcal/mol) was higher than its affinity for MAO-B (-33.9kcal/mol), and that Ile 207 and Gly 443 of MAO-A were key residues for hydrogen bonding with purpurin. The findings of this study suggest purpurin is a potent, selective, reversible inhibitor of MAO-A, and that it be considered a new potential lead compound for development of novel reversible inhibitors of MAO-A (RIMAs). Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Directional Positive Selection on an Allele of Arbitrary Dominance

    OpenAIRE

    Teshima, Kosuke M.; Przeworski, Molly

    2006-01-01

    Most models of positive directional selection assume codominance of the beneficial allele. We examine the importance of this assumption by implementing a coalescent model of positive directional selection with arbitrary dominance. We find that, for a given mean fixation time, a beneficial allele has a much weaker effect on diversity at linked neutral sites when the allele is recessive.

  14. Scalable gastroscopic video summarization via similar-inhibition dictionary selection.

    Science.gov (United States)

    Wang, Shuai; Cong, Yang; Cao, Jun; Yang, Yunsheng; Tang, Yandong; Zhao, Huaici; Yu, Haibin

    2016-01-01

    This paper aims at developing an automated gastroscopic video summarization algorithm to assist clinicians to more effectively go through the abnormal contents of the video. To select the most representative frames from the original video sequence, we formulate the problem of gastroscopic video summarization as a dictionary selection issue. Different from the traditional dictionary selection methods, which take into account only the number and reconstruction ability of selected key frames, our model introduces the similar-inhibition constraint to reinforce the diversity of selected key frames. We calculate the attention cost by merging both gaze and content change into a prior cue to help select the frames with more high-level semantic information. Moreover, we adopt an image quality evaluation process to eliminate the interference of the poor quality images and a segmentation process to reduce the computational complexity. For experiments, we build a new gastroscopic video dataset captured from 30 volunteers with more than 400k images and compare our method with the state-of-the-arts using the content consistency, index consistency and content-index consistency with the ground truth. Compared with all competitors, our method obtains the best results in 23 of 30 videos evaluated based on content consistency, 24 of 30 videos evaluated based on index consistency and all videos evaluated based on content-index consistency. For gastroscopic video summarization, we propose an automated annotation method via similar-inhibition dictionary selection. Our model can achieve better performance compared with other state-of-the-art models and supplies more suitable key frames for diagnosis. The developed algorithm can be automatically adapted to various real applications, such as the training of young clinicians, computer-aided diagnosis or medical report generation. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Selective inhibition of Biotin Protein Ligase from Staphylococcus aureus*

    Science.gov (United States)

    Soares da Costa, Tatiana P.; Tieu, William; Yap, Min Y.; Pendini, Nicole R.; Polyak, Steven W.; Sejer Pedersen, Daniel; Morona, Renato; Turnidge, John D.; Wallace, John C.; Wilce, Matthew C. J.; Booker, Grant W.; Abell, Andrew D.

    2012-01-01

    There is a well documented need to replenish the antibiotic pipeline with new agents to combat the rise of drug resistant bacteria. One strategy to combat resistance is to discover new chemical classes immune to current resistance mechanisms that inhibit essential metabolic enzymes. Many of the obvious drug targets that have no homologous isozyme in the human host have now been investigated. Bacterial drug targets that have a closely related human homologue represent a new frontier in antibiotic discovery. However, to avoid potential toxicity to the host, these inhibitors must have very high selectivity for the bacterial enzyme over the human homolog. We have demonstrated that the essential enzyme biotin protein ligase (BPL) from the clinically important pathogen Staphylococcus aureus could be selectively inhibited. Linking biotin to adenosine via a 1,2,3 triazole yielded the first BPL inhibitor selective for S. aureus BPL over the human equivalent. The synthesis of new biotin 1,2,3-triazole analogues using click chemistry yielded our most potent structure (Ki 90 nm) with a >1100-fold selectivity for the S. aureus BPL over the human homologue. X-ray crystallography confirmed the mechanism of inhibitor binding. Importantly, the inhibitor showed cytotoxicity against S. aureus but not cultured mammalian cells. The biotin 1,2,3-triazole provides a novel pharmacophore for future medicinal chemistry programs to develop this new antibiotic class. PMID:22437830

  16. Selective inhibition of biotin protein ligase from Staphylococcus aureus.

    Science.gov (United States)

    Soares da Costa, Tatiana P; Tieu, William; Yap, Min Y; Pendini, Nicole R; Polyak, Steven W; Sejer Pedersen, Daniel; Morona, Renato; Turnidge, John D; Wallace, John C; Wilce, Matthew C J; Booker, Grant W; Abell, Andrew D

    2012-05-18

    There is a well documented need to replenish the antibiotic pipeline with new agents to combat the rise of drug resistant bacteria. One strategy to combat resistance is to discover new chemical classes immune to current resistance mechanisms that inhibit essential metabolic enzymes. Many of the obvious drug targets that have no homologous isozyme in the human host have now been investigated. Bacterial drug targets that have a closely related human homologue represent a new frontier in antibiotic discovery. However, to avoid potential toxicity to the host, these inhibitors must have very high selectivity for the bacterial enzyme over the human homolog. We have demonstrated that the essential enzyme biotin protein ligase (BPL) from the clinically important pathogen Staphylococcus aureus could be selectively inhibited. Linking biotin to adenosine via a 1,2,3 triazole yielded the first BPL inhibitor selective for S. aureus BPL over the human equivalent. The synthesis of new biotin 1,2,3-triazole analogues using click chemistry yielded our most potent structure (K(i) 90 nM) with a >1100-fold selectivity for the S. aureus BPL over the human homologue. X-ray crystallography confirmed the mechanism of inhibitor binding. Importantly, the inhibitor showed cytotoxicity against S. aureus but not cultured mammalian cells. The biotin 1,2,3-triazole provides a novel pharmacophore for future medicinal chemistry programs to develop this new antibiotic class.

  17. Innovative Strategies for Selective Inhibition of Histone Deacetylases

    DEFF Research Database (Denmark)

    Maolanon, Alex Ramalak; Madsen, Andreas Stahl; Olsen, Christian Adam

    2016-01-01

    Histone deacetylases (HDAC) are a family of closely related enzymes involved in epigenetic and posttranscriptional regulation of numerous genes and proteins. Their deregulation is associated with a number of diseases, and a handful of HDAC inhibitors have been approved for cancer treatment. None......, functionally important, features. Based on this analysis, we suggest alternative strategies to achieve selective HDAC inhibition that does not rely on chelation of the zinc ion in the active site but rather on disruption of protein-protein interactions important for HDAC activity. We believe that, although...

  18. Selective small-molecule inhibition of an RNA structural element

    Energy Technology Data Exchange (ETDEWEB)

    Howe, John A.; Wang, Hao; Fischmann, Thierry O.; Balibar, Carl J.; Xiao, Li; Galgoci, Andrew M.; Malinverni, Juliana C.; Mayhood, Todd; Villafania, Artjohn; Nahvi, Ali; Murgolo, Nicholas; Barbieri, Christopher M.; Mann, Paul A.; Carr, Donna; Xia, Ellen; Zuck, Paul; Riley, Dan; Painter, Ronald E.; Walker, Scott S.; Sherborne, Brad; de Jesus, Reynalda; Pan, Weidong; Plotkin, Michael A.; Wu, Jin; Rindgen, Diane; Cummings, John; Garlisi, Charles G.; Zhang, Rumin; Sheth, Payal R.; Gill, Charles J.; Tang, Haifeng; Roemer , Terry (Merck)

    2015-09-30

    Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.

  19. Position paper - peer review and design verification of selected activities

    International Nuclear Information System (INIS)

    Stine, M.D.

    1994-09-01

    Position Paper to develop and document a position on the performance of independent peer reviews on selected design and analysis components of the Title I (preliminary) and Title II (detailed) design phases of the Multi-Function Waste Tank Facility project

  20. Selective control of attention supports the positivity effect in aging.

    Directory of Open Access Journals (Sweden)

    Laura K Sasse

    Full Text Available There is emerging evidence for a positivity effect in healthy aging, which describes an age-specific increased focus on positive compared to negative information. Life-span researchers have attributed this effect to the selective allocation of cognitive resources in the service of prioritized emotional goals. We explored the basic principles of this assumption by assessing selective attention and memory for visual stimuli, differing in emotional content and self-relevance, in young and old participants. To specifically address the impact of cognitive control, voluntary attentional selection during the presentation of multiple-item displays was analyzed and linked to participants' general ability of cognitive control. Results revealed a positivity effect in older adults' selective attention and memory, which was particularly pronounced for self-relevant stimuli. Focusing on positive and ignoring negative information was most evident in older participants with a generally higher ability to exert top-down control during visual search. Our findings highlight the role of controlled selectivity in the occurrence of a positivity effect in aging. Since the effect has been related to well-being in later life, we suggest that the ability to selectively allocate top-down control might represent a resilience factor for emotional health in aging.

  1. Selective control of attention supports the positivity effect in aging.

    Science.gov (United States)

    Sasse, Laura K; Gamer, Matthias; Büchel, Christian; Brassen, Stefanie

    2014-01-01

    There is emerging evidence for a positivity effect in healthy aging, which describes an age-specific increased focus on positive compared to negative information. Life-span researchers have attributed this effect to the selective allocation of cognitive resources in the service of prioritized emotional goals. We explored the basic principles of this assumption by assessing selective attention and memory for visual stimuli, differing in emotional content and self-relevance, in young and old participants. To specifically address the impact of cognitive control, voluntary attentional selection during the presentation of multiple-item displays was analyzed and linked to participants' general ability of cognitive control. Results revealed a positivity effect in older adults' selective attention and memory, which was particularly pronounced for self-relevant stimuli. Focusing on positive and ignoring negative information was most evident in older participants with a generally higher ability to exert top-down control during visual search. Our findings highlight the role of controlled selectivity in the occurrence of a positivity effect in aging. Since the effect has been related to well-being in later life, we suggest that the ability to selectively allocate top-down control might represent a resilience factor for emotional health in aging.

  2. A map of recent positive selection in the human genome.

    Directory of Open Access Journals (Sweden)

    Benjamin F Voight

    2006-03-01

    Full Text Available The identification of signals of very recent positive selection provides information about the adaptation of modern humans to local conditions. We report here on a genome-wide scan for signals of very recent positive selection in favor of variants that have not yet reached fixation. We describe a new analytical method for scanning single nucleotide polymorphism (SNP data for signals of recent selection, and apply this to data from the International HapMap Project. In all three continental groups we find widespread signals of recent positive selection. Most signals are region-specific, though a significant excess are shared across groups. Contrary to some earlier low resolution studies that suggested a paucity of recent selection in sub-Saharan Africans, we find that by some measures our strongest signals of selection are from the Yoruba population. Finally, since these signals indicate the existence of genetic variants that have substantially different fitnesses, they must indicate loci that are the source of significant phenotypic variation. Though the relevant phenotypes are generally not known, such loci should be of particular interest in mapping studies of complex traits. For this purpose we have developed a set of SNPs that can be used to tag the strongest approximately 250 signals of recent selection in each population.

  3. Tiamulin selectively inhibits oxidative hepatic steroid and drug metabolism in vitro in the pig.

    Science.gov (United States)

    Witkamp, R F; Nijmeijer, S M; Csikó, G; van Miert, A S

    1994-08-01

    The simultaneous use of the antibiotic tiamulin with certain ionophoric antibiotics (monensin, salinomycin) may give rise to a toxic interaction in pigs and poultry. In the present study, effects of tiamulin on hepatic cytochrome P450 activities in vitro were studied using pig liver microsomes. When tiamulin was added to the incubation medium the N-demethylation rate of ethylmorphine and the hydroxylation of testosterone at the 6 beta- and 11 alpha-positions was strongly inhibited. Tiamulin inhibited these activities more than SKF525A or cimetidine, but less than ketoconazole. The microsomal N-demethylation rate of erythromycin and the hydroxylation of testosterone at the 2 beta-position were inhibited to a lesser degree, whereas the ethoxyresorufin-O-deethylation, aniline hydroxylation and testosterone hydroxylations at the 15 alpha- and 15 beta-positions were not affected by tiamulin. No in vitro complexation by tiamulin of cytochrome P450 resulting in a loss of CO-binding capacity could be demonstrated. Results from the present study suggest a selective inhibition of cytochrome P450 enzymes in pigs, probably belonging to the P4503A subfamily. The mechanism of this interaction is still unclear. However, interactions between tiamulin and those veterinary drugs or endogenous compounds which undergo oxidative metabolism by P450 enzymes must be considered. More research is needed to reveal which of the P450 enzymes are affected by tiamulin in order to improve the understanding and probably the predictability of this interaction.

  4. Patterns of positive selection in six Mammalian genomes

    DEFF Research Database (Denmark)

    Kosiol, Carolin; Vinar, Tomás; da Fonseca, Rute R

    2008-01-01

    Genome-wide scans for positively selected genes (PSGs) in mammals have provided insight into the dynamics of genome evolution, the genetic basis of differences between species, and the functions of individual genes. However, previous scans have been limited in power and accuracy owing to small...... several new lineage- and clade-specific tests to be applied. Of approximately 16,500 human genes with high-confidence orthologs in at least two other species, 400 genes showed significant evidence of positive selection (FDR... showed evidence of positive selection on particular lineages or clades. As in previous studies, the identified PSGs were enriched for roles in defense/immunity, chemosensory perception, and reproduction, but enrichments were also evident for more specific functions, such as complement-mediated immunity...

  5. The signature of positive selection at randomly chosen loci.

    OpenAIRE

    Przeworski, Molly

    2002-01-01

    In Drosophila and humans, there are accumulating examples of loci with a significant excess of high-frequency-derived alleles or high levels of linkage disequilibrium, relative to a neutral model of a random-mating population of constant size. These are features expected after a recent selective sweep. Their prevalence suggests that positive directional selection may be widespread in both species. However, as I show here, these features do not persist long after the sweep ends: The high-frequ...

  6. Enzalutamide inhibits androgen receptor-positive bladder cancer cell growth.

    Science.gov (United States)

    Kawahara, Takashi; Ide, Hiroki; Kashiwagi, Eiji; El-Shishtawy, Kareem A; Li, Yi; Reis, Leonardo O; Zheng, Yichun; Miyamoto, Hiroshi

    2016-10-01

    Emerging preclinical evidence suggests that androgen-mediated androgen receptor (AR) signals promote bladder cancer progression. However, little is known about the efficacy of an AR signaling inhibitor, enzalutamide, in the growth of bladder cancer cells. In this study, we compared the effects of enzalutamide and 2 other classic antiandrogens, flutamide and bicalutamide, on androgen-induced bladder cancer cell proliferation, migration, and invasion as well as tumor growth in vivo. Thiazolyl blue cell viability assay, flow cytometry, scratch wound-healing assay, transwell invasion assay, real-time polymerase chain reaction, and reporter gene assay were performed in AR-positive (e.g., UMUC3, TCCSUP, and 647V-AR) and AR-negative (e.g., UMUC3-AR-short hairpin RNA [shRNA], TCCSUP-AR-shRNA, 647V) bladder cancer lines treated with dihydrotestosterone and each AR antagonist. We also used a mouse xenograft model for bladder cancer. Dihydrotestosterone increased bladder cancer cell proliferation, migration, and invasion indicating that endogenous or exogenous AR was functional. Enzalutamide, hydroxyflutamide, and bicalutamide showed similar inhibitory effects, without significant agonist activity, on androgen-mediated cell viability/apoptosis, cell migration, and cell invasion in AR-positive lines. No significant effects of dihydrotestosterone as well as AR antagonists on the growth of AR-negative cells were seen. Correspondingly, in UMUC3 cells, these AR antagonists down-regulated androgen-induced expression of AR, matrix metalloproteinase-2, and interleukin-6. Androgen-enhanced AR-mediated transcriptional activity was also blocked by each AR antagonist exhibiting insignificant agonist activity. In UMUC3 xenograft-bearing mice, oral gavage treatment with each antiandrogen retarded tumor growth, and only enzalutamide demonstrated a statistically significant suppression compared with mock treatment. Our current data support recent observations indicating the involvement of

  7. A Demonstration of Regression False Positive Selection in Data Mining

    Science.gov (United States)

    Pinder, Jonathan P.

    2014-01-01

    Business analytics courses, such as marketing research, data mining, forecasting, and advanced financial modeling, have substantial predictive modeling components. The predictive modeling in these courses requires students to estimate and test many linear regressions. As a result, false positive variable selection ("type I errors") is…

  8. Evidence for Very Recent Positive Selection in Mongolians.

    Science.gov (United States)

    Nakayama, Kazuhiro; Ohashi, Jun; Watanabe, Kazuhisa; Munkhtulga, Lkagvasuren; Iwamoto, Sadahiko

    2017-08-01

    Mongols, the founders of the largest continental empire in history, successfully adapted to the harsh environments of Inner Asia through nomadic pastoralism. Considerable interest exists in ascertaining whether genetic adaptation also contributed to the Mongols' success, and dissecting the genome diversity of present-day populations in Mongolia can help address this question. To this end, we determined the genotypes of nearly 2.4 million single nucleotide polymorphisms (SNPs) of 96 unrelated Mongolian individuals in Ulaanbaatar city, and performed genome-wide scans for population-specific positive selection. We discovered signatures of Mongolian-specific positive selection at the chromosomal region 3p12.1, in which hits in genome-wide association studies were reported for medical and biological traits related to energy metabolism and reproduction. The top SNP, rs117799927, showed a distinctive geographic distribution: the frequency of the derived allele, rs117799927 G, was extremely low among worldwide populations (0.005) but exceptionally high in Mongolians (0.247). Approximate Bayesian computation-based age estimation showed that the rs117799927 G allele emerged or positive selection began to operate 50 generations before the present, near the age of the climate anomaly named Late Antique Little Ice Age. Furthermore, rs117799927 showed significant associations with multiple adiposity-related traits in Mongolians and allelic difference in enhancer activity in cells of adipocyte lineage, suggesting that positive selection at 3p12.1 might be related to adaptation in the energy metabolism system. These findings provide novel evidence for a very recent positive-selection event in Homo sapiens and offer insights into the roles of genes in 3p12.1 in the adaptive evolution of our species. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Positive selection for unpreferred codon usage in eukaryotic genomes

    Directory of Open Access Journals (Sweden)

    Galagan James E

    2007-07-01

    Full Text Available Abstract Background Natural selection has traditionally been understood as a force responsible for pushing genes to states of higher translational efficiency, whereas lower translational efficiency has been explained by neutral mutation and genetic drift. We looked for evidence of directional selection resulting in increased unpreferred codon usage (and presumably reduced translational efficiency in three divergent clusters of eukaryotic genomes using a simple optimal-codon-based metric (Kp/Ku. Results Here we show that for some genes natural selection is indeed responsible for causing accelerated unpreferred codon substitution, and document the scope of this selection. In Cryptococcus and to a lesser extent Drosophila, we find many genes showing a statistically significant signal of selection for unpreferred codon usage in one or more lineages. We did not find evidence for this type of selection in Saccharomyces. The signal of positive selection observed from unpreferred synonymous codon substitutions is coincident in Cryptococcus and Drosophila with the distribution of upstream open reading frames (uORFs, another genic feature known to reduce translational efficiency. Functional enrichment analysis of genes exhibiting low Kp/Ku ratios reveals that genes in regulatory roles are particularly subject to this type of selection. Conclusion Through genome-wide scans, we find recent selection for unpreferred codon usage at approximately 1% of genetic loci in a Cryptococcus and several genes in Drosophila. Unpreferred codons can impede translation efficiency, and we find that genes with translation-impeding uORFs are enriched for this selection signal. We find that regulatory genes are particularly likely to be subject to selection for unpreferred codon usage. Given that expression noise can propagate through regulatory cascades, and that low translational efficiency can reduce expression noise, this finding supports the hypothesis that translational

  10. Positive Selection Linked with Generation of Novel Mammalian Dentition Patterns.

    Science.gov (United States)

    Machado, João Paulo; Philip, Siby; Maldonado, Emanuel; O'Brien, Stephen J; Johnson, Warren E; Antunes, Agostinho

    2016-09-11

    A diverse group of genes are involved in the tooth development of mammals. Several studies, focused mainly on mice and rats, have provided a detailed depiction of the processes coordinating tooth formation and shape. Here we surveyed 236 tooth-associated genes in 39 mammalian genomes and tested for signatures of selection to assess patterns of molecular adaptation in genes regulating mammalian dentition. Of the 236 genes, 31 (∼13.1%) showed strong signatures of positive selection that may be responsible for the phenotypic diversity observed in mammalian dentition. Mammalian-specific tooth-associated genes had accelerated mutation rates compared with older genes found across all vertebrates. More recently evolved genes had fewer interactions (either genetic or physical), were associated with fewer Gene Ontology terms and had faster evolutionary rates compared with older genes. The introns of these positively selected genes also exhibited accelerated evolutionary rates, which may reflect additional adaptive pressure in the intronic regions that are associated with regulatory processes that influence tooth-gene networks. The positively selected genes were mainly involved in processes like mineralization and structural organization of tooth specific tissues such as enamel and dentin. Of the 236 analyzed genes, 12 mammalian-specific genes (younger genes) provided insights on diversification of mammalian teeth as they have higher evolutionary rates and exhibit different expression profiles compared with older genes. Our results suggest that the evolution and development of mammalian dentition occurred in part through positive selection acting on genes that previously had other functions. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  11. Positively selected sites in cetacean myoglobins contribute to protein stability

    DEFF Research Database (Denmark)

    Dasmeh, Pouria; Serohijos, Adrian W R; Kepp, Kasper P

    2013-01-01

    Since divergence ∼50 Ma ago from their terrestrial ancestors, cetaceans underwent a series of adaptations such as a ∼10-20 fold increase in myoglobin (Mb) concentration in skeletal muscle, critical for increasing oxygen storage capacity and prolonging dive time. Whereas the O2-binding affinity...... between Mb folding stability and protein abundance, suggesting that a selection pressure for stability acts proportionally to higher expression. We also identify a major divergence event leading to the common ancestor of whales, during which major stabilization occurred. Most of the positively selected...

  12. Positive selection on gene expression in the human brain

    DEFF Research Database (Denmark)

    Khaitovich, Philipp; Tang, Kun; Franz, Henriette

    2006-01-01

    Recent work has shown that the expression levels of genes transcribed in the brains of humans and chimpanzees have changed less than those of genes transcribed in other tissues [1] . However, when gene expression changes are mapped onto the evolutionary lineage in which they occurred, the brain...... shows more changes than other tissues in the human lineage compared to the chimpanzee lineage [1] , [2] and [3] . There are two possible explanations for this: either positive selection drove more gene expression changes to fixation in the human brain than in the chimpanzee brain, or genes expressed...... in the brain experienced less purifying selection in humans than in chimpanzees, i.e. gene expression in the human brain is functionally less constrained. The first scenario would be supported if genes that changed their expression in the brain in the human lineage showed more selective sweeps than other genes...

  13. Inhibition of Action, Thought, and Emotion: A Selective Neurobiological Review

    OpenAIRE

    Dillon, Daniel; Pizzagalli, Diego

    2007-01-01

    The neural bases of inhibitory function are reviewed, covering data from paradigms assessing inhibition of motor responses (antisaccade, go/nogo, stop-signal), cognitive sets (e.g., Wisconsin Card Sort Test), and emotion (fear extinction). The frontal cortex supports performance on these paradigms, but the specific neural circuitry varies: response inhibition depends upon fronto-basal ganglia networks, inhibition of cognitive sets is supported by orbitofrontal cortex, and retention of fear ex...

  14. The signature of positive selection at randomly chosen loci.

    Science.gov (United States)

    Przeworski, Molly

    2002-03-01

    In Drosophila and humans, there are accumulating examples of loci with a significant excess of high-frequency-derived alleles or high levels of linkage disequilibrium, relative to a neutral model of a random-mating population of constant size. These are features expected after a recent selective sweep. Their prevalence suggests that positive directional selection may be widespread in both species. However, as I show here, these features do not persist long after the sweep ends: The high-frequency alleles drift to fixation and no longer contribute to polymorphism, while linkage disequilibrium is broken down by recombination. As a result, loci chosen without independent evidence of recent selection are not expected to exhibit either of these features, even if they have been affected by numerous sweeps in their genealogical history. How then can we explain the patterns in the data? One possibility is population structure, with unequal sampling from different subpopulations. Alternatively, positive selection may not operate as is commonly modeled. In particular, the rate of fixation of advantageous mutations may have increased in the recent past.

  15. Positive selection within the Schizophrenia-associated GABA(A receptor beta(2 gene.

    Directory of Open Access Journals (Sweden)

    Wing-Sze Lo

    Full Text Available The gamma-aminobutyric acid type-A (GABA(A receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABA(A receptor beta(2 subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced beta(2 isoforms. In the present study, using chimpanzee as an ancestral reference, high frequencies were observed for the derived (D alleles of the four SNPs rs6556547, rs187269, rs1816071 and rs1816072 in GABRB2, suggesting the occurrence of positive selection for these derived alleles. Coalescence-based simulation showed that the population frequency spectra and the frequencies of H56, the haplotype having all four D alleles, significantly deviated from neutral-evolution expectation in various demographic models. Haplotypes containing the derived allele of rs1816072 displayed significantly less diversity compared to haplotypes containing its ancestral allele, further supporting positive selection. The variations in DD-genotype frequencies in five human populations provided a snapshot of the evolutionary history, which suggested that the positive selections of the D alleles are recent and likely ongoing. The divergence between the DD-genotype profiles of schizophrenic and control samples pointed to the schizophrenia-relevance of positive selections, with the schizophrenic samples showing weakened selections compared to the controls. These DD-genotypes were previously found to increase the expression of beta(2, especially its long isoform. Electrophysiological analysis showed that this long beta(2 isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABA(A receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene.

  16. Antibacterial properties of biosurfactants against selected Gram-positive and -negative bacteria.

    Science.gov (United States)

    Díaz De Rienzo, Mayri A; Stevenson, Paul; Marchant, Roger; Banat, Ibrahim M

    2016-01-01

    The antibacterial properties and ability to disrupt biofilms of biosurfactants (rhamnolipids, sophorolipids) and sodium dodecyl sulphate (SDS) in the presence and absence of selected organic acids were investigated. Pseudomonas aeruginosa PAO1 was inhibited by sophorolipids and SDS at concentrations >5% v/v, and the growth of Escherichia coli NCTC 10418 was also inhibited by sophorolipids and SDS at concentrations >5% and 0.1% v/v, respectively. Bacillus subtilis NCTC 10400 was inhibited by rhamnolipids, sophorolipids and SDS at concentrations >0.5% v/v of all three; the same effect was observed with Staphylococcus aureus ATCC 9144. The ability to attach to surfaces and biofilm formation of P. aeruginosa PAO1, E. coli NCTC 10418 and B. subtilis NCTC 10400 was inhibited by sophorolipids (1% v/v) in the presence of caprylic acid (0.8% v/v). In the case of S. aureus ATCC 9144, the best results were obtained using caprylic acid on its own. It was concluded that sophorolipids are promising compounds for the inhibition/disruption of biofilms formed by Gram-positive and Gram-negative microorganisms and this activity can be enhanced by the presence of booster compounds such as caprylic acid. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  17. A genome scan for positive selection in thoroughbred horses.

    Science.gov (United States)

    Gu, Jingjing; Orr, Nick; Park, Stephen D; Katz, Lisa M; Sulimova, Galina; MacHugh, David E; Hill, Emmeline W

    2009-06-02

    Thoroughbred horses have been selected for exceptional racing performance resulting in system-wide structural and functional adaptations contributing to elite athletic phenotypes. Because selection has been recent and intense in a closed population that stems from a small number of founder animals Thoroughbreds represent a unique population within which to identify genomic contributions to exercise-related traits. Employing a population genetics-based hitchhiking mapping approach we performed a genome scan using 394 autosomal and X chromosome microsatellite loci and identified positively selected loci in the extreme tail-ends of the empirical distributions for (1) deviations from expected heterozygosity (Ewens-Watterson test) in Thoroughbred (n = 112) and (2) global differentiation among four geographically diverse horse populations (F(ST)). We found positively selected genomic regions in Thoroughbred enriched for phosphoinositide-mediated signalling (3.2-fold enrichment; PThoroughbred athletic phenotype. We report for the first time candidate athletic-performance genes within regions targeted by selection in Thoroughbred horses that are principally responsible for fatty acid oxidation, increased insulin sensitivity and muscle strength: ACSS1 (acyl-CoA synthetase short-chain family member 1), ACTA1 (actin, alpha 1, skeletal muscle), ACTN2 (actinin, alpha 2), ADHFE1 (alcohol dehydrogenase, iron containing, 1), MTFR1 (mitochondrial fission regulator 1), PDK4 (pyruvate dehydrogenase kinase, isozyme 4) and TNC (tenascin C). Understanding the genetic basis for exercise adaptation will be crucial for the identification of genes within the complex molecular networks underlying obesity and its consequential pathologies, such as type 2 diabetes. Therefore, we propose Thoroughbred as a novel in vivo large animal model for understanding molecular protection against metabolic disease.

  18. Metformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma

    International Nuclear Information System (INIS)

    Ma, Ji; Zhang, Jian; Liu, Wenchao; Guo, Yan; Chen, Suning; Zhong, Cuiping; Xue, Yan; Zhang, Yuan; Lai, Xiaofeng; Wei, Yifang; Yu, Shentong

    2014-01-01

    Tamoxifen, an endocrine therapy drug used to treat breast cancer, is designed to interrupt estrogen signaling by blocking the estrogen receptor (ER). However, many ER-positive patients are low reactive or resistant to tamoxifen. Metformin is a widely used anti-diabetic drug with noteworthy anti-cancer effects. We investigated whether metformin has the additive effects with tamoxifen in ER-positive breast cancer therapy. The efficacy of metformin alone and in combination with tamoxifen against ER-positive breast cancer was analyzed by cell survival, DNA replication activity, plate colony formation, soft-agar, flow cytometry, immunohistochemistry, and nude mice model assays. The involved signaling pathways were detected by western blot assay. When metformin was combined with tamoxifen, the concentration of tamoxifen required for growth inhibition was substantially reduced. Moreover, metformin enhanced tamoxifen-mediated inhibition of proliferation, DNA replication activity, colony formation, soft-agar colony formation, and induction of apoptosis in ER-positive breast cancer cells. In addition, these tamoxifen-induced effects that were enhanced by metformin may be involved in the bax/bcl-2 apoptotic pathway and the AMPK/mTOR/p70S6 growth pathway. Finally, two-drug combination therapy significantly inhibited tumor growth in vivo. The present work shows that metformin and tamoxifen additively inhibited the growth and augmented the apoptosis of ER-positive breast cancer cells. It provides leads for future research on this drug combination for the treatment of ER-positive breast cancer

  19. Positive selection on a bacterial oncoprotein associated with gastric cancer

    Directory of Open Access Journals (Sweden)

    Delgado-Rosado Gisela

    2011-11-01

    Full Text Available Background Helicobacter pylori is a vertically inherited gut commensal that is carcinogenic if it possesses the cag pathogenicity island (cag PaI; infection with H.pylori is the major risk factor for gastric cancer, the second leading cause of death from cancer worldwide (WHO. The cag PaI locus encodes the cagA gene, whose protein product is injected into stomach epithelial cells via a Type IV secretion system, also encoded by the cag PaI. Once there, the cagA protein binds to various cellular proteins, resulting in dysregulation of cell division and carcinogenesis. For this reason, cagA may be described as an oncoprotein. A clear understanding of the mechanism of action of cagA and its benefit to the bacteria is lacking. Results Here, we reveal that the cagA gene displays strong signatures of positive selection in bacteria isolated from amerindian populations, using the Ka/Ks ratio. Weaker signatures are also detected in the gene from bacteria isolated from asian populations, using the Ka/Ks ratio and the more sensitive branches-sites model of the PAML package. When the cagA gene isolated from amerindian populations was examined in more detail it was found that the region under positive selection contains the EPIYA domains, which are known to modulate the carcinogenicity of the gene. This means that the carcinogenicity modulating region of the gene is undergoing adaptation. The results are discussed in relation to the high incidences of stomach cancer in some latin american and asian populations. Conclusion Positive selection on cagA indicates antagonistic coevolution between host and bacteria, which appears paradoxical given that cagA is detrimental to the human host upon which the bacteria depends. This suggests several non-exclusive possibilities; that gastric cancer has not been a major selective pressure on human populations, that cagA has an undetermined benefit to the human host, or that horizontal transmission of H.pylori between hosts

  20. Selection of proteolytic bacteria with ability to inhibit Vibrio harveyi during white shrimp (Litopenaeus vannamei cultivation

    Directory of Open Access Journals (Sweden)

    Suntinanalert, P.

    2007-03-01

    Full Text Available Five isolates of bacteria with high proteolytic activity, isolated from water samples of intensive shrimp ponds in southern Thailand, were selected to test for the ability to control the shrimp pathogen Vibrioharveyi. 70 μl of each culture broth were investigated for their ability to inhibit V. harveyi using an agar well diffusion test but only one isolate W3 gave a reasonable sized inhibition zone of 21.62 mm. This zone wassimilar to that of oxolinic acid (2 μg and sulfamethoxazole (25 μg. The W3 isolate was identified as Pseudomonas sp. Shrimp cultivation in aquaria was conducted to investigate the inhibition of V. harveyi bythe isolate W3. The experiment consisted of a treatment of the shrimp culture with an inoculum of the isolate W3 and V. harveyi (biocontrol set, a positive control set (only inoculation of V. harveyi and a negativecontrol set as without inoculation. No mortality was found in the negative control. Shrimp mortality in the biocontrol set (33% was lower than that in the positive control set (40%; however, it showed no significantdifference (p>0.05. The average numbers of V. harveyi over 12 days of the biocontrol set were lower than those in the positive control set by about 1 log cycle although the numbers were not significantly different(p>0.05. The shrimp growth rate at day 32 of cultivation was in order of the biocontrol treatment (10.17% > the negative control treatment (9.44% > the positive control set (9.28%, but no significant difference (p>0.05 was observed among treatments.

  1. How Do Parameters of Motor Response Influence Selective Inhibition? Evidence from the Stop-Signal Paradigm

    Directory of Open Access Journals (Sweden)

    Chien Hui Tang

    2011-05-01

    Full Text Available The ability to selectively inhibit the execution of an action while performing other ones is crucial in humans' multitasking daily life. The current study aims to compare selective inhibition for choice reaction involving two effectors or response directions. We adopted a variation of the stop-signal paradigm to examine how selective inhibition is modulated by the way potential motor responses are combined and inhibited. Experiment 1 investigated selective inhibition under different combinations of effectors, namely “index and middle fingers” versus “hand and foot”. The results showed SSRT of the index finger was longer when the other response option was the foot than the middle finger. Experiment 2 examined how selective inhibition differs between selective stopping of effectors and movement directions, and that for most of the situations SSRT is longer for stopping a response based on its direction than effector. After equating complexity of response mapping between direction and effector conditions in Experiment 2, Experiment 3 still showed that SSRT differs between selecting direction or effectors. To summarize, SSRT varies depending on the way response effectors are paired and selectively stopped. Selective inhibition is thus likely not amodal and may involve different inhibitory mechanisms depending on parameters specifying the motor response.

  2. A genome scan for positive selection in thoroughbred horses.

    Directory of Open Access Journals (Sweden)

    Jingjing Gu

    2009-06-01

    Full Text Available Thoroughbred horses have been selected for exceptional racing performance resulting in system-wide structural and functional adaptations contributing to elite athletic phenotypes. Because selection has been recent and intense in a closed population that stems from a small number of founder animals Thoroughbreds represent a unique population within which to identify genomic contributions to exercise-related traits. Employing a population genetics-based hitchhiking mapping approach we performed a genome scan using 394 autosomal and X chromosome microsatellite loci and identified positively selected loci in the extreme tail-ends of the empirical distributions for (1 deviations from expected heterozygosity (Ewens-Watterson test in Thoroughbred (n = 112 and (2 global differentiation among four geographically diverse horse populations (F(ST. We found positively selected genomic regions in Thoroughbred enriched for phosphoinositide-mediated signalling (3.2-fold enrichment; P<0.01, insulin receptor signalling (5.0-fold enrichment; P<0.01 and lipid transport (2.2-fold enrichment; P<0.05 genes. We found a significant overrepresentation of sarcoglycan complex (11.1-fold enrichment; P<0.05 and focal adhesion pathway (1.9-fold enrichment; P<0.01 genes highlighting the role for muscle strength and integrity in the Thoroughbred athletic phenotype. We report for the first time candidate athletic-performance genes within regions targeted by selection in Thoroughbred horses that are principally responsible for fatty acid oxidation, increased insulin sensitivity and muscle strength: ACSS1 (acyl-CoA synthetase short-chain family member 1, ACTA1 (actin, alpha 1, skeletal muscle, ACTN2 (actinin, alpha 2, ADHFE1 (alcohol dehydrogenase, iron containing, 1, MTFR1 (mitochondrial fission regulator 1, PDK4 (pyruvate dehydrogenase kinase, isozyme 4 and TNC (tenascin C. Understanding the genetic basis for exercise adaptation will be crucial for the identification of genes

  3. Positive allometry and the prehistory of sexual selection.

    Science.gov (United States)

    Tomkins, Joseph L; LeBas, Natasha R; Witton, Mark P; Martill, David M; Humphries, Stuart

    2010-08-01

    The function of the exaggerated structures that adorn many fossil vertebrates remains largely unresolved. One recurrent hypothesis is that these elaborated traits had a role in thermoregulation. This orthodoxy persists despite the observation that traits exaggerated to the point of impracticality in extant organisms are almost invariably sexually selected. We use allometric scaling to investigate the role of sexual selection and thermoregulation in the evolution of exaggerated traits of the crested pterosaur Pteranodon longiceps and the sail-backed eupelycosaurs Dimetrodon and Edaphosaurus. The extraordinarily steep positive allometry of the head crest of Pteranodon rules out all of the current hypotheses for this trait's main function other than sexual signaling. We also find interspecific patterns of allometry and sexual dimorphism in the sails of Dimetrodon and patterns of elaboration in Edaphosaurus consistent with a sexually selected function. Furthermore, small ancestral, sail-backed pelycosaurs would have been too small to need adaptations to thermoregulation. Our results question the popular view that the elaborated structures of these fossil species evolved as thermoregulatory organs and provide evidence in support of the hypothesis that Pteranodon crests and eupelycosaur sails are among the earliest and most extreme examples of elaborate sexual signals in the evolution of terrestrial vertebrates.

  4. The role of positive selection in hepatitis C virus.

    Science.gov (United States)

    Cuevas, José M; Gonzalez, Michael; Torres-Puente, Manuela; Jiménez-Hernández, Nuria; Bracho, María A; García-Robles, Inmaculada; González-Candelas, Fernando; Moya, Andrés

    2009-09-01

    Hepatitis C virus (HCV) is a major health problem worldwide, infecting an estimated 170 million people. In this study, we have employed a large data set of sequences (14,654 sequences from between 25 and 100 clone sequences per analyzed region and per patient) from 67 patients infected with HCV genotype 1 (23 subtype 1a and 44 subtype 1b). For all patients, a sample prior to combined therapy with alpha interferon plus ribavirin was available, whereas for some patients additional samples after 6 or 12 months of treatment were also available. Twenty-seven patients responded to treatment (12 subtype 1a and 15 subtype 1b) and forty patients did not respond to treatment (11 subtype 1a vs. 29 subtype 1b). Two regions of the HCV genome were analyzed, one compressing the hypervariable regions (HVR1, HVR2 and HVR3) of the envelope 2 glycoprotein and another one including the interferon sensitive determining region (ISDR) and the V3 domain of the NS5A protein. Previously (Cuevas, J.M., Torres-Puente, M., Jiménez-Hernández, N., Bracho, M.A., García-Robles, I., Wrobel, B., Carnicer, F., del Olmo, J., Ortega, E., Moya, A., González-Candelas, F., 2008b. Genetic variability of hepatitis C virus before and after combined therapy of interferon plus ribavirin. Plos One 3 (8), e3058), several amino acid positions in both regions analyzed were detected to be under positive selection. Here, we have compared the amino acid composition of each positively selected position between responder and non-responder patients for both subtypes. If we exclude some non-conclusive cases, no clear differences were detected in any case. In conclusion, identifying specific positions as completely discriminatory of treatment response seems to be a difficult task. Our results, in concordance with previous studies, suggest that HCV evasion strategies are more likely based on a global increased variability, which would yield combinations of mutations with an increased resistance, than on the fixation of

  5. Evidence of recombination and positive selection in cetacean papillomaviruses

    International Nuclear Information System (INIS)

    Robles-Sikisaka, Refugio; Rivera, Rebecca; Nollens, Hendrik H.; St Leger, Judy; Durden, Wendy N.; Stolen, Megan; Burchell, Jennifer; Wellehan, James F.X.

    2012-01-01

    Papillomaviruses (PVs) are small DNA viruses that have been associated with increased epithelial proliferation. Over one hundred PV types have been identified in humans; however, only three have been identified in bottlenose dolphins (Tursiops truncatus) to date. Using rolling circle amplification and degenerate PCR, we identified four novel PV genomes of bottlenose dolphins. TtPV4, TtPV5 and TtPV6 were identified in genital lesions while TtPV7 was identified in normal genital mucosa. Bayesian analysis of the full-length L1 genes found that TtPV4 and TtPV7 group within the Upsilonpapillomavirus genus while TtPV5 and TtPV6 group with Omikronpapillomavirus. However, analysis of the E1 gene did not distinguish these genera, implying that these genes may not share a common history, consistent with recombination. Recombination analyses identified several probable events. Signals of positive selection were found mostly in the E1 and E2 genes. Recombination and diversifying selection pressures constitute important driving forces of cetacean PV evolution.

  6. Positive-negative-selection-mediated gene targeting in rice

    Directory of Open Access Journals (Sweden)

    Zenpei eShimatani

    2015-01-01

    Full Text Available Gene targeting (GT refers to the designed modification of genomic sequence(s through homologous recombination (HR. GT is a powerful tool both for the study of gene function and for molecular breeding. However, in transformation of higher plants, non-homologous end joining (NHEJ occurs overwhelmingly in somatic cells, masking HR-mediated GT. Positive-negative selection (PNS is an approach for finding HR-mediated GT events because it can eliminate NHEJ effectively by expression of a negative-selection marker gene. In rice—a major crop worldwide—reproducible PNS-mediated GT of endogenous genes has now been successfully achieved. The procedure is based on strong PNS using diphtheria toxin A-fragment as a negative marker, and has succeeded in the directed modification of several endogenous rice genes in various ways. In addition to gene knock-outs and knock-ins, a nucleotide substitution in a target gene was also achieved recently. This review presents a summary of the development of the rice PNS system, highlighting its advantages. Different types of gene modification and gene editing aimed at developing new plant breeding technology (NPBT based on PNS are discussed.

  7. Evidence of recombination and positive selection in cetacean papillomaviruses

    Energy Technology Data Exchange (ETDEWEB)

    Robles-Sikisaka, Refugio, E-mail: refugio.robles1@gmail.com [Hubbs-SeaWorld Research Institute, Center for Marine Veterinary Virology, 2595 Ingraham Street, San Diego, CA 92109 (United States); Rivera, Rebecca, E-mail: RRivera@hswri.org [Hubbs-SeaWorld Research Institute, Center for Marine Veterinary Virology, 2595 Ingraham Street, San Diego, CA 92109 (United States); Nollens, Hendrik H., E-mail: Hendrik.Nollens@SeaWorld.com [Hubbs-SeaWorld Research Institute, Center for Marine Veterinary Virology, 2595 Ingraham Street, San Diego, CA 92109 (United States); College of Veterinary Medicine, University of Florida, PO Box 110885, Gainesville, FL 32611 (United States); SeaWorld San Diego, 500 SeaWorld Drive, San Diego, CA 92109 (United States); St Leger, Judy, E-mail: Judy.St.Leger@SeaWorld.com [SeaWorld San Diego, 500 SeaWorld Drive, San Diego, CA 92109 (United States); Durden, Wendy N., E-mail: WNoke@hswri.org [Hubbs-SeaWorld Research Institute, 3830 South Highway A1A 4-181, Melbourne Beach, FL 32951 (United States); Stolen, Megan, E-mail: MStolen@hswri.org [Hubbs-SeaWorld Research Institute, 3830 South Highway A1A 4-181, Melbourne Beach, FL 32951 (United States); Burchell, Jennifer, E-mail: JBurchell@hswri.org [Hubbs-SeaWorld Research Institute, Center for Marine Veterinary Virology, 2595 Ingraham Street, San Diego, CA 92109 (United States); Wellehan, James F.X., E-mail: WellehanJ@ufl.edu [College of Veterinary Medicine, University of Florida, PO Box 110885, Gainesville, FL 32611 (United States)

    2012-06-05

    Papillomaviruses (PVs) are small DNA viruses that have been associated with increased epithelial proliferation. Over one hundred PV types have been identified in humans; however, only three have been identified in bottlenose dolphins (Tursiops truncatus) to date. Using rolling circle amplification and degenerate PCR, we identified four novel PV genomes of bottlenose dolphins. TtPV4, TtPV5 and TtPV6 were identified in genital lesions while TtPV7 was identified in normal genital mucosa. Bayesian analysis of the full-length L1 genes found that TtPV4 and TtPV7 group within the Upsilonpapillomavirus genus while TtPV5 and TtPV6 group with Omikronpapillomavirus. However, analysis of the E1 gene did not distinguish these genera, implying that these genes may not share a common history, consistent with recombination. Recombination analyses identified several probable events. Signals of positive selection were found mostly in the E1 and E2 genes. Recombination and diversifying selection pressures constitute important driving forces of cetacean PV evolution.

  8. Selective bowel decontamination results in gram-positive translocation.

    Science.gov (United States)

    Jackson, R J; Smith, S D; Rowe, M I

    1990-05-01

    Colonization by enteric gram-negative bacteria with subsequent translocation is believed to be a major mechanism for infection in the critically ill patient. Selective bowel decontamination (SBD) has been used to control gram-negative infections by eliminating these potentially pathogenic bacteria while preserving anaerobic and other less pathogenic organisms. Infection with gram-positive organisms and anaerobes in two multivisceral transplant patients during SBD led us to investigate the effect of SBD on gut colonization and translocation. Twenty-four rats received enteral polymixin E, tobramycin, amphotericin B, and parenteral cefotaxime for 7 days (PTA + CEF); 23 received parenteral cefotaxime alone (CEF), 19 received the enteral antibiotics alone (PTA), 21 controls received no antibiotics. Cecal homogenates, mesenteric lymph node (MLN), liver, and spleen were cultured. Only 8% of the PTA + CEF group had gram-negative bacteria in cecal culture vs 52% CEF, 84% PTA, and 100% in controls. Log Enterococcal colony counts were higher in the PTA + CEF group (8.0 + 0.9) vs controls (5.4 + 0.4) P less than 0.01. Translocation of Enterococcus to the MLN was significantly increased in the PTA + CEF group (67%) vs controls (0%) P less than 0.01. SBD effectively eliminates gram-negative organisms from the gut in the rat model. Overgrowth and translocation of Enterococcus suggests that infection with gram-positive organisms may be a limitation of SBD.

  9. Inhibition of vicariously learned fear in children using positive modeling and prior exposure.

    Science.gov (United States)

    Askew, Chris; Reynolds, Gemma; Fielding-Smith, Sarah; Field, Andy P

    2016-02-01

    One of the challenges to conditioning models of fear acquisition is to explain how different individuals can experience similar learning events and only some of them subsequently develop fear. Understanding factors moderating the impact of learning events on fear acquisition is key to understanding the etiology and prevention of fear in childhood. This study investigates these moderators in the context of vicarious (observational) learning. Two experiments tested predictions that the acquisition or inhibition of fear via vicarious learning is driven by associative learning mechanisms similar to direct conditioning. In Experiment 1, 3 groups of children aged 7 to 9 years received 1 of 3 inhibitive information interventions-psychoeducation, factual information, or no information (control)-prior to taking part in a vicarious fear learning procedure. In Experiment 2, 3 groups of children aged 7 to 10 years received 1 of 3 observational learning interventions-positive modeling (immunization), observational familiarity (latent inhibition), or no prevention (control)-before vicarious fear learning. Results indicated that observationally delivered manipulations inhibited vicarious fear learning, while preventions presented via written information did not. These findings confirm that vicarious learning shares some of the characteristics of direct conditioning and can explain why not all individuals will develop fear following a vicarious learning event. They also suggest that the modality of inhibitive learning is important and should match the fear learning pathway for increased chances of inhibition. Finally, the results demonstrate that positive modeling is likely to be a particularly effective method for preventing fear-related observational learning in children. (c) 2016 APA, all rights reserved).

  10. Molecular Basis for the Selective Inhibition of Respiratory Syncytial Virus RNA Polymerase by 2'-Fluoro-4'-Chloromethyl-Cytidine Triphosphate.

    Directory of Open Access Journals (Sweden)

    Jerome Deval

    2015-06-01

    Full Text Available Respiratory syncytial virus (RSV causes severe lower respiratory tract infections, yet no vaccines or effective therapeutics are available. ALS-8176 is a first-in-class nucleoside analog prodrug effective in RSV-infected adult volunteers, and currently under evaluation in hospitalized infants. Here, we report the mechanism of inhibition and selectivity of ALS-8176 and its parent ALS-8112. ALS-8176 inhibited RSV replication in non-human primates, while ALS-8112 inhibited all strains of RSV in vitro and was specific for paramyxoviruses and rhabdoviruses. The antiviral effect of ALS-8112 was mediated by the intracellular formation of its 5'-triphosphate metabolite (ALS-8112-TP inhibiting the viral RNA polymerase. ALS-8112 selected for resistance-associated mutations within the region of the L gene of RSV encoding the RNA polymerase. In biochemical assays, ALS-8112-TP was efficiently recognized by the recombinant RSV polymerase complex, causing chain termination of RNA synthesis. ALS-8112-TP did not inhibit polymerases from host or viruses unrelated to RSV such as hepatitis C virus (HCV, whereas structurally related molecules displayed dual RSV/HCV inhibition. The combination of molecular modeling and enzymatic analysis showed that both the 2'F and the 4'ClCH2 groups contributed to the selectivity of ALS-8112-TP. The lack of antiviral effect of ALS-8112-TP against HCV polymerase was caused by Asn291 that is well-conserved within positive-strand RNA viruses. This represents the first comparative study employing recombinant RSV and HCV polymerases to define the selectivity of clinically relevant nucleotide analogs. Understanding nucleotide selectivity towards distant viral RNA polymerases could not only be used to repurpose existing drugs against new viral infections, but also to design novel molecules.

  11. Selective mutism and temperament: the silence and behavioral inhibition to the unfamiliar.

    Science.gov (United States)

    Gensthaler, Angelika; Khalaf, Sally; Ligges, Marc; Kaess, Michael; Freitag, Christine M; Schwenck, Christina

    2016-10-01

    Behavioral inhibition (BI) is a suspected precursor of selective mutism. However, investigations on early behavioral inhibition of children with selective mutism are lacking. Children aged 3-18 with lifetime selective mutism (n = 109), social phobia (n = 61), internalizing behavior (n = 46) and healthy controls (n = 118) were assessed using the parent-rated Retrospective Infant Behavioral Inhibition (RIBI) questionnaire. Analyses showed that children with lifetime selective mutism and social phobia were more inhibited as infants and toddlers than children of the internalizing and healthy control groups, who displayed similar low levels of behavioral inhibition. Moreover, behavioral inhibition was higher in infants with lifetime selective mutism than in participants with social phobia according to the Total BI score (p = 0.012) and the Shyness subscale (p selective mutism. Results yield first evidence of the recently hypothesized temperamental origin of selective mutism. Children at risk should be screened for this debilitating child psychiatric condition.

  12. Transcriptome sequencing and positive selected genes analysis of Bombyx mandarina.

    Directory of Open Access Journals (Sweden)

    Tingcai Cheng

    Full Text Available The wild silkworm Bombyx mandarina is widely believed to be an ancestor of the domesticated silkworm, Bombyx mori. Silkworms are often used as a model for studying the mechanism of species domestication. Here, we performed transcriptome sequencing of the wild silkworm using an Illumina HiSeq2000 platform. We produced 100,004,078 high-quality reads and assembled them into 50,773 contigs with an N50 length of 1764 bp and a mean length of 941.62 bp. A total of 33,759 unigenes were identified, with 12,805 annotated in the Nr database, 8273 in the Pfam database, and 9093 in the Swiss-Prot database. Expression profile analysis found significant differential expression of 1308 unigenes between the middle silk gland (MSG and posterior silk gland (PSG. Three sericin genes (sericin 1, sericin 2, and sericin 3 were expressed specifically in the MSG and three fibroin genes (fibroin-H, fibroin-L, and fibroin/P25 were expressed specifically in the PSG. In addition, 32,297 Single-nucleotide polymorphisms (SNPs and 361 insertion-deletions (INDELs were detected. Comparison with the domesticated silkworm p50/Dazao identified 5,295 orthologous genes, among which 400 might have experienced or to be experiencing positive selection by Ka/Ks analysis. These data and analyses presented here provide insights into silkworm domestication and an invaluable resource for wild silkworm genomics research.

  13. The inhibition of PARP but not EGFR results in the radiosensitization of HPV/p16-positive HNSCC cell lines

    International Nuclear Information System (INIS)

    Güster, Julian David; Weissleder, Stephanie Valerie; Busch, Chia-Jung; Kriegs, Malte; Petersen, Cordula; Knecht, Rainald; Dikomey, Ekkehard; Rieckmann, Thorsten

    2014-01-01

    Background and purpose: HPV-negative and HPV-positive HNSCC comprise distinct tumor entities with different biological characteristics. Specific regimens for the comparably well curable HPV-positive entity that reduce side effects without compromising outcome have yet to be established. Therefore, we tested here whether the inhibition of EGFR or PARP may be used to specifically enhance the radiosensitivity of HPV-positive HNSCC cells. Materials and methods: Experiments were performed with five HPV/p16-positive HNSCC cell lines. Inhibitors used were cetuximab, olaparib and PF-00477736. The respective inhibition of EGFR, PARP and Chk1 was evaluated by Western blot, immunofluorescence analysis and assessment of cell cycle distribution. Cell survival was assessed by colony formation assay. Results: Inhibition of EGFR by cetuximab failed to radiosensitize any of the HPV-positive HNSCC cell lines tested. In contrast, PARP-inhibition resulted in a substantial radiosensitization of all strains, with the sensitization being further enhanced by the additional inhibition of Chk1. Conclusions: PARP-inhibition effectively radiosensitizes HPV-positive HNSCC cells and may therefore represent a viable alternative to chemotherapy possibly even allowing for a reduction in radiation dose. For the latter, PARP-inhibition may be combined with the inhibition of Chk1. In contrast, the inhibition of EGFR cannot be expected to radiosensitize HPV-positive HNSCC through the modulation of cellular radiosensitivity

  14. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro

    DEFF Research Database (Denmark)

    Vinggaard, A.M.; Hnida, C.; Breinholt, V.

    2000-01-01

    than 50 mu M. The positive control 4-hydroxyandrostendione (1 mu M) caused an inhibition of aromatase activity by 74%. The compounds, which did not affect the aromatase activity, were bromopropylate, chlorfenvinphos. chlorobenzilate, chlorpyrifos, diuron, heptachlor, iprodion, linuron, pentachlorphenol...

  15. Impact of selected troposphere models on Precise Point Positioning convergence

    Science.gov (United States)

    Kalita, Jakub; Rzepecka, Zofia

    2016-04-01

    The Precise Point Positioning (PPP) absolute method is currently intensively investigated in order to reach fast convergence time. Among various sources that influence the convergence of the PPP, the tropospheric delay is one of the most important. Numerous models of tropospheric delay are developed and applied to PPP processing. However, with rare exceptions, the quality of those models does not allow fixing the zenith path delay tropospheric parameter, leaving difference between nominal and final value to the estimation process. Here we present comparison of several PPP result sets, each of which based on different troposphere model. The respective nominal values are adopted from models: VMF1, GPT2w, MOPS and ZERO-WET. The PPP solution admitted as reference is based on the final troposphere product from the International GNSS Service (IGS). The VMF1 mapping function was used for all processing variants in order to provide capability to compare impact of applied nominal values. The worst case initiates zenith wet delay with zero value (ZERO-WET). Impact from all possible models for tropospheric nominal values should fit inside both IGS and ZERO-WET border variants. The analysis is based on data from seven IGS stations located in mid-latitude European region from year 2014. For the purpose of this study several days with the most active troposphere were selected for each of the station. All the PPP solutions were determined using gLAB open-source software, with the Kalman filter implemented independently by the authors of this work. The processing was performed on 1 hour slices of observation data. In addition to the analysis of the output processing files, the presented study contains detailed analysis of the tropospheric conditions for the selected data. The overall results show that for the height component the VMF1 model outperforms GPT2w and MOPS by 35-40% and ZERO-WET variant by 150%. In most of the cases all solutions converge to the same values during first

  16. Autonomous site selection and instrument positioning for sample acquisition

    Science.gov (United States)

    Shaw, A.; Barnes, D.; Pugh, S.

    The European Space Agency Aurora Exploration Program aims to establish a European long-term programme for the exploration of Space, culminating in a human mission to space in the 2030 timeframe. Two flagship missions, namely Mars Sample Return and ExoMars, have been proposed as recognised steps along the way. The Exomars Rover is the first of these flagship missions and includes a rover carrying the Pasteur Payload, a mobile exobiology instrumentation package, and the Beagle 2 arm. The primary objective is the search for evidence of past or present life on mars, but the payload will also study the evolution of the planet and the atmosphere, look for evidence of seismological activity and survey the environment in preparation for future missions. The operation of rovers in unknown environments is complicated, and requires large resources not only on the planet but also in ground based operations. Currently, this can be very labour intensive, and costly, if large teams of scientists and engineers are required to assess mission progress, plan mission scenarios, and construct a sequence of events or goals for uplink. Furthermore, the constraints in communication imposed by the time delay involved over such large distances, and line-of-sight required, make autonomy paramount to mission success, affording the ability to operate in the event of communications outages and be opportunistic with respect to scientific discovery. As part of this drive to reduce mission costs and increase autonomy the Space Robotics group at the University of Wales, Aberystwyth is researching methods of autonomous site selection and instrument positioning, directly applicable to the ExoMars mission. The site selection technique used builds on the geometric reasoning algorithms used previously for localisation and navigation [Shaw 03]. It is proposed that a digital elevation model (DEM) of the local surface, generated during traverse and without interaction from ground based operators, can be

  17. Selected Phytochemicals and Culinary Plant Extracts Inhibit Fructose Uptake in Caco-2 Cells.

    Science.gov (United States)

    Lee, Yurim; Lim, Yeni; Kwon, Oran

    2015-09-18

    This study compared the ability of nine culinary plant extracts containing a wide array of phytochemicals to inhibit fructose uptake and then explored the involvement of intestinal fructose transporters and phytochemicals for selected samples. The chemical signature was characterized by high performance liquid chromatography with mass spectrometry. Inhibition of [(14)C]-fructose uptake was tested by using human intestinal Caco-2 cells. Then, the relative contribution of the two apical-facing intestinal fructose transporters, GLUT2 and GLUT5, and the signature components for fructose uptake inhibition was confirmed in naive, phloretin-treated and forskolin-treated Caco-2 cells. HPLC/MS analysis of the chemical signature revealed that guava leaf contained quercetin and catechin, and turmeric contained curcumin, bisdemethoxycurcumin and dimethoxycurcumin. Similar inhibition of fructose uptake (by ~50%) was observed with guava leaf and turmeric in Caco-2 cells, but with a higher contribution of GLUT2 for turmeric and that of GLUT5 for guava leaf. The data suggested that, in turmeric, demethoxycurcumin specifically contributed to GLUT2-mediated fructose uptake inhibition, and curcumin did the same to GLUT5-mediated fructose uptake inhibition, but GLUT2 inhibition was more potent. By contrast, in guava leaf, catechin specifically contributed to GLUT5-mediated fructose uptake inhibition, and quercetin affected both GLUT5- and GLUT2-mediated fructose uptake inhibition, resulting in the higher contribution of GLUT5. These results suggest that demethoxycurcumin is an important contributor to GLUT2-mediated fructose uptake inhibition for turmeric extract, and catechin is the same to GLUT5-mediated fructose uptake inhibition for guava leaf extract. Quercetin, curcumin and bisdemethoxycurcumin contributed to both GLUT5- and GLUT2-mediated fructose uptake inhibition, but the contribution to GLUT5 inhibition was higher than the contribution to GLUT2 inhibition.

  18. Targeted Radiosensitization of ETS Fusion-Positive Prostate Cancer through PARP1 Inhibition

    Directory of Open Access Journals (Sweden)

    Sumin Han

    2013-10-01

    Full Text Available ETS gene fusions, which result in overexpression of an ETS transcription factor, are considered driving mutations in approximately half of all prostate cancers. Dysregulation of ETS transcription factors is also known to exist in Ewing's sarcoma, breast cancer, and acute lymphoblastic leukemia. We previously discovered that ERG, the predominant ETS family member in prostate cancer, interacts with the DNA damage response protein poly (ADP-ribose polymerase 1 (PARP1 in human prostate cancer specimens. Therefore, we hypothesized that the ERG-PARP1 interaction may confer radiation resistance by increasing DNA repair efficiency and that this radio-resistance could be reversed through PARP1 inhibition. Using lentiviral approaches, we established isogenic models of ERG overexpression in PC3 and DU145 prostate cancer cell lines. In both cell lines, ERG overexpression increased clonogenic survival following radiation by 1.25 (±0.07 fold (mean ± SEM and also resulted in increased PARP1 activity. PARP1 inhibition with olaparib preferentially radiosensitized ERG-positive cells by a factor of 1.52 (±0.03 relative to ERG-negative cells (P < .05. Neutral and alkaline COMET assays and immunofluorescence microscopy assessing γ-H2AX foci showed increased short- and long-term efficiencies of DNA repair, respectively, following radiation that was preferentially reversed by PARP1 inhibition. These findings were verified in an in vivo xenograft model. Our findings demonstrate that ERG overexpression confers radiation resistance through increased efficiency of DNA repair following radiation that can be reversed through inhibition of PARP1. These results motivate the use of PARP1 inhibitors as radiosensitizers in patients with localized ETS fusion-positive cancers.

  19. Whole genome detection of signature of positive selection in African cattle reveals selection for thermotolerance.

    Science.gov (United States)

    Taye, Mengistie; Lee, Wonseok; Caetano-Anolles, Kelsey; Dessie, Tadelle; Hanotte, Olivier; Mwai, Okeyo Ally; Kemp, Stephen; Cho, Seoae; Oh, Sung Jong; Lee, Hak-Kyo; Kim, Heebal

    2017-12-01

    As African indigenous cattle evolved in a hot tropical climate, they have developed an inherent thermotolerance; survival mechanisms include a light-colored and shiny coat, increased sweating, and cellular and molecular mechanisms to cope with high environmental temperature. Here, we report the positive selection signature of genes in African cattle breeds which contribute for their heat tolerance mechanisms. We compared the genomes of five indigenous African cattle breeds with the genomes of four commercial cattle breeds using cross-population composite likelihood ratio (XP-CLR) and cross-population extended haplotype homozygosity (XP-EHH) statistical methods. We identified 296 (XP-EHH) and 327 (XP-CLR) positively selected genes. Gene ontology analysis resulted in 41 biological process terms and six Kyoto Encyclopedia of Genes and Genomes pathways. Several genes and pathways were found to be involved in oxidative stress response, osmotic stress response, heat shock response, hair and skin properties, sweat gland development and sweating, feed intake and metabolism, and reproduction functions. The genes and pathways identified directly or indirectly contribute to the superior heat tolerance mechanisms in African cattle populations. The result will improve our understanding of the biological mechanisms of heat tolerance in African cattle breeds and opens an avenue for further study. © 2017 Japanese Society of Animal Science.

  20. Structural, Biochemical, and Computational Studies Reveal the Mechanism of Selective Aldehyde Dehydrogenase 1A1 Inhibition by Cytotoxic Duocarmycin Analogues.

    Science.gov (United States)

    Koch, Maximilian F; Harteis, Sabrina; Blank, Iris D; Pestel, Galina; Tietze, Lutz F; Ochsenfeld, Christian; Schneider, Sabine; Sieber, Stephan A

    2015-11-09

    Analogues of the natural product duocarmycin bearing an indole moiety were shown to bind aldehyde dehydrogenase 1A1 (ALDH1A1) in addition to DNA, while derivatives without the indole solely addressed the ALDH1A1 protein. The molecular mechanism of selective ALDH1A1 inhibition by duocarmycin analogues was unraveled through cocrystallization, mutational studies, and molecular dynamics simulations. The structure of the complex shows the compound embedded in a hydrophobic pocket, where it is stabilized by several crucial π-stacking and van der Waals interactions. This binding mode positions the cyclopropyl electrophile for nucleophilic attack by the noncatalytic residue Cys302, thereby resulting in covalent attachment, steric occlusion of the active site, and inhibition of catalysis. The selectivity of duocarmycin analogues for ALDH1A1 is unique, since only minor alterations in the sequence of closely related protein isoforms restrict compound accessibility. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Positive allometry and the prehistory of sexual selection

    OpenAIRE

    Tomkins, Joseph L.; LeBas, Natasha R.; Witton, Mark P.; Martill, David M.; Humphries, Stuart

    2010-01-01

    The function of the exaggerated structures that adorn many fossil vertebrates remains largely unresolved. One recurrent hypothesis is that these elaborated traits had a role in thermoregulation. This orthodoxy persists despite the observation that traits exaggerated to the point of impracticality in extant organisms are almost invariably sexually selected. We use allometric scaling to investigate the role of sexual selection and thermoregulation in the evolution of exaggerated traits of the c...

  2. Positive Selection on Loci Associated with Drug and Alcohol Dependence.

    Directory of Open Access Journals (Sweden)

    Brooke Sadler

    Full Text Available Much of the evolution of human behavior remains a mystery, including how certain disadvantageous behaviors are so prevalent. Nicotine addiction is one such phenotype. Several loci have been implicated in nicotine related phenotypes including the nicotinic receptor gene clusters (CHRNs on chromosomes 8 and 15. Here we use 1000 Genomes sequence data from 3 populations (Africans, Asians and Europeans to examine whether natural selection has occurred at these loci. We used Tajima's D and the integrated haplotype score (iHS to test for evidence of natural selection. Our results provide evidence for strong selection in the nicotinic receptor gene cluster on chromosome 8, previously found to be significantly associated with both nicotine and cocaine dependence, as well as evidence selection acting on the region containing the CHRNA5 nicotinic receptor gene on chromosome 15, that is genome wide significant for risk for nicotine dependence. To examine the possibility that this selection is related to memory and learning, we utilized genetic data from the Collaborative Studies on the Genetics of Alcoholism (COGA to test variants within these regions with three tests of memory and learning, the Wechsler Adult Intelligence Scale (WAIS Block Design, WAIS Digit Symbol and WAIS Information tests. Of the 17 SNPs genotyped in COGA in this region, we find one significantly associated with WAIS digit symbol test results. This test captures aspects of reaction time and memory, suggesting that a phenotype relating to memory and learning may have been the driving force behind selection at these loci. This study could begin to explain why these seemingly deleterious SNPs are present at their current frequencies.

  3. Potency and selectivity of carprofen enantiomers for inhibition of bovine cyclooxygenase in whole blood assays.

    Science.gov (United States)

    Brentnall, Claire; Cheng, Zhangrui; McKellar, Quintin A; Lees, Peter

    2012-12-01

    Whole blood in vitro assays were used to determine the potency and selectivity of carprofen enantiomers for inhibition of the isoforms of cyclooxygenase (COX), COX-1 and COX-2, in the calf. S(+)-carprofen possessed preferential activity for COX-2 inhibition but, because the slopes of inhibition curves differed, the COX-1:COX-2 inhibition ratio decreased from 9.04:1 for inhibitory concentration (IC)10 to 1.84:1 for IC95. R(-) carprofen inhibited COX-2 preferentially only for low inhibition of the COX isoforms (IC10 COX-1:COX-2=6.63:1), whereas inhibition was preferential for COX-1 for a high level of inhibition (IC95 COX-1:COX-2=0.20:1). S(+) carprofen was the more potent inhibitor of COX isoforms; potency ratios S(+):R(-) carprofen were 11.6:1 for IC10 and 218:1 for IC90. Based on serum concentrations of carprofen enantiomers obtained after administration of a therapeutic dose of 1.4 mg/kg to calves subcutaneously, S(+)-carprofen concentrations exceeded the in vitro IC80 COX-2 value for 32 h and the IC20 for COX-1 for 33 h. The findings are discussed in relation to efficacy and safety of carprofen in calves. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Positional Differences in Elite Basketball: Selecting Appropriate Training - Load Measures.

    Science.gov (United States)

    Svilar, Luka; Castellano, Julen; Jukic, Igor; Casamichana, David

    2018-01-18

    The purpose of this paper was to study the structure of interrelationships among external training load measures and how these vary among different positions in elite basketball. Eight external variables of jumping (JUMP), acceleration (ACC), deceleration (DEC) and change of direction (COD), and two internal load variables (RPE and sRPE) were collected from 13 professional players with 300 session records. Three playing positions were considered: guards (n=4), forwards (n=4) and centers (n=5). High and total external variables (hJUMP and tJUMP, hACC and tACC, hDEC and tDEC, hCOD and tCOD) were used for the principal component analysis. Extraction criteria were set at the eigenvalue of greater than one. Varimax rotation mode was used to extract multiple principal components. The analysis showed that all positions had two or three principal components (explaining almost all of the variance), but the configuration of each factor was different: tACC, tDEC, tCOD and hJUMP for centers, hACC, tACC, tCOD and hJUMP for guards, and tACC, hDEC, tDEC, hCOD, and tCOD for forwards are specifically demanded in training sessions and, therefore, these variables must be prioritized in load monitoring. Furthermore, for all playing positions, RPE and sRPE have high correlation with the total amount of ACC, DEC and COD. This would suggest that, although players perform the same training tasks, the demands of each position can vary. A particular combination of external load measures is required to describe training load of each playing position, especially to better understand internal responses among players.

  5. A strategy for position-selective epoxidation of polyprenols.

    Science.gov (United States)

    Gnanadesikan, Vijay; Corey, E J

    2008-06-25

    An effective strategy has been developed for the efficient site-selective epoxidation of poylolefinic isoprenoid alcohols, based on the use of an internal control element for intramolecular reaction. The approach is illustrated by application to a series of polyisoprenoid alcohols (polyprenols) at substrate concentration of 0.5 mM. With polyprenol substrates having the hydroxyl function at one terminus, the internal epoxidation can be directed at the double bond of the polyprenol, which is either four or five away from the terminal hydroxyprenyl subunit.

  6. Mean-field analysis of orientation selectivity in inhibition-dominated networks of spiking neurons.

    Science.gov (United States)

    Sadeh, Sadra; Cardanobile, Stefano; Rotter, Stefan

    2014-01-01

    Mechanisms underlying the emergence of orientation selectivity in the primary visual cortex are highly debated. Here we study the contribution of inhibition-dominated random recurrent networks to orientation selectivity, and more generally to sensory processing. By simulating and analyzing large-scale networks of spiking neurons, we investigate tuning amplification and contrast invariance of orientation selectivity in these networks. In particular, we show how selective attenuation of the common mode and amplification of the modulation component take place in these networks. Selective attenuation of the baseline, which is governed by the exceptional eigenvalue of the connectivity matrix, removes the unspecific, redundant signal component and ensures the invariance of selectivity across different contrasts. Selective amplification of modulation, which is governed by the operating regime of the network and depends on the strength of coupling, amplifies the informative signal component and thus increases the signal-to-noise ratio. Here, we perform a mean-field analysis which accounts for this process.

  7. Inhibition of CYP1 by berberine, palmatine, and jatrorrhizine: Selectivity, kinetic characterization, and molecular modeling

    International Nuclear Information System (INIS)

    Lo, Sheng-Nan; Chang, Yu-Ping; Tsai, Keng-Chang; Chang, Chia-Yu; Wu, Tian-Shung; Ueng, Yune-Fang

    2013-01-01

    Cytochrome P450 (P450, CYP) 1 family plays a primary role in the detoxification and bioactivation of polycyclic aromatic hydrocarbons. Human CYP1A1, CYP1A2, and CYP1B1 exhibit differential substrate specificity and tissue distribution. Berberine, palmatine, and jatrorrhizine are protoberberine alkaloids present in several medicinal herbs, such as Coptis chinensis (Huang-Lian) and goldenseal. These protoberberines inhibited CYP1A1.1- and CYP1B1.1-catalyzed 7-ethoxyresorufin O-deethylation (EROD) activities, whereas CYP1A2.1 activity was barely affected. Kinetic analysis revealed that berberine noncompetitively inhibited EROD activities of CYP1A1.1 and CYP1B1.1, whereas palmatine and jatrorrhizine caused either competitive or mixed type of inhibition. Among protoberberines, berberine caused the most potent and selective inhibitory effect on CYP1B1.1 with the least K i value of 44 ± 16 nM. Berberine also potently inhibited CYP1B1.1 activities toward 7-ethoxycoumarin and 7-methoxyresorufin, whereas the inhibition of benzo(a)pyrene hydroxylation activity was less pronounced. Berberine inhibited the polymorphic variants, CYP1B1.3 (V432L) and CYP1B1.4 (N453S), with IC 50 values comparable to that for CYP1B1.1 inhibition. Berberine-mediated inhibition was abolished by a mutation of Asn228 to Thr in CYP1B1.1, whereas the inhibition was enhanced by a reversal mutation of Thr223 to Asn in CYP1A2.1. This result in conjugation with the molecular modeling revealed the crucial role of hydrogen-bonding interaction of Asn228 on CYP1B1.1 with the methoxy moiety of berberine. These findings demonstrate that berberine causes a selective CYP1B1-inhibition, in which Asn228 appears to be crucial. The inhibitory effects of berberine on CYP1B1 activities toward structurally diverse substrates can be different. - Highlights: • Berberine preferentially inhibited CYP1B1 activity. • Berberine caused similar inhibitory effects on CYP1B1.1, CYP1B1.3 and CYP1B1.4. • Asn228 in CYP1B1 was an

  8. Inhibition of CYP1 by berberine, palmatine, and jatrorrhizine: Selectivity, kinetic characterization, and molecular modeling

    Energy Technology Data Exchange (ETDEWEB)

    Lo, Sheng-Nan [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC (China); Chang, Yu-Ping; Tsai, Keng-Chang [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Chang, Chia-Yu [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Institute of Medical Sciences, Taipei Medical University, Taipei 101, Taiwan, ROC (China); Wu, Tian-Shung [Department of Chemistry, National Chung-Kung University, Tainan 701, Taiwan, ROC (China); Ueng, Yune-Fang, E-mail: ueng@nricm.edu.tw [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC (China); Institute of Medical Sciences, Taipei Medical University, Taipei 101, Taiwan, ROC (China)

    2013-11-01

    Cytochrome P450 (P450, CYP) 1 family plays a primary role in the detoxification and bioactivation of polycyclic aromatic hydrocarbons. Human CYP1A1, CYP1A2, and CYP1B1 exhibit differential substrate specificity and tissue distribution. Berberine, palmatine, and jatrorrhizine are protoberberine alkaloids present in several medicinal herbs, such as Coptis chinensis (Huang-Lian) and goldenseal. These protoberberines inhibited CYP1A1.1- and CYP1B1.1-catalyzed 7-ethoxyresorufin O-deethylation (EROD) activities, whereas CYP1A2.1 activity was barely affected. Kinetic analysis revealed that berberine noncompetitively inhibited EROD activities of CYP1A1.1 and CYP1B1.1, whereas palmatine and jatrorrhizine caused either competitive or mixed type of inhibition. Among protoberberines, berberine caused the most potent and selective inhibitory effect on CYP1B1.1 with the least K{sub i} value of 44 ± 16 nM. Berberine also potently inhibited CYP1B1.1 activities toward 7-ethoxycoumarin and 7-methoxyresorufin, whereas the inhibition of benzo(a)pyrene hydroxylation activity was less pronounced. Berberine inhibited the polymorphic variants, CYP1B1.3 (V432L) and CYP1B1.4 (N453S), with IC{sub 50} values comparable to that for CYP1B1.1 inhibition. Berberine-mediated inhibition was abolished by a mutation of Asn228 to Thr in CYP1B1.1, whereas the inhibition was enhanced by a reversal mutation of Thr223 to Asn in CYP1A2.1. This result in conjugation with the molecular modeling revealed the crucial role of hydrogen-bonding interaction of Asn228 on CYP1B1.1 with the methoxy moiety of berberine. These findings demonstrate that berberine causes a selective CYP1B1-inhibition, in which Asn228 appears to be crucial. The inhibitory effects of berberine on CYP1B1 activities toward structurally diverse substrates can be different. - Highlights: • Berberine preferentially inhibited CYP1B1 activity. • Berberine caused similar inhibitory effects on CYP1B1.1, CYP1B1.3 and CYP1B1.4. • Asn228 in CYP

  9. Stimulation of the subthalamic region facilitates the selection and inhibition of motor responses in Parkinson's disease

    NARCIS (Netherlands)

    van den Wildenberg, Wery P. M.; van Boxtel, Geert J. M.; van der Molen, Maurits W.; Bosch, D. Andries; Speelman, Johannes D.; Brunia, Cornelis H. M.

    2006-01-01

    The aim of the present study was to specify the involvement of the basal ganglia in motor response selection and response inhibition. Two samples were studied. The first sample consisted of patients diagnosed with Parkinson's disease (PD) who received deep-brain stimulation (DBS) of the subthalamic

  10. A scan for positively selected genes in the genomes of humans and chimpanzees.

    Directory of Open Access Journals (Sweden)

    Rasmus Nielsen

    2005-06-01

    Full Text Available Since the divergence of humans and chimpanzees about 5 million years ago, these species have undergone a remarkable evolution with drastic divergence in anatomy and cognitive abilities. At the molecular level, despite the small overall magnitude of DNA sequence divergence, we might expect such evolutionary changes to leave a noticeable signature throughout the genome. We here compare 13,731 annotated genes from humans to their chimpanzee orthologs to identify genes that show evidence of positive selection. Many of the genes that present a signature of positive selection tend to be involved in sensory perception or immune defenses. However, the group of genes that show the strongest evidence for positive selection also includes a surprising number of genes involved in tumor suppression and apoptosis, and of genes involved in spermatogenesis. We hypothesize that positive selection in some of these genes may be driven by genomic conflict due to apoptosis during spermatogenesis. Genes with maximal expression in the brain show little or no evidence for positive selection, while genes with maximal expression in the testis tend to be enriched with positively selected genes. Genes on the X chromosome also tend to show an elevated tendency for positive selection. We also present polymorphism data from 20 Caucasian Americans and 19 African Americans for the 50 annotated genes showing the strongest evidence for positive selection. The polymorphism analysis further supports the presence of positive selection in these genes by showing an excess of high-frequency derived nonsynonymous mutations.

  11. Reference satellite selection method for GNSS high-precision relative positioning

    Directory of Open Access Journals (Sweden)

    Xiao Gao

    2017-03-01

    Full Text Available Selecting the optimal reference satellite is an important component of high-precision relative positioning because the reference satellite directly influences the strength of the normal equation. The reference satellite selection methods based on elevation and positional dilution of precision (PDOP value were compared. Results show that all the above methods cannot select the optimal reference satellite. We introduce condition number of the design matrix in the reference satellite selection method to improve structure of the normal equation, because condition number can indicate the ill condition of the normal equation. The experimental results show that the new method can improve positioning accuracy and reliability in precise relative positioning.

  12. CyPPA, a Positive SK3/SK2 Modulator, Reduces Activity of Dopaminergic Neurons, Inhibits Dopamine Release, and Counteracts Hyperdopaminergic Behaviors Induced by Methylphenidate

    DEFF Research Database (Denmark)

    Herrik, Kjartan F; Redrobe, John P; Holst, Dorte

    2012-01-01

    Dopamine (DA) containing midbrain neurons play critical roles in several psychiatric and neurological diseases, including schizophrenia and attention deficit hyperactivity disorder, and the substantia nigra pars compacta neurons selectively degenerate in Parkinson's disease. Pharmacological......]-amine (CyPPA), a subtype-selective positive modulator of SK channels (SK3¿>¿SK2¿>¿>¿>¿SK1, IK), decreased spontaneous firing rate, increased the duration of the apamin-sensitive afterhyperpolarization, and caused an activity-dependent inhibition of current-evoked action potentials in DA neurons from both...

  13. Selective inhibition of Bacillus subtilis sporulation by acridine orange and promethazine.

    Science.gov (United States)

    Burke, W F; Spizizen, J

    1977-03-01

    Two structurally similar compounds were found to inhibit sporulation in Bacillus subtilis 168. A dye, acridine orange, and an antischizophrenic drug, promethazine, blocked spore formation at concentrations subinhibitory to vegetative growth, while allowing synthesis of serine protease, antibiotic, and certain catabolite-repressed enzymes. The sporulation process was sensitive to promethazine through T2, whereas acridine orange was inhibitory until T4. The drug-treated cells were able to support the replication of phages phie and phi29, although the lytic cycles were altered slightly. The selective inhibition of sporulation by these compounds may be related to the affinity of some sporulation-specific genes to intercalating compounds.

  14. Selective inhibition of type 2 fatty acid synthetase by the antibiotic thiolactomycin

    International Nuclear Information System (INIS)

    Nishida, Ikuo; Kawaguchi, Akihiko; Yamada, Mitsuhiro

    1984-01-01

    The antibiotic thiolactomycin inhibits the fatty acid synthesis from both [1- 14 C]-acetate and [2 14 C] malonyl-CoA of spinach leaves, developing castor bean endosperms and avocado mesocarp. On the other hand, fatty acid synthetases of Brevibacterium ammoniagenes and Corynebacterium glutamicum are much less sensitive to this antibiotic. As Hayashi et al. have indicated in their paper that thiolactomycin inhibits fatty acid synthetase of Escherichia coli but has little effect on the synthetases of yeast and rat liver, thiolactomycin is suggested to be a selective inhibitor of type 2 fatty acid synthetases. (author)

  15. Selective inhibition of type 2 fatty acid synthetase by the antibiotic thiolactomycin

    Energy Technology Data Exchange (ETDEWEB)

    Nishida, Ikuo; Kawaguchi, Akihiko; Yamada, Mitsuhiro (Tokyo Univ. (Japan). Faculty of Science)

    1984-03-01

    The antibiotic thiolactomycin inhibits the fatty acid synthesis from both (1-/sup 14/C)-acetate and (2/sup 14/C) malonyl-CoA of spinach leaves, developing castor bean endosperms and avocado mesocarp. On the other hand, fatty acid synthetases of Brevibacterium ammoniagenes and Corynebacterium glutamicum are much less sensitive to this antibiotic. As Hayashi et al. have indicated in their paper that thiolactomycin inhibits fatty acid synthetase of Escherichia coli but has little effect on the synthetases of yeast and rat liver, thiolactomycin is suggested to be a selective inhibitor of type 2 fatty acid synthetases.

  16. The collective benefits of feeling good and letting go: positive emotion and (dis)inhibition interact to predict cooperative behavior.

    Science.gov (United States)

    Rand, David G; Kraft-Todd, Gordon; Gruber, June

    2015-01-01

    Cooperation is central to human existence, forming the bedrock of everyday social relationships and larger societal structures. Thus, understanding the psychological underpinnings of cooperation is of both scientific and practical importance. Recent work using a dual-process framework suggests that intuitive processing can promote cooperation while deliberative processing can undermine it. Here we add to this line of research by more specifically identifying deliberative and intuitive processes that affect cooperation. To do so, we applied automated text analysis using the Linguistic Inquiry and Word Count (LIWC) software to investigate the association between behavior in one-shot anonymous economic cooperation games and the presence inhibition (a deliberative process) and positive emotion (an intuitive process) in free-response narratives written after (Study 1, N = 4,218) or during (Study 2, N = 236) the decision-making process. Consistent with previous results, across both studies inhibition predicted reduced cooperation while positive emotion predicted increased cooperation (even when controlling for negative emotion). Importantly, there was a significant interaction between positive emotion and inhibition, such that the most cooperative individuals had high positive emotion and low inhibition. This suggests that inhibition (i.e., reflective or deliberative processing) may undermine cooperative behavior by suppressing the prosocial effects of positive emotion.

  17. Selective Inhibition and Naming Performance in Semantic Blocking, Picture-Word Interference, and Color-Word Stroop Tasks

    Science.gov (United States)

    Shao, Zeshu; Roelofs, Ardi; Martin, Randi C.; Meyer, Antje S.

    2015-01-01

    In 2 studies, we examined whether explicit distractors are necessary and sufficient to evoke selective inhibition in 3 naming tasks: the semantic blocking, picture-word interference, and color-word Stroop task. Delta plots were used to quantify the size of the interference effects as a function of reaction time (RT). Selective inhibition was…

  18. The selective estrogen receptor modulator raloxifene inhibits neutrophil extracellular trap formation.

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    Roxana Flores

    2016-12-01

    Full Text Available Raloxifene is a selective estrogen receptor modulator typically prescribed for the prevention/treatment of osteoporosis in postmenopausal women. Although raloxifene is known to have anti-inflammatory properties, its effect on human neutrophils, the primary phagocytic leukocytes of the immune system, remain poorly understood. Here, through a screen of pharmacologically active small molecules, we find that raloxifene prevents neutrophil cell death in response to the classical activator phorbol 12-myristate 13-acetate (PMA, a compound known to induce formation of DNA-based neutrophil extracellular traps (NETs. Inhibition of PMA-induced NET production by raloxifene was confirmed using quantitative and imaging-based assays. Human neutrophils from both male and female donors express the nuclear estrogen receptors ERα and ERβ, known targets of raloxifene. Like raloxifene, selective antagonists of these receptors inhibit PMA-induced NET production. Furthermore, raloxifene inhibited PMA-induced ERK phosphorylation but not reactive oxygen species (ROS production, pathways known to be key modulators of NET production. Finally, we found that raloxifene inhibited PMA-induced, NET-based killing of the leading human bacterial pathogen, methicillin-resistant Staphylococcus aureus (MRSA. Our results reveal that raloxifene is a potent modulator of neutrophil function and NET production.

  19. Kaempferol nanoparticles achieve strong and selective inhibition of ovarian cancer cell viability

    Science.gov (United States)

    Luo, Haitao; Jiang, Bingbing; Li, Bingyun; Li, Zhaoliang; Jiang, Bing-Hua; Chen, Yi Charlie

    2012-01-01

    Ovarian cancer is one of the leading causes of cancer death for women throughout the Western world. Kaempferol, a natural flavonoid, has shown promise in the chemoprevention of ovarian cancer. A common concern about using dietary supplements for chemoprevention is their bioavailability. Nanoparticles have shown promise in increasing the bioavailability of some chemicals. Here we developed five different types of nanoparticles incorporating kaempferol and tested their efficacy in the inhibition of viability of cancerous and normal ovarian cells. We found that positively charged nanoparticle formulations did not lead to a significant reduction in cancer cell viability, whereas nonionic polymeric nanoparticles resulted in enhanced reduction of cancer cell viability. Among the nonionic polymeric nanoparticles, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) nanoparticles incorporating kaempferol led to significant reduction in cell viability of both cancerous and normal cells. Poly(DL-lactic acid-co-glycolic acid) (PLGA) nanoparticles incorporating kaempferol resulted in enhanced reduction of cancer cell viability together with no significant reduction in cell viability of normal cells compared with kaempferol alone. Therefore, both PEO-PPO-PEO and PLGA nanoparticle formulations were effective in reducing cancer cell viability, while PLGA nanoparticles incorporating kaempferol had selective toxicity against cancer cells and normal cells. A PLGA nanoparticle formulation could be advantageous in the prevention and treatment of ovarian cancers. On the other hand, PEO-PPO-PEO nanoparticles incorporating kaempferol were more effective inhibitors of cancer cells, but they also significantly reduced the viability of normal cells. PEO-PPO-PEO nanoparticles incorporating kaempferol may be suitable as a cancer-targeting strategy, which could limit the effects of the nanoparticles on normal cells while retaining their potency against cancer cells. We

  20. NAC selectively inhibit cancer telomerase activity: A higher redox homeostasis threshold exists in cancer cells

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    Pengying Li

    2016-08-01

    Full Text Available Telomerase activity controls telomere length, and this plays an important role in stem cells, aging and tumors. Antioxidant was shown to protect telomerase activity in normal cells but inhibit that in cancer cells, but the underlying mechanism is elusive. Here we found that 7721 hepatoma cells held a higher redox homeostasis threshold than L02 normal liver cells which caused 7721 cells to have a higher demand for ROS; MnSOD over-expression in 7721 decreased endogenous reactive oxygen species (ROS and inhibited telomerase activity; Akt phosphorylation inhibitor and NAC both inhibited 7721 telomerase activity. The over-elimination of ROS by NAC resulted in the inhibition of Akt pathway. Our results suggest that ROS is involved in the regulation of cancer telomerase activity through Akt pathway. The different intracellular redox homeostasis and antioxidant system in normal cells and tumor cells may be the cause of the opposite effect on telomerase activity in response to NAC treatment. Our results provide a theoretical base of using antioxidants selectively inhibit cancer telomerase activity. Findings of the present study may provide insights into novel approaches for cancer treatment.

  1. Recent adaptive events in human brain revealed by meta-analysis of positively selected genes.

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    Yue Huang

    Full Text Available BACKGROUND AND OBJECTIVES: Analysis of positively-selected genes can help us understand how human evolved, especially the evolution of highly developed cognitive functions. However, previous works have reached conflicting conclusions regarding whether human neuronal genes are over-represented among genes under positive selection. METHODS AND RESULTS: We divided positively-selected genes into four groups according to the identification approaches, compiling a comprehensive list from 27 previous studies. We showed that genes that are highly expressed in the central nervous system are enriched in recent positive selection events in human history identified by intra-species genomic scan, especially in brain regions related to cognitive functions. This pattern holds when different datasets, parameters and analysis pipelines were used. Functional category enrichment analysis supported these findings, showing that synapse-related functions are enriched in genes under recent positive selection. In contrast, immune-related functions, for instance, are enriched in genes under ancient positive selection revealed by inter-species coding region comparison. We further demonstrated that most of these patterns still hold even after controlling for genomic characteristics that might bias genome-wide identification of positively-selected genes including gene length, gene density, GC composition, and intensity of negative selection. CONCLUSION: Our rigorous analysis resolved previous conflicting conclusions and revealed recent adaptation of human brain functions.

  2. Selective antibacterial activity of patchouli alcohol against Helicobacter pylori based on inhibition of urease.

    Science.gov (United States)

    Yu, Xiao-Dan; Xie, Jian-Hui; Wang, Yong-Hong; Li, Yu-Cui; Mo, Zhi-Zhun; Zheng, Yi-Feng; Su, Ji-Yan; Liang, Ye-er; Liang, Jin-Zhi; Su, Zi-Ren; Huang, Ping

    2015-01-01

    The aim of this study is to evaluate the antibacterial activity and urease inhibitory effects of patchouli alcohol (PA), the bioactive ingredient isolated from Pogostemonis Herba, which has been widely used for the treatment of gastrointestinal disorders. The activities of PA against selected bacteria and fungi were determined by agar dilution method. It was demonstrated that PA exhibited selective antibacterial activity against Helicobacter pylori, without influencing the major normal gastrointestinal bacteria. Noticeably, the antibacterial activity of PA was superior to that of amoxicillin, with minimal inhibition concentration value of 78 µg/mL. On the other hand, PA inhibited ureases from H.pylori and jack bean in concentration-dependent fashion with IC50 values of 2.67 ± 0.79 mM and 2.99 ± 0.41 mM, respectively. Lineweaver-Burk plots indicated that the type of inhibition was non-competitive against H.pylori urease whereas uncompetitive against jack bean urease. Reactivation of PA-inactivated urease assay showed DL-dithiothreitol, the thiol reagent, synergistically inactivated urease with PA instead of enzymatic activity recovery. In conclusion, the selective H.pylori antibacterial activity along with urease inhibitory potential of PA could make it a possible drug candidate for the treatment of H.pylori infection. Copyright © 2014 John Wiley & Sons, Ltd.

  3. Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Crowley, Vincent M. [Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Dr. Malott 4070 Lawrence KS 66045 USA; Huard, Dustin J. E. [School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta GA 30332 USA; Lieberman, Raquel L. [School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta GA 30332 USA; Blagg, Brian S. J. [Warren Family Research Center for Drug Discovery and Development, and Department of Chemistry & Biochemistry, University of Notre Dame, 305 McCourtney Hall Notre Dame IN 46556 USA

    2017-09-27

    Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum (ER) resident isoform of the 90 kDa heat shock protein (Hsp90) family and its inhibition represents a promising therapeutic target for the treatment of many diseases. Modification of the first generation cis-amide bioisostere imidazole to alter the angle between the resorcinol ring and the benzyl side chain via cis-amide replacements produced compounds with improved Grp94 affinity and selectivity. Structure–activity relationship studies led to the discovery of compound 30, which exhibits 540 nm affinity and 73-fold selectivity towards Grp94. Grp94 is responsible for the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins. The Grp94-selective inhibitor 30 was shown to exhibit potent anti-migratory effects against multiple aggressive and metastatic cancers.

  4. Selective anti-proliferation of HER2-positive breast cancer cells by anthocyanins identified by high-throughput screening.

    Directory of Open Access Journals (Sweden)

    Weihua Liu

    Full Text Available Overexpressed Human epidermal growth factor receptor 2 (HER2 drives the biology of 20% breast cancer and is a prediction of a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients. Traditional Chinese herbs/medicines have been used to treat breast cancer patients including HER2-positive patients in Asia for decades. Although the traditional medicines demonstrate efficacy in clinics for HER2-positive patients, the mechanism is largely unknown. In this article, we screened a 10,000 natural product library in 6 different cell lines representing breast cancer, and assessed the ability of each drug to cause cytotoxicity through a high-throughput screening approach. We have identified eight natural compounds that selectively inhibit the proliferation of HER2-positive cells. Two of the hit compounds, peonidin-3-glucoside and cyaniding-3-glucoside, are both extracts from black rice. They inhibit the phospho-HER2 and phospho-AKT and were confirmed to induce HER2-psotive breast cancer cells apoptosis both in vitro and in vivo. Peonidin-3-glucoside and cyaniding-3-glucoside treatments significantly reduced the tumor size and volume in vivo compared to the control group. There is no significant difference of antitumorgenic effects between peonidin-3-glucoside and cyaniding-3-glucoside treatments.

  5. PSP: rapid identification of orthologous coding genes under positive selection across multiple closely related prokaryotic genomes.

    Science.gov (United States)

    Su, Fei; Ou, Hong-Yu; Tao, Fei; Tang, Hongzhi; Xu, Ping

    2013-12-27

    With genomic sequences of many closely related bacterial strains made available by deep sequencing, it is now possible to investigate trends in prokaryotic microevolution. Positive selection is a sub-process of microevolution, in which a particular mutation is favored, causing the allele frequency to continuously shift in one direction. Wide scanning of prokaryotic genomes has shown that positive selection at the molecular level is much more frequent than expected. Genes with significant positive selection may play key roles in bacterial adaption to different environmental pressures. However, selection pressure analyses are computationally intensive and awkward to configure. Here we describe an open access web server, which is designated as PSP (Positive Selection analysis for Prokaryotic genomes) for performing evolutionary analysis on orthologous coding genes, specially designed for rapid comparison of dozens of closely related prokaryotic genomes. Remarkably, PSP facilitates functional exploration at the multiple levels by assignments and enrichments of KO, GO or COG terms. To illustrate this user-friendly tool, we analyzed Escherichia coli and Bacillus cereus genomes and found that several genes, which play key roles in human infection and antibiotic resistance, show significant evidence of positive selection. PSP is freely available to all users without any login requirement at: http://db-mml.sjtu.edu.cn/PSP/. PSP ultimately allows researchers to do genome-scale analysis for evolutionary selection across multiple prokaryotic genomes rapidly and easily, and identify the genes undergoing positive selection, which may play key roles in the interactions of host-pathogen and/or environmental adaptation.

  6. How to Make a Dolphin: Molecular Signature of Positive Selection in Cetacean Genome.

    Directory of Open Access Journals (Sweden)

    Mariana F Nery

    Full Text Available Cetaceans are unique in being the only mammals completely adapted to an aquatic environment. This adaptation has required complex changes and sometimes a complete restructuring of physiology, behavior and morphology. Identifying genes that have been subjected to selection pressure during cetacean evolution would greatly enhance our knowledge of the ways in which genetic variation in this mammalian order has been shaped by natural selection. Here, we performed a genome-wide scan for positive selection in the dolphin lineage. We employed models of codon substitution that account for variation of selective pressure over branches on the tree and across sites in a sequence. We analyzed 7,859 nuclear-coding ortholog genes and using a series of likelihood ratio tests (LRTs, we identified 376 genes (4.8% with molecular signatures of positive selection in the dolphin lineage. We used the cow as the sister group and compared estimates of selection in the cetacean genome to this using the same methods. This allowed us to define which genes have been exclusively under positive selection in the dolphin lineage. The enrichment analysis found that the identified positively selected genes are significantly over-represented for three exclusive functional categories only in the dolphin lineage: segment specification, mesoderm development and system development. Of particular interest for cetacean adaptation to an aquatic life are the following GeneOntology targets under positive selection: genes related to kidney, heart, lung, eye, ear and nervous system development.

  7. Laser isotope separation using selective inhibition and encouragement of dimer formation

    International Nuclear Information System (INIS)

    Kivel, B.

    1979-01-01

    Method and apparatus for inhibiting dimer formation of molecules of a selected isotope type in a cooled flow of gas to enhance the effectiveness of mass difference isotope separation techniques are described. Molecules in the flow containing atoms of the selected isotope type are selectively excited by infrared radiation in order to inhibit the formation of dimers and larger clusters of such molecules, while the molecules not containing atoms of the selected, excited type are encouraged to form dimers and higher order aggregates by the cooling of the gaseous flow. The molecules with the excited isotope will predominate in monomers and will constitute the enriched product stream, while the aggregated group comprising molecules having the unexcited isotope will predominate in dimers and larger clusters of molecules, forming the tails stream. The difference in diffusion coefficientts between particles of the excited and unexcited isotopes is enhanced by the greater mass differences resulting from aggregation of unexcited particles into dimers and larger clusters. Prior art separation techniques which exploit differences in isotopic diffusion rates will consequently exhibit enhanced enrichment per stage by the utilization of the present invention

  8. Signatures of positive selection: from selective sweeps at individual loci to subtle allele frequency changes in polygenic adaptation.

    Science.gov (United States)

    Stephan, Wolfgang

    2016-01-01

    In the past 15 years, numerous methods have been developed to detect selective sweeps underlying adaptations. These methods are based on relatively simple population genetic models, including one or two loci at which positive directional selection occurs, and one or two marker loci at which the impact of selection on linked neutral variation is quantified. Information about the phenotype under selection is not included in these models (except for fitness). In contrast, in the quantitative genetic models of adaptation, selection acts on one or more phenotypic traits, such that a genotype-phenotype map is required to bridge the gap to population genetics theory. Here I describe the range of population genetic models from selective sweeps in a panmictic population of constant size to evolutionary traffic when simultaneous sweeps at multiple loci interfere, and I also consider the case of polygenic selection characterized by subtle allele frequency shifts at many loci. Furthermore, I present an overview of the statistical tests that have been proposed based on these population genetics models to detect evidence for positive selection in the genome. © 2015 John Wiley & Sons Ltd.

  9. Impaired distractor inhibition on a selective attention task in unmedicated, depressed subjects.

    Science.gov (United States)

    MacQueen, G M; Tipper, S P; Young, L T; Joffe, R T; Levitt, A J

    2000-05-01

    Impaired distractor inhibition may contribute to the selective attention deficits observed in depressed patients, but studies to date have not tested the distractor inhibition theory against the possibility that processes such as transient memory review processes may account for the observed deficits. A negative priming paradigm can dissociate inhibition from such a potentially confounding process called object review. The negative priming task also isolates features of the distractor such as colour and location for independent examination. A computerized negative priming task was used in which colour, identification and location features of a stimulus and distractor were systematically manipulated across successive prime and probe trials. Thirty-two unmedicated subjects with DSM-IV diagnoses of non-psychotic unipolar depression were compared with 32 age, sex and IQ matched controls. Depressed subjects had reduced levels of negative priming for conditions where the colour feature of the stimulus was repeated across prime and probe trials but not when identity or location was the repeated feature. When both the colour and location feature were the repeated feature across trials, facilitation in response was apparent. The pattern of results supports studies that found reduced distractor inhibition in depressed subjects, and suggests that object review is intact in these subjects. Greater impairment in negative priming for colour versus location suggests that subjects may have greater impairment in the visual stream associated with processing colour features.

  10. D1 and D2 Inhibitions of the Soleus H-Reflex Are Differentially Modulated during Plantarflexion Force and Position Tasks.

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    Fernando Henrique Magalhães

    Full Text Available Presynaptic inhibition (PSI has been shown to modulate several neuronal pathways of functional relevance by selectively gating the connections between sensory inputs and spinal motoneurons, thereby regulating the contribution of the stretch reflex circuitry to the ongoing motor activity. In this study, we investigated whether a differential regulation of Ia afferent inflow by PSI may be associated with the performance of two types of plantarflexion sensoriomotor tasks. The subjects (in a seated position controlled either: 1 the force level exerted by the foot against a rigid restraint (force task, FT; or 2 the angular position of the ankle when sustaining inertial loads (position task, PT that required the same level of muscle activation observed in FT. Subjects were instructed to maintain their force/position at target levels set at ~10% of maximum isometric voluntary contraction for FT and 90° for PT, while visual feedback of the corresponding force/position signals were provided. Unconditioned H-reflexes (i.e. control reflexes and H-reflexes conditioned by electrical pulses applied to the common peroneal nerve with conditioning-to-test intervals of 21 ms and 100 ms (corresponding to D1 and D2 inhibitions, respectively were evoked in a random fashion. A significant main effect for the type of the motor task (FT vs PT (p = 0.005, η2p = 0.603 indicated that PTs were undertaken with lower levels of Ia PSI converging onto the soleus motoneuron pool. Additionally, a significant interaction between the type of inhibition (D1 vs D2 and the type of motor task (FT vs PT (p = 0.038, η2p = 0.395 indicated that D1 inhibition was associated with a significant reduction in PSI levels from TF to TP (p = 0.001, η2p = 0.731, whereas no significant difference between the tasks was observed for D2 inhibition (p = 0.078, η2p = 0.305. These results suggest that D1 and D2 inhibitions of the soleus H-reflex are differentially modulated during the performance of

  11. Positive Selection and Centrality in the Yeast and Fly Protein-Protein Interaction Networks

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    Sandip Chakraborty

    2016-01-01

    Full Text Available Proteins within a molecular network are expected to be subject to different selective pressures depending on their relative hierarchical positions. However, it is not obvious what genes within a network should be more likely to evolve under positive selection. On one hand, only mutations at genes with a relatively high degree of control over adaptive phenotypes (such as those encoding highly connected proteins are expected to be “seen” by natural selection. On the other hand, a high degree of pleiotropy at these genes is expected to hinder adaptation. Previous analyses of the human protein-protein interaction network have shown that genes under long-term, recurrent positive selection (as inferred from interspecific comparisons tend to act at the periphery of the network. It is unknown, however, whether these trends apply to other organisms. Here, we show that long-term positive selection has preferentially targeted the periphery of the yeast interactome. Conversely, in flies, genes under positive selection encode significantly more connected and central proteins. These observations are not due to covariation of genes’ adaptability and centrality with confounding factors. Therefore, the distribution of proteins encoded by genes under recurrent positive selection across protein-protein interaction networks varies from one species to another.

  12. Genome-wide analysis of positively selected genes in seasonal and non-seasonal breeding species.

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    Yuhuan Meng

    Full Text Available Some mammals breed throughout the year, while others breed only at certain times of year. These differences in reproductive behavior can be explained by evolution. We identified positively-selected genes in two sets of species with different degrees of relatedness including seasonal and non-seasonal breeding species, using branch-site models. After stringent filtering by sum of pairs scoring, we revealed that more genes underwent positive selection in seasonal compared with non-seasonal breeding species. Positively-selected genes were verified by cDNA mapping of the positive sites with the corresponding cDNA sequences. The design of the evolutionary analysis can effectively lower the false-positive rate and thus identify valid positive genes. Validated, positively-selected genes, including CGA, DNAH1, INVS, and CD151, were related to reproductive behaviors such as spermatogenesis and cell proliferation in non-seasonal breeding species. Genes in seasonal breeding species, including THRAP3, TH1L, and CMTM6, may be related to the evolution of sperm and the circadian rhythm system. Identification of these positively-selected genes might help to identify the molecular mechanisms underlying seasonal and non-seasonal reproductive behaviors.

  13. Aluminium and hydrogen ions inhibit a mechanosensory calcium-selective cation channel

    Science.gov (United States)

    Ding, J. P.; Pickard, B. G.

    1993-01-01

    The tension-dependent activity of mechanosensory calcium-selective cation channels in excised plasmalemmal patches from onion bulb scale epidermis is modulated by pH in the physiologically meaningful range between 4.5 and 7.2. It is rapidly lowered by lowering pH and rapidly raised by raising pH. Channel activity is effectively inhibited by low levels of aluminium ions and activity can be partially restored by washing for a few minutes. We suggest that under normal conditions the sensitivity of the mechanosensory channels to pH of the wall free space plays important roles in regulation of plant activities such as growth. We further suggest that, when levels of acid and aluminium ions in the soil solution are high, they might inhibit similar sensory channels in cells of the root tip, thus contributing critically to the acid soil syndrome.

  14. Selective increase of in vivo firing frequencies in DA SN neurons after proteasome inhibition in the ventral midbrain.

    Science.gov (United States)

    Subramaniam, Mahalakshmi; Kern, Beatrice; Vogel, Simone; Klose, Verena; Schneider, Gaby; Roeper, Jochen

    2014-09-01

    The impairment of protein degradation via the ubiquitin-proteasome system (UPS) is present in sporadic Parkinson's disease (PD), and might play a key role in selective degeneration of vulnerable dopamine (DA) neurons in the substantia nigra pars compacta (SN). Further evidence for a causal role of dysfunctional UPS in familial PD comes from mutations in parkin, which results in a loss of function of an E3-ubiquitin-ligase. In a mouse model, genetic inactivation of an essential component of the 26S proteasome lead to widespread neuronal degeneration including DA midbrain neurons and the formation of alpha-synuclein-positive inclusion bodies, another hallmark of PD. Studies using pharmacological UPS inhibition in vivo had more mixed results, varying from extensive degeneration to no loss of DA SN neurons. However, it is currently unknown whether UPS impairment will affect the neurophysiological functions of DA midbrain neurons. To answer this question, we infused a selective proteasome inhibitor into the ventral midbrain in vivo and recorded single DA midbrain neurons 2 weeks after the proteasome challenge. We found a selective increase in the mean in vivo firing frequencies of identified DA SN neurons in anesthetized mice, while those in the ventral tegmental area (VTA) were unaffected. Our results demonstrate that a single-hit UPS inhibition is sufficient to induce a stable and selective hyperexcitability phenotype in surviving DA SN neurons in vivo. This might imply that UPS dysfunction sensitizes DA SN neurons by enhancing 'stressful pacemaking'. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  15. Positive selection neighboring functionally essential sites and disease-implicated regions of mammalian reproductive proteins.

    LENUS (Irish Health Repository)

    Morgan, Claire C

    2010-01-01

    ABSTRACT: BACKGROUND: Reproductive proteins are central to the continuation of all mammalian species. The evolution of these proteins has been greatly influenced by environmental pressures induced by pathogens, rival sperm, sexual selection and sexual conflict. Positive selection has been demonstrated in many of these proteins with particular focus on primate lineages. However, the mammalia are a diverse group in terms of mating habits, population sizes and germ line generation times. We have examined the selective pressures at work on a number of novel reproductive proteins across a wide variety of mammalia. RESULTS: We show that selective pressures on reproductive proteins are highly varied. Of the 10 genes analyzed in detail, all contain signatures of positive selection either across specific sites or in specific lineages or a combination of both. Our analysis of SP56 and Col1a1 are entirely novel and the results show positively selected sites present in each gene. Our findings for the Col1a1 gene are suggestive of a link between positive selection and severe disease type. We find evidence in our dataset to suggest that interacting proteins are evolving in symphony: most likely to maintain interacting functionality. CONCLUSION: Our in silico analyses show positively selected sites are occurring near catalytically important regions suggesting selective pressure to maximize efficient fertilization. In those cases where a mechanism of protein function is not fully understood, the sites presented here represent ideal candidates for mutational study. This work has highlighted the widespread rate heterogeneity in mutational rates across the mammalia and specifically has shown that the evolution of reproductive proteins is highly varied depending on the species and interacting partners. We have shown that positive selection and disease are closely linked in the Col1a1 gene.

  16. Positive Selection on Hemagglutinin and Neuraminidase Genes of H1N1 Influenza Viruses

    LENUS (Irish Health Repository)

    Li, Wenfu

    2011-04-21

    Abstract Background Since its emergence in March 2009, the pandemic 2009 H1N1 influenza A virus has posed a serious threat to public health. To trace the evolutionary path of these new pathogens, we performed a selection-pressure analysis of a large number of hemagglutinin (HA) and neuraminidase (NA) gene sequences of H1N1 influenza viruses from different hosts. Results Phylogenetic analysis revealed that both HA and NA genes have evolved into five distinct clusters, with further analyses indicating that the pandemic 2009 strains have experienced the strongest positive selection. We also found evidence of strong selection acting on the seasonal human H1N1 isolates. However, swine viruses from North America and Eurasia were under weak positive selection, while there was no significant evidence of positive selection acting on the avian isolates. A site-by-site analysis revealed that the positively selected sites were located in both of the cleaved products of HA (HA1 and HA2), as well as NA. In addition, the pandemic 2009 strains were subject to differential selection pressures compared to seasonal human, North American swine and Eurasian swine H1N1 viruses. Conclusions Most of these positively and\\/or differentially selected sites were situated in the B-cell and\\/or T-cell antigenic regions, suggesting that selection at these sites might be responsible for the antigenic variation of the viruses. Moreover, some sites were also associated with glycosylation and receptor-binding ability. Thus, selection at these positions might have helped the pandemic 2009 H1N1 viruses to adapt to the new hosts after they were introduced from pigs to humans. Positive selection on position 274 of NA protein, associated with drug resistance, might account for the prevalence of drug-resistant variants of seasonal human H1N1 influenza viruses, but there was no evidence that positive selection was responsible for the spread of the drug resistance of the pandemic H1N1 strains.

  17. Continental-scale footprint of balancing and positive selection in a small rodent (Microtus arvalis.

    Directory of Open Access Journals (Sweden)

    Martin C Fischer

    Full Text Available Genetic adaptation to different environmental conditions is expected to lead to large differences between populations at selected loci, thus providing a signature of positive selection. Whereas balancing selection can maintain polymorphisms over long evolutionary periods and even geographic scale, thus leads to low levels of divergence between populations at selected loci. However, little is known about the relative importance of these two selective forces in shaping genomic diversity, partly due to difficulties in recognizing balancing selection in species showing low levels of differentiation. Here we address this problem by studying genomic diversity in the European common vole (Microtus arvalis presenting high levels of differentiation between populations (average F ST = 0.31. We studied 3,839 Amplified Fragment Length Polymorphism (AFLP markers genotyped in 444 individuals from 21 populations distributed across the European continent and hence over different environmental conditions. Our statistical approach to detect markers under selection is based on a Bayesian method specifically developed for AFLP markers, which treats AFLPs as a nearly codominant marker system, and therefore has increased power to detect selection. The high number of screened populations allowed us to detect the signature of balancing selection across a large geographic area. We detected 33 markers potentially under balancing selection, hence strong evidence of stabilizing selection in 21 populations across Europe. However, our analyses identified four-times more markers (138 being under positive selection, and geographical patterns suggest that some of these markers are probably associated with alpine regions, which seem to have environmental conditions that favour adaptation. We conclude that despite favourable conditions in this study for the detection of balancing selection, this evolutionary force seems to play a relatively minor role in shaping the genomic

  18.  Molecular evolution and positive selection of the symbiotic gene NORK in Medicago truncatula

    DEFF Research Database (Denmark)

    De Mita, Stephane; Santoni, Sylvain; Hochu, Isabelle

    2006-01-01

     Understanding the selective constraints of partner specificity in mutually beneficial symbiosis is a significant, yet largely unexplored, prospect of evolutionary biology. These selective constraints can be explored through the study of nucleotide polymorphism at loci controlling specificity...... domain of the protein, evolved under the regime of positive selection. Further research should focus on the rate and direction of molecular coevolution between microorganisms' signaling molecules and legumes' receptors....

  19. Distinction of Gram-positive and -negative bacteria using a colorimetric microbial viability assay based on the reduction of water-soluble tetrazolium salts with a selection medium.

    Science.gov (United States)

    Tsukatani, Tadayuki; Suenaga, Hikaru; Higuchi, Tomoko; Shiga, Masanobu; Noguchi, Katsuya; Matsumoto, Kiyoshi

    2011-01-01

    Bacteria are fundamentally divided into two groups: Gram-positive and Gram-negative. Although the Gram stain and other techniques can be used to differentiate these groups, some issues exist with traditional approaches. In this study, we developed a method for differentiating Gram-positive and -negative bacteria using a colorimetric microbial viability assay based on the reduction of the tetrazolium salt {2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt} (WST-8) via 2-methyl-1,4-napthoquinone with a selection medium. We optimized the composition of the selection medium to allow the growth of Gram-negative bacteria while inhibiting the growth of Gram-positive bacteria. When the colorimetric viability assay was carried out in a selection medium containing 0.5µg/ml crystal violet, 5.0 µg/ml daptomycin, and 5.0µg/ml vancomycin, the reduction in WST-8 by Gram-positive bacteria was inhibited. On the other hand, Gram-negative bacteria produced WST-8-formazan in the selection medium. The proposed method was also applied to determine the Gram staining characteristics of bacteria isolated from various foodstuffs. There was good agreement between the results obtained using the present method and those obtained using a conventional staining method. These results suggest that the WST-8 colorimetric assay with selection medium is a useful technique for accurately differentiating Gram-positive and -negative bacteria.

  20. Role of inhibition in the specification of orientation selectivity of cells in the cat striate cortex.

    Science.gov (United States)

    Bonds, A B

    1989-01-01

    Mechanisms supporting orientation selectivity of cat striate cortical cells were studied by stimulation with two superimposed sine-wave gratings of different orientations. One grating (base) generated a discharge of known amplitude which could be modified by the second grating (mask). Masks presented at nonoptimal orientations usually reduced the base-generated response, but the degree of reduction varied widely between cells. Cells with narrow orientation tuning tended to be more susceptible to mask presence than broadly tuned cells; similarly, simple cells generally showed more response reduction than did complex cells. The base and mask stimuli were drifted at different temporal frequencies which, in simple cells, permitted the identification of individual response components from each stimulus. This revealed that the reduction of the base response by the mask usually did not vary regularly with mask orientation, although response facilitation from the mask was orientation selective. In some sharply tuned simple cells, response reduction had clear local maxima near the limits of the cell's orientation-tuning function. Response reduction resulted from a nearly pure rightward shift of the response versus log contrast function. The lowest mask contrast yielding reduction was within 0.1-0.3 log unit of the lowest contrast effective for excitation. The temporal-frequency bandpass of the response-reduction mechanism resembled that of most cortical cells. The spatial-frequency bandpass was much broader than is typical for single cortical cells, spanning essentially the entire visual range of the cat. These findings are compatible with a model in which weak intrinsic orientation-selective excitation is enhanced in two stages: (1) control of threshold by nonorientation-selective inhibition that is continuously dependent on stimulus contrast; and (2) in the more narrowly tuned cells, orientation-selective inhibition that has local maxima serving to increase the slope of

  1. The role of positive selection in determining the molecular cause of species differences in disease

    Directory of Open Access Journals (Sweden)

    Foord Steven M

    2008-10-01

    Full Text Available Abstract Background Related species, such as humans and chimpanzees, often experience the same disease with varying degrees of pathology, as seen in the cases of Alzheimer's disease, or differing symptomatology as in AIDS. Furthermore, certain diseases such as schizophrenia, epithelial cancers and autoimmune disorders are far more frequent in humans than in other species for reasons not associated with lifestyle. Genes that have undergone positive selection during species evolution are indicative of functional adaptations that drive species differences. Thus we investigate whether biomedical disease differences between species can be attributed to positively selected genes. Results We identified genes that putatively underwent positive selection during the evolution of humans and four mammals which are often used to model human diseases (mouse, rat, chimpanzee and dog. We show that genes predicted to have been subject to positive selection pressure during human evolution are implicated in diseases such as epithelial cancers, schizophrenia, autoimmune diseases and Alzheimer's disease, all of which differ in prevalence and symptomatology between humans and their mammalian relatives. In agreement with previous studies, the chimpanzee lineage was found to have more genes under positive selection than any of the other lineages. In addition, we found new evidence to support the hypothesis that genes that have undergone positive selection tend to interact with each other. This is the first such evidence to be detected widely among mammalian genes and may be important in identifying molecular pathways causative of species differences. Conclusion Our dataset of genes predicted to have been subject to positive selection in five species serves as an informative resource that can be consulted prior to selecting appropriate animal models during drug target validation. We conclude that studying the evolution of functional and biomedical disease differences

  2. Positive diversifying selection is a pervasive adaptive force throughout the Drosophila radiation

    DEFF Research Database (Denmark)

    Cicconardi, Francesco; Marcatili, Paolo; Arthofer, Wolfgang

    2017-01-01

    The growing genomic information on non-model organisms eases exploring the evolutionary history of biodiversity. This is particularly true for Drosophila flies, in which the number of sequenced species doubled recently. Because of its outstanding diversity of species, Drosophila has become one....... grimshawi, a strong putative signal of positive diversifying selection was found related to cell, morphological, neuronal, and sensorial development and function. A recurrent signal of positive diversifying selection was found on genes related to aging and lifespan, suggesting that selection had shaped...

  3. Inhibition shapes selectivity to vocalizations in the inferior colliculus of awake mice

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    Zachary eMayko

    2012-10-01

    Full Text Available The inferior colliculus (IC is a major center for integration of auditory information as itreceives ascending projections from a variety of brainstem nuclei as well as descending projectionsfrom the thalamus and auditory cortex. The ascending projections are both excitatory andinhibitory and their convergence at the IC results in a microcircuitry that is important forshaping responses to simple, binaural, and modulated sounds in the IC. Here, we examined therole inhibition plays in shaping selectivity to vocalizations in the IC of awake, normal-hearingadult mice (CBA/CaJ strain. Neurons in the IC of mice show selectivity in their responses tovocalizations, and we hypothesized that this selectivity is created by inhibitory microcircuitryin the IC. We compared single unit responses in the IC to pure tones and a variety of ultrasonicmouse vocalizations before and after iontophoretic application of GABAA receptor (GABAARand glycine receptor (GlyR antagonists. The most pronounced effects of blocking GABAAR andGlyR on IC neurons were to increase spike rates and broaden excitatory frequency tuning curvesin response to pure tone stimuli, and to decrease selectivity to vocalizations. Thus, inhibitionplays an important role in creating selectivity to vocalizations in the inferior colliculus.

  4. Selective inhibition of plant serine hydrolases by agrochemicals revealed by competitive ABPP.

    Science.gov (United States)

    Kaschani, Farnusch; Nickel, Sabrina; Pandey, Bikram; Cravatt, Benjamin F; Kaiser, Markus; van der Hoorn, Renier A L

    2012-01-15

    Organophosphate and -phosphonates and their thio derivatives are often used in agroindustry as herbicides and insecticides, but their potential off-targets in the plant are poorly investigated. Here, we use competitive activity-based protein profiling (ABPP) of serine hydrolases (SHs) to detect targets of these agrochemicals and other compounds in Arabidopsis thaliana. Using broad-range and specific probes, and by overexpression of various SHs in planta, we are able to confirm eight SH-compound interactions, including selective inhibition of carboxylesterase CXE12, prolyloligopeptidase, methylesterase MES2 and tripeptidyl peptidase TPP2. These observations can be used for the design of novel probes and selective inhibitors and may help to assess physiological effects of agrochemicals on crop plants. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. Genome-scale detection of positive selection in nine primates predicts human-virus evolutionary conflicts.

    Science.gov (United States)

    van der Lee, Robin; Wiel, Laurens; van Dam, Teunis J P; Huynen, Martijn A

    2017-10-13

    Hotspots of rapid genome evolution hold clues about human adaptation. We present a comparative analysis of nine whole-genome sequenced primates to identify high-confidence targets of positive selection. We find strong statistical evidence for positive selection in 331 protein-coding genes (3%), pinpointing 934 adaptively evolving codons (0.014%). Our new procedure is stringent and reveals substantial artefacts (20% of initial predictions) that have inflated previous estimates. The final 331 positively selected genes (PSG) are strongly enriched for innate and adaptive immunity, secreted and cell membrane proteins (e.g. pattern recognition, complement, cytokines, immune receptors, MHC, Siglecs). We also find evidence for positive selection in reproduction and chromosome segregation (e.g. centromere-associated CENPO, CENPT), apolipoproteins, smell/taste receptors and mitochondrial proteins. Focusing on the virus-host interaction, we retrieve most evolutionary conflicts known to influence antiviral activity (e.g. TRIM5, MAVS, SAMHD1, tetherin) and predict 70 novel cases through integration with virus-human interaction data. Protein structure analysis further identifies positive selection in the interaction interfaces between viruses and their cellular receptors (CD4-HIV; CD46-measles, adenoviruses; CD55-picornaviruses). Finally, primate PSG consistently show high sequence variation in human exomes, suggesting ongoing evolution. Our curated dataset of positive selection is a rich source for studying the genetics underlying human (antiviral) phenotypes. Procedures and data are available at https://github.com/robinvanderlee/positive-selection. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  6. The use of naturally occurring selectively isolated bacteria for inhibiting paraffin deposition

    Energy Technology Data Exchange (ETDEWEB)

    Lazar, I.; Voicu, A.; Dobrota, S.; Petrisor, I.G.; Stefanescu, M.; Sandulescu, L. [Institute of Biology of the Romanian Academy, Spl. Independentei 296, Bucharest (Romania); Nicolescu, C.; Mucenica, D. [PETROSTAR Ploiesti, Bdul Bucuresti 35, Ploiesti (Romania)

    1999-01-01

    One of the most severe problems at any oil fields producing paraffinic oils is that of paraffin depositions. Romania which has a long experience in oil production is also faced with this problem in many oil fields. The microbial treatment, based on the activity of naturally occurring, selectively isolated bacteria, is already proved as an effective alternative to conventional methods to prevent and remove paraffin damage. Using such kind of bacterial products, exciting results for inhibiting paraffin depositions have been obtained. In this paper results concerning the naturally occurring bacteria selectively isolated from hydrocarbon polluted sites as well as from paraffinic oils, semi-solid and solid paraffin depositions are presented. After a laboratory screening, 15 bacterial strains (BS 1-15), three bacterial consortia (BC 1-3) and a Special Bacterial Consortium (SBC1) were selected. For the selection of bacterial consortia, the classical enrichment culture method has been used. The Special Bacterial Consortium resulted from a mixture of BS 1-15 and BC 1-3 following the steps of the classical enrichment culture method. The BS 1-15, BC 1-3 and SBC1 have been tested for their performances in producing biosurfactants and biosolvents as well as for hydrocarbon utilisation. The SBC1 has been tested for its ability in degradation of hydrocarbons contained in several types of paraffinic or non-paraffinic oils, and then for inhibiting paraffin deposition on a `flow equipment` using two types of paraffinic oils. The SBC1 has been also tested for degradation of hydrocarbons contained in semi-solid and solid paraffin depositions. The results obtained could support further applications to prevent and control paraffin depositions

  7. The use of naturally occurring selectively isolated bacteria for inhibiting paraffin deposition

    International Nuclear Information System (INIS)

    Lazar, I.; Voicu, A.; Dobrota, S.; Petrisor, I.G.; Stefanescu, M.; Sandulescu, L.; Nicolescu, C.; Mucenica, D.

    1999-01-01

    One of the most severe problems at any oil fields producing paraffinic oils is that of paraffin depositions. Romania which has a long experience in oil production is also faced with this problem in many oil fields. The microbial treatment, based on the activity of naturally occurring, selectively isolated bacteria, is already proved as an effective alternative to conventional methods to prevent and remove paraffin damage. Using such kind of bacterial products, exciting results for inhibiting paraffin depositions have been obtained. In this paper results concerning the naturally occurring bacteria selectively isolated from hydrocarbon polluted sites as well as from paraffinic oils, semi-solid and solid paraffin depositions are presented. After a laboratory screening, 15 bacterial strains (BS 1-15), three bacterial consortia (BC 1-3) and a Special Bacterial Consortium (SBC1) were selected. For the selection of bacterial consortia, the classical enrichment culture method has been used. The Special Bacterial Consortium resulted from a mixture of BS 1-15 and BC 1-3 following the steps of the classical enrichment culture method. The BS 1-15, BC 1-3 and SBC1 have been tested for their performances in producing biosurfactants and biosolvents as well as for hydrocarbon utilisation. The SBC1 has been tested for its ability in degradation of hydrocarbons contained in several types of paraffinic or non-paraffinic oils, and then for inhibiting paraffin deposition on a 'flow equipment' using two types of paraffinic oils. The SBC1 has been also tested for degradation of hydrocarbons contained in semi-solid and solid paraffin depositions. The results obtained could support further applications to prevent and control paraffin depositions

  8. Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder.

    Directory of Open Access Journals (Sweden)

    Renato Polimanti

    2017-02-01

    Full Text Available The human brain is the outcome of innumerable evolutionary processes; the systems genetics of psychiatric disorders could bear their signatures. On this basis, we analyzed five psychiatric disorders, attention deficit hyperactivity disorder, autism spectrum disorder (ASD, bipolar disorder, major depressive disorder, and schizophrenia (SCZ, using GWAS summary statistics from the Psychiatric Genomics Consortium. Machine learning-derived scores were used to investigate two natural-selection scenarios: complete selection (loci where a selected allele reached fixation and incomplete selection (loci where a selected allele has not yet reached fixation. ASD GWAS results positively correlated with incomplete-selection (p = 3.53*10-4. Variants with ASD GWAS p<0.1 were shown to have a 19%-increased probability to be in the top-5% for incomplete-selection score (OR = 1.19, 95%CI = 1.11-1.8, p = 9.56*10-7. Investigating the effect directions of minor alleles, we observed an enrichment for positive associations in SNPs with ASD GWAS p<0.1 and top-5% incomplete-selection score (permutation p<10-4. Considering the set of these ASD-positive-associated variants, we observed gene-expression enrichments for brain and pituitary tissues (p = 2.3*10-5 and p = 3*10-5, respectively and 53 gene ontology (GO enrichments, such as nervous system development (GO:0007399, p = 7.57*10-12, synapse organization (GO:0050808, p = 8.29*10-7, and axon guidance (GO:0007411, p = 1.81*10-7. Previous genetic studies demonstrated that ASD positively correlates with childhood intelligence, college completion, and years of schooling. Accordingly, we hypothesize that certain ASD risk alleles were under positive selection during human evolution due to their involvement in neurogenesis and cognitive ability.

  9. The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning

    Science.gov (United States)

    Brown, Holden D.; Amodeo, Dionisio A.; Sweeney, John A.; Ragozzino, Michael E.

    2011-01-01

    Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally-biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 minutes prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with a SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally-biased response pattern or a learned choice pattern. PMID:22219222

  10. Selective Inhibition of Histone Deacetylation in Melanoma Increases Targeted Gene Delivery by a Bacteriophage Viral Vector

    Directory of Open Access Journals (Sweden)

    Samuel Campbell

    2018-04-01

    Full Text Available The previously developed adeno-associated virus/phage (AAVP vector, a hybrid between M13 bacteriophage (phage viruses that infect bacteria only and human Adeno-Associated Virus (AAV, is a promising tool in targeted gene therapy against cancer. AAVP can be administered systemically and made tissue specific through the use of ligand-directed targeting. Cancer cells and tumor-associated blood vessels overexpress the αν integrin receptors, which are involved in tumor angiogenesis and tumor invasion. AAVP is targeted to these integrins via a double cyclic RGD4C ligand displayed on the phage capsid. Nevertheless, there remain significant host-defense hurdles to the use of AAVP in targeted gene delivery and subsequently in gene therapy. We previously reported that histone deacetylation in cancer constitutes a barrier to AAVP. Herein, to improve AAVP-mediated gene delivery to cancer cells, we combined the vector with selective adjuvant chemicals that inhibit specific histone deacetylases (HDAC. We examined the effects of the HDAC inhibitor C1A that mainly targets HDAC6 and compared this to sodium butyrate, a pan-HDAC inhibitor with broad spectrum HDAC inhibition. We tested the effects on melanoma, known for HDAC6 up-regulation, and compared this side by side with a normal human kidney HEK293 cell line. Varying concentrations were tested to determine cytotoxic levels as well as effects on AAVP gene delivery. We report that the HDAC inhibitor C1A increased AAVP-mediated transgene expression by up to ~9-fold. These findings indicate that selective HDAC inhibition is a promising adjuvant treatment for increasing the therapeutic value of AAVP.

  11. Evidence for positive selection in putative virulence factors within the Paracoccidioides brasiliensis species complex.

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    Daniel R Matute

    Full Text Available Paracoccidioides brasiliensis is a dimorphic fungus that is the causative agent of paracoccidioidomycosis, the most important prevalent systemic mycosis in Latin America. Recently, the existence of three genetically isolated groups in P. brasiliensis was demonstrated, enabling comparative studies of molecular evolution among P. brasiliensis lineages. Thirty-two gene sequences coding for putative virulence factors were analyzed to determine whether they were under positive selection. Our maximum likelihood-based approach yielded evidence for selection in 12 genes that are involved in different cellular processes. An in-depth analysis of four of these genes showed them to be either antigenic or involved in pathogenesis. Here, we present evidence indicating that several replacement mutations in gp43 are under positive balancing selection. The other three genes (fks, cdc42 and p27 show very little variation among the P. brasiliensis lineages and appear to be under positive directional selection. Our results are consistent with the more general observations that selective constraints are variable across the genome, and that even in the genes under positive selection, only a few sites are altered. We present our results within an evolutionary framework that may be applicable for studying adaptation and pathogenesis in P. brasiliensis and other pathogenic fungi.

  12. Tracing evolutionary relicts of positive selection on eight malaria-related immune genes in mammals.

    Science.gov (United States)

    Huang, Bing-Hong; Liao, Pei-Chun

    2015-07-01

    Plasmodium-induced malaria widely infects primates and other mammals. Multiple past studies have revealed that positive selection could be the main evolutionary force triggering the genetic diversity of anti-malaria resistance-associated genes in human or primates. However, researchers focused most of their attention on the infra-generic and intra-specific genome evolution rather than analyzing the complete evolutionary history of mammals. Here we extend previous research by testing the evolutionary link of natural selection on eight candidate genes associated with malaria resistance in mammals. Three of the eight genes were detected to be affected by recombination, including TNF-α, iNOS and DARC. Positive selection was detected in the rest five immunogenes multiple times in different ancestral lineages of extant species throughout the mammalian evolution. Signals of positive selection were exposed in four malaria-related immunogenes in primates: CCL2, IL-10, HO1 and CD36. However, selection signals of G6PD have only been detected in non-primate eutherians. Significantly higher evolutionary rates and more radical amino acid replacement were also detected in primate CD36, suggesting its functional divergence from other eutherians. Prevalent positive selection throughout the evolutionary trajectory of mammalian malaria-related genes supports the arms race evolutionary hypothesis of host genetic response of mammalian immunogenes to infectious pathogens. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  13. Dendrimer-Based Selective Proteostasis-Inhibition Strategy to Control NSCLC Growth and Progression.

    Directory of Open Access Journals (Sweden)

    Kyla Walworth

    -DDN. Moreover, we confirmed by clonogenic-assay that DDNDBeQ treatment significantly (p<0.001 inhibits H1299 colony-formation as compared to control/DDN. Overall, encapsulation of potent VCP-inhibitor DBeQ into a dendrimer allows selective VCP-mediated proteostasis-inhibition for controlling NSCLC-tumor growth and progression to allow tumor-targeted sustained drug delivery.

  14. Positive Selection or Free to Vary? Assessing the Functional Significance of Sequence Change Using Molecular Dynamics.

    Directory of Open Access Journals (Sweden)

    Jane R Allison

    Full Text Available Evolutionary arms races between pathogens and their hosts may be manifested as selection for rapid evolutionary change of key genes, and are sometimes detectable through sequence-level analyses. In the case of protein-coding genes, such analyses frequently predict that specific codons are under positive selection. However, detecting positive selection can be non-trivial, and false positive predictions are a common concern in such analyses. It is therefore helpful to place such predictions within a structural and functional context. Here, we focus on the p19 protein from tombusviruses. P19 is a homodimer that sequesters siRNAs, thereby preventing the host RNAi machinery from shutting down viral infection. Sequence analysis of the p19 gene is complicated by the fact that it is constrained at the sequence level by overprinting of a viral movement protein gene. Using homology modeling, in silico mutation and molecular dynamics simulations, we assess how non-synonymous changes to two residues involved in forming the dimer interface-one invariant, and one predicted to be under positive selection-impact molecular function. Interestingly, we find that both observed variation and potential variation (where a non-synonymous change to p19 would be synonymous for the overprinted movement protein does not significantly impact protein structure or RNA binding. Consequently, while several methods identify residues at the dimer interface as being under positive selection, MD results suggest they are functionally indistinguishable from a site that is free to vary. Our analyses serve as a caveat to using sequence-level analyses in isolation to detect and assess positive selection, and emphasize the importance of also accounting for how non-synonymous changes impact structure and function.

  15. Positive selection on MHC class II DRB and DQB genes in the bank vole (Myodes glareolus).

    Science.gov (United States)

    Scherman, Kristin; Råberg, Lars; Westerdahl, Helena

    2014-05-01

    The major histocompatibility complex (MHC) class IIB genes show considerable sequence similarity between loci. The MHC class II DQB and DRB genes are known to exhibit a high level of polymorphism, most likely maintained by parasite-mediated selection. Studies of the MHC in wild rodents have focused on DRB, whilst DQB has been given much less attention. Here, we characterised DQB genes in Swedish bank voles Myodes glareolus, using full-length transcripts. We then designed primers that specifically amplify exon 2 from DRB (202 bp) and DQB (205 bp) and investigated molecular signatures of natural selection on DRB and DQB alleles. The presence of two separate gene clusters was confirmed using BLASTN and phylogenetic analysis, where our seven transcripts clustered according to either DQB or DRB homologues. These gene clusters were again confirmed on exon 2 data from 454-amplicon sequencing. Our DRB primers amplify a similar number of alleles per individual as previously published DRB primers, though our reads are longer. Traditional d N/d S analyses of DRB sequences in the bank vole have not found a conclusive signal of positive selection. Using a more advanced substitution model (the Kumar method) we found positive selection in the peptide binding region (PBR) of both DRB and DQB genes. Maximum likelihood models of codon substitutions detected positively selected sites located in the PBR of both DQB and DRB. Interestingly, these analyses detected at least twice as many positively selected sites in DQB than DRB, suggesting that DQB has been under stronger positive selection than DRB over evolutionary time.

  16. Na(+)/Ca(2+) exchanger inhibition exerts a positive inotropic effect in the rat heart, but fails to influence the contractility of the rabbit heart.

    Science.gov (United States)

    Farkas, A S; Acsai, K; Nagy, N; Tóth, A; Fülöp, F; Seprényi, G; Birinyi, P; Nánási, P P; Forster, T; Csanády, M; Papp, J G; Varró, A; Farkas, A

    2008-05-01

    The Na(+)/Ca(2+) exchanger (NCX) may play a key role in myocardial contractility. The operation of the NCX is affected by the action potential (AP) configuration and the intracellular Na(+) concentration. This study examined the effect of selective NCX inhibition by 0.1, 0.3 and 1.0 microM SEA0400 on the myocardial contractility in the setting of different AP configurations and different intracellular Na(+) concentrations in rabbit and rat hearts. The concentration-dependent effects of SEA0400 on I(Na/Ca) were studied in rat and rabbit ventricular cardiomyocytes using a patch clamp technique. Starling curves were constructed for isolated, Langendorff-perfused rat and rabbit hearts. The cardiac sarcolemmal NCX protein densities of both species were compared by immunohistochemistry. SEA0400 inhibited I(Na/Ca) with similar efficacy in the two species; there was no difference between the inhibitions of the forward or reverse mode of the NCX in either species. SEA0400 increased the systolic and the developed pressure in the rat heart in a concentration-dependent manner, for example, 1.0 microM SEA0400 increased the maximum systolic pressures by 12% relative to the control, whereas it failed to alter the contractility in the rabbit heart. No interspecies difference was found in the cardiac sarcolemmal NCX protein densities. NCX inhibition exerted a positive inotropic effect in the rat heart, but it did not influence the contractility of the rabbit heart. This implies that the AP configuration and the intracellular Na(+) concentration may play an important role in the contractility response to NCX inhibition.

  17. A Scan for Positively Selected Genes in the Genomes of Humans and Chimpanzees

    DEFF Research Database (Denmark)

    Nielsen, Rasmus; Bustamente, Carlos; Clark, Andrew G.

    2005-01-01

    Since the divergence of humans and chimpanzees about 5 million years ago, these species have undergone a remarkable evolution with drastic divergence in anatomy and cognitive abilities. At the molecular level, despite the small overall magnitude of DNA sequence divergence, we might expect...... such evolutionary changes to leave a noticeable signature throughout the genome. We here compare 13,731 annotated genes from humans to their chimpanzee orthologs to identify genes that show evidence of positive selection. Many of the genes that present a signature of positive selection tend to be involved...

  18. Recruitment and selection for the packer position in a supermarket network

    Directory of Open Access Journals (Sweden)

    Lucila Moraes Cardoso

    2013-06-01

    Full Text Available The method of personnel recruitment and selection is a common practice to hire people in organizations. The goal of this study is to report and to reflect about this process in a supermarket chain, which operates in food and non-food retail in the state of Sao Paulo. The purpose of the present intervention was to facilitate the recruitment and selection process for the packer position. After the intervention, we noticed an improvement on the hiring process, on the working conditions and a turnover reduction in this position.

  19. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5

    Science.gov (United States)

    Huang, Yue; Yan, Jingli; Li, Qi; Li, Jiafei; Gong, Shouzhe; Zhou, Hu; Gan, Jianhua; Jiang, Hualiang; Jia, Gui-Fang; Luo, Cheng; Yang, Cai-Guang

    2015-01-01

    Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N6-methyladenosine (m6A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m6A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m6A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine. PMID:25452335

  20. Positive and purifying selection influence the evolution of doublesex in the Anastrepha fraterculus species group.

    Directory of Open Access Journals (Sweden)

    Iderval S Sobrinho

    Full Text Available The gene doublesex (dsx is considered to be under strong selective constraint along its evolutionary history because of its central role in somatic sex differentiation in insects. However, previous studies of dsx used global estimates of evolutionary rates to investigate its molecular evolution, which potentially miss signals of adaptive changes in generally conserved genes. In this work, we investigated the molecular evolution of dsx in the Anastrepha fraterculus species group (Diptera, Tephritidae, and test the hypothesis that this gene evolved solely by purifying selection using divergence-based and population-based methods. In the first approach, we compared sequences from Anastrepha and other Tephritidae with other Muscomorpha species, analyzed variation in nonsynonymous to synonymous rate ratios (dN/dS in the Tephritidae, and investigated radical and conservative changes in amino acid physicochemical properties. We show a general selective constraint on dsx, but with signs of positive selection mainly in the common region. Such changes were localized in alpha-helices previously reported to be involved in dimer formation in the OD2 domain and near the C-terminal of the OD1 domain. In the population-based approach, we amplified a region of 540 bp that spanned almost all of the region common to both sexes from 32 different sites in Brazil. We investigated patterns of selection using neutrality tests based on the frequency spectrum and locations of synonymous and nonsynonymous mutations in a haplotype network. As in the divergence-based approach, these analyses showed that dsx has evolved under an overall selective constraint, but with some events of positive selection. In contrast to previous studies, our analyses indicate that even though dsx has indeed evolved as a conserved gene, the common region of dsx has also experienced bouts of positive selection, perhaps driven by sexual selection, during its evolution.

  1. Flexible selection process based on skills applied to the communication manager position

    Directory of Open Access Journals (Sweden)

    Rita Jácome López

    2016-03-01

    Full Text Available The Communication Manager position is relevant to the reputation of an organization, because it influences through its own personal image and reputation; therefore, the selection of this manager has to be painstaking. In this paper we propose a flexible selection process based on fuzzy logic, to fit the skills of candidates for the job and to support decision making. We present two techniques:one that selects the best applicant and another one that compares candidates with an ideal constructed with information provided by Spanish managers.

  2. Selective inhibition by a synthetic hirudin peptide of fibrin-dependent thrombosis in baboons

    International Nuclear Information System (INIS)

    Cadroy, Y.; Hanson, S.R.; Harker, L.A.; Maraganore, J.M.

    1991-01-01

    To determine the importance of the thrombin substrate recognition exosite for fibrinogen binding in the formation of both arterial and venous thrombi the authors evaluated the antithrombotic effects of the tyrosine-sulfated dodecapeptide from residues 53-64 of hirudin (H peptide) in a nonhuman primate model. This peptide was studied because it inhibits thrombin cleavages of fibrinogen by simple competition without blocking enzyme catalytic-site function. When an exteriorized arteriovenous access shunt model was used in baboons (Papio anubis), thrombus formation was induced by placing a thrombogenic device made of (i) a segment of tubing coated covalently with type I collagen, which generated platelet-rich thrombi under arterial flow conditions, and (ii) two subsequent annular regions of flow expansion that produced fibrin-rich thrombi typically associated with venous valves and veins. Thrombus formation was quantified by measurements of 111 In-labeled platelet and 125 I-labeled fibrinogen deposition in both arterial-flow and venous-flow portions of the device. These finding suggest that, by competitive inhibition of fibrinogen binding to thrombin, fibrin-rich venous-type thrombus formation may be selectively prevented. This strategy may be therapeutically attractive for preserving normal platelet function when conventional anticoagulant therapy is contraindicated

  3. Inhibition of microbial metabolism in anaerobic lagoons by selected sulfonamides, tetracyclines, lincomycin, and tylosin tartrate

    Science.gov (United States)

    Loftin, Keith A.; Henny, Cynthia; Adams, Craig D.; Surampali, Rao; Mormile, Melanie R.

    2005-01-01

    Antibiotics are used to maintain healthy livestock and to promote weight gain in concentrated animal feed operations. Antibiotics rarely are metabolized completely by livestock and, thus, are often present in livestock waste and in waste-treatment lagoons. The introduction of antibiotics into anaerobic lagoons commonly used for swine waste treatment has the potential for negative impacts on lagoon performance, which relies on a consortium of microbes ranging from fermentative microorganisms to methanogens. To address this concern, the effects of eight common veterinary antibiotics on anaerobic activity were studied. Anaerobic microcosms, prepared from freshly collected lagoon slurries, were amended with individual antibiotics at 10 mg/L for the initial screening study and at 1, 5, and 25 mg/L for the dose-response study. Monitored metabolic indicators included hydrogen, methane, and volatile fatty acid concentrations as well as chemical oxygen demand. The selected antibiotics significantly inhibited methane production relative to unamended controls, thus indicating that antibiotics at concentrations commonly found in swine lagoons can negatively impact anaerobic metabolism. Additionally, historical antibiotic usage seems to be a potential factor in affecting methane production. Specifically, less inhibition of methane production was noted in samples taken from the lagoon with a history of multiple-antibiotic use.

  4. Inhibition of microbial metabolism in anaerobic lagoons by selected sulfonamides, tetracyclines, lincomycin, and tylosin tartrate.

    Science.gov (United States)

    Loftin, Keith A; Henny, Cynthia; Adams, Craig D; Surampali, Rao; Mormile, Melanie R

    2005-04-01

    Antibiotics are used to maintain healthy livestock and to promote weight gain in concentrated animal feed operations. Antibiotics rarely are metabolized completely by livestock and, thus, are often present in livestock waste and in waste-treatment lagoons. The introduction of antibiotics into anaerobic lagoons commonly used for swine waste treatment has the potential for negative impacts on lagoon performance, which relies on a consortium of microbes ranging from fermentative microorganisms to methanogens. To address this concern, the effects of eight common veterinary antibiotics on anaerobic activity were studied. Anaerobic microcosms, prepared from freshly collected lagoon slurries, were amended with individual antibiotics at 10 mg/L for the initial screening study and at 1, 5, and 25 mg/L for the dose-response study. Monitored metabolic indicators included hydrogen, methane, and volatile fatty acid concentrations as well as chemical oxygen demand. The selected antibiotics significantly inhibited methane production relative to unamended controls, thus indicating that antibiotics at concentrations commonly found in swine lagoons can negatively impact anaerobic metabolism. Additionally, historical antibiotic usage seems to be a potential factor in affecting methane production. Specifically, less inhibition of methane production was noted in samples taken from the lagoon with a history of multiple-antibiotic use.

  5. Examining Mechanical Strength Characteristics of Selective Inhibition Sintered HDPE Specimens Using RSM and Desirability Approach

    Science.gov (United States)

    Rajamani, D.; Esakki, Balasubramanian

    2017-09-01

    Selective inhibition sintering (SIS) is a powder based additive manufacturing (AM) technique to produce functional parts with an inexpensive system compared with other AM processes. Mechanical properties of SIS fabricated parts are of high dependence on various process parameters importantly layer thickness, heat energy, heater feedrate, and printer feedrate. In this paper, examining the influence of these process parameters on evaluating mechanical properties such as tensile and flexural strength using Response Surface Methodology (RSM) is carried out. The test specimens are fabricated using high density polyethylene (HDPE) and mathematical models are developed to correlate the control factors to the respective experimental design response. Further, optimal SIS process parameters are determined using desirability approach to enhance the mechanical properties of HDPE specimens. Optimization studies reveal that, combination of high heat energy, low layer thickness, medium heater feedrate and printer feedrate yielded superior mechanical strength characteristics.

  6. Disturbed prepulse inhibition in patients with schizophrenia is consequential to dysfunction of selective attention.

    Science.gov (United States)

    Scholes, Kirsty E; Martin-Iverson, Mathew T

    2010-03-01

    Controversy exists as to the cause of disturbed prepulse inhibition (PPI) in patients with schizophrenia. This study aimed to clarify the nature of PPI in schizophrenia using improved methodology. Startle and PPI were measured in 44 patients with schizophrenia and 32 controls across a range of startling stimulus intensities under two conditions, one while participants were attending to the auditory stimuli (ATTEND condition) and one while participants completed a visual task in order to ensure they were ignoring the auditory stimuli (IGNORE condition). Patients showed reduced PPI of R(MAX) (reflex capacity) and increased PPI of Hillslope (reflex efficacy) only under the INGORE condition, and failed to show the same pattern of attentional modulation of the reflex parameters as controls. In conclusion, disturbed PPI in schizophrenia appears to result from deficits in selective attention, rather than from preattentive dysfunction.

  7. Genetic signature of strong recent positive selection at interleukin-32 gene in goat

    Directory of Open Access Journals (Sweden)

    Akhtar Rasool Asif

    2017-07-01

    Full Text Available Objective Identification of the candidate genes that play key roles in phenotypic variations can provide new information about evolution and positive selection. Interleukin (IL-32 is involved in many biological processes, however, its role for the immune response against various diseases in mammals is poorly understood. Therefore, the current investigation was performed for the better understanding of the molecular evolution and the positive selection of single nucleotide polymorphisms in IL-32 gene. Methods By using fixation index (FST based method, IL-32 (9375 gene was found to be outlier and under significant positive selection with the provisional combined allocation of mean heterozygosity and FST. Using nucleotide sequences of 11 mammalian species from National Center for Biotechnology Information database, the evolutionary selection of IL-32 gene was determined using Maximum likelihood model method, through four models (M1a, M2a, M7, and M8 in Codeml program of phylogenetic analysis by maximum liklihood. Results IL-32 is detected under positive selection using the FST simulations method. The phylogenetic tree revealed that goat IL-32 was in close resemblance with sheep IL-32. The coding nucleotide sequences were compared among 11 species and it was found that the goat IL-32 gene shared identity with sheep (96.54%, bison (91.97%, camel (58.39%, cat (56.59%, buffalo (56.50%, human (56.13%, dog (50.97%, horse (54.04%, and rabbit (53.41% respectively. Conclusion This study provides evidence for IL-32 gene as under significant positive selection in goat.

  8. Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes

    DEFF Research Database (Denmark)

    Dasmeh, Pouria; Kepp, Kasper Planeta

    2017-01-01

    Positive (adaptive) selection has recently been implied in human superoxide dismutase 1 (SOD1), a highly abundant antioxidant protein with energy signaling and antiaging functions, one of very few examples of direct selection on a human protein product (exon); the molecular drivers...... and SOD1 aggregates and triggered by aging. Our study thus marks an example of direct selection for a particular chemical phenotype (high net charge and stability) in a single human protein with possible implications for the evolution of aging....... of this selection are unknown. We mapped 30 extant SOD1 sequences to the recently established mammalian species tree and inferred ancestors, key substitutions, and signatures of selection during the protein's evolution. We detected elevated substitution rates leading to great apes (Hominidae) at ~1 per 2 million...

  9. Selectivity improvement of positive photoionization ion mobility spectrometry for rapid detection of organophosphorus pesticides by switching dopant concentration.

    Science.gov (United States)

    Zhou, Qinghua; Li, Jia; Wang, Bin; Wang, Shuang; Li, Haiyang; Chen, Jinyuan

    2018-01-01

    Ion mobility spectrometry (IMS) opened a potential avenue for the rapid detection of organophosphorus pesticides (OPPs), though an improved selectivity of stand-alone IMS was still in high demand. In this study, a stand-alone positive photoionization ion mobility spectrometry (PP-IMS) apparatus was constructed for the rapid detection of OPPs with acetone as dopant. The photoionization of acetone molecules was induced by the ultraviolet irradiation to produce the reactant ions (Ac) 2 H + , which were employed to ionize the OPPs including fenthion, imidan, phosphamidon, dursban, dimethoate and isocarbophos via the proton transfer reaction. Due to the difference in proton affinity, the tested OPPs exhibited the different dopant-dependent manners. Based on this observation, the switching of dopant concentration was implemented to improve the selectivity of PP-IMS for OPPs detection. For instance, a mixture of fenthion, dursban and dimethoate was tested. By switching the concentration of doped acetone from 0.07 to 2.33 to 19.94mgL -1 , the ion peaks of fenthion and dursban were inhibited in succession, achieving the selective detection of dimethoate at last. In addition, another mixture of imidan and phosphamidon was initially detected by PP-IMS with a dose of 0.07mgL -1 acetone, indicating that their ion peaks were severely overlapped; when the concentration of doped acetone was switched to 19.94mgL -1 , the inhibition of imidan signals promised the accurate identification of phosphamidon in mixture. Finally, the PP-IMS in combination of switching dopant concentration was applied to detect the mixed fenthion, dursban and dimethoate in Chinese cabbage, demonstrating the applicability of proposed method to real samples. Copyright © 2017. Published by Elsevier B.V.

  10. MDEP Common Position CP-DICWG-07. Common position on selection and use of industrial digital devices of limited functionality

    International Nuclear Information System (INIS)

    2014-01-01

    The nuclear power industry is increasingly interested in using industrial digital devices of limited functionality in systems important to safety, but that have not been developed specifically for use in nuclear power applications. These devices should meet certain specific requirements in order to be selected and used in systems important to safety at nuclear power plants. Typically, some of these devices are found embedded in plant components and actuating devices, e.g. sensing instrumentation, motors, pumps, actuators, breakers. The Digital Instrumentation and Controls Working Group (DICWG) has agreed that a common position on this topic is warranted given the increase of use of Digital I and C in new reactor designs, its safety implications, and the need to develop a common understanding from the perspectives of regulatory authorities. This action follows the DICWG examination of the regulatory requirements of the participating members and of relevant industry standards and IAEA documents. The DICWG proposes a common position based on its recent experience with the new reactor application reviews and operating plant issues

  11. Positive selection rather than relaxation of functional constraint drives the evolution of vision during chicken domestication.

    Science.gov (United States)

    Wang, Ming-Shan; Zhang, Rong-Wei; Su, Ling-Yan; Li, Yan; Peng, Min-Sheng; Liu, He-Qun; Zeng, Lin; Irwin, David M; Du, Jiu-Lin; Yao, Yong-Gang; Wu, Dong-Dong; Zhang, Ya-Ping

    2016-05-01

    As noted by Darwin, chickens have the greatest phenotypic diversity of all birds, but an interesting evolutionary difference between domestic chickens and their wild ancestor, the Red Junglefowl, is their comparatively weaker vision. Existing theories suggest that diminished visual prowess among domestic chickens reflect changes driven by the relaxation of functional constraints on vision, but the evidence identifying the underlying genetic mechanisms responsible for this change has not been definitively characterized. Here, a genome-wide analysis of the domestic chicken and Red Junglefowl genomes showed significant enrichment for positively selected genes involved in the development of vision. There were significant differences between domestic chickens and their wild ancestors regarding the level of mRNA expression for these genes in the retina. Numerous additional genes involved in the development of vision also showed significant differences in mRNA expression between domestic chickens and their wild ancestors, particularly for genes associated with phototransduction and photoreceptor development, such as RHO (rhodopsin), GUCA1A, PDE6B and NR2E3. Finally, we characterized the potential role of the VIT gene in vision, which experienced positive selection and downregulated expression in the retina of the village chicken. Overall, our results suggest that positive selection, rather than relaxation of purifying selection, contributed to the evolution of vision in domestic chickens. The progenitors of domestic chickens harboring weaker vision may have showed a reduced fear response and vigilance, making them easier to be unconsciously selected and/or domesticated.

  12. Genome-wide detection and characterization of positive selection in human populations.

    Science.gov (United States)

    Sabeti, Pardis C; Varilly, Patrick; Fry, Ben; Lohmueller, Jason; Hostetter, Elizabeth; Cotsapas, Chris; Xie, Xiaohui; Byrne, Elizabeth H; McCarroll, Steven A; Gaudet, Rachelle; Schaffner, Stephen F; Lander, Eric S; Frazer, Kelly A; Ballinger, Dennis G; Cox, David R; Hinds, David A; Stuve, Laura L; Gibbs, Richard A; Belmont, John W; Boudreau, Andrew; Hardenbol, Paul; Leal, Suzanne M; Pasternak, Shiran; Wheeler, David A; Willis, Thomas D; Yu, Fuli; Yang, Huanming; Zeng, Changqing; Gao, Yang; Hu, Haoran; Hu, Weitao; Li, Chaohua; Lin, Wei; Liu, Siqi; Pan, Hao; Tang, Xiaoli; Wang, Jian; Wang, Wei; Yu, Jun; Zhang, Bo; Zhang, Qingrun; Zhao, Hongbin; Zhao, Hui; Zhou, Jun; Gabriel, Stacey B; Barry, Rachel; Blumenstiel, Brendan; Camargo, Amy; Defelice, Matthew; Faggart, Maura; Goyette, Mary; Gupta, Supriya; Moore, Jamie; Nguyen, Huy; Onofrio, Robert C; Parkin, Melissa; Roy, Jessica; Stahl, Erich; Winchester, Ellen; Ziaugra, Liuda; Altshuler, David; Shen, Yan; Yao, Zhijian; Huang, Wei; Chu, Xun; He, Yungang; Jin, Li; Liu, Yangfan; Shen, Yayun; Sun, Weiwei; Wang, Haifeng; Wang, Yi; Wang, Ying; Xiong, Xiaoyan; Xu, Liang; Waye, Mary M Y; Tsui, Stephen K W; Xue, Hong; Wong, J Tze-Fei; Galver, Luana M; Fan, Jian-Bing; Gunderson, Kevin; Murray, Sarah S; Oliphant, Arnold R; Chee, Mark S; Montpetit, Alexandre; Chagnon, Fanny; Ferretti, Vincent; Leboeuf, Martin; Olivier, Jean-François; Phillips, Michael S; Roumy, Stéphanie; Sallée, Clémentine; Verner, Andrei; Hudson, Thomas J; Kwok, Pui-Yan; Cai, Dongmei; Koboldt, Daniel C; Miller, Raymond D; Pawlikowska, Ludmila; Taillon-Miller, Patricia; Xiao, Ming; Tsui, Lap-Chee; Mak, William; Song, You Qiang; Tam, Paul K H; Nakamura, Yusuke; Kawaguchi, Takahisa; Kitamoto, Takuya; Morizono, Takashi; Nagashima, Atsushi; Ohnishi, Yozo; Sekine, Akihiro; Tanaka, Toshihiro; Tsunoda, Tatsuhiko; Deloukas, Panos; Bird, Christine P; Delgado, Marcos; Dermitzakis, Emmanouil T; Gwilliam, Rhian; Hunt, Sarah; Morrison, Jonathan; Powell, Don; Stranger, Barbara E; Whittaker, Pamela; Bentley, David R; Daly, Mark J; de Bakker, Paul I W; Barrett, Jeff; Chretien, Yves R; Maller, Julian; McCarroll, Steve; Patterson, Nick; Pe'er, Itsik; Price, Alkes; Purcell, Shaun; Richter, Daniel J; Sabeti, Pardis; Saxena, Richa; Schaffner, Stephen F; Sham, Pak C; Varilly, Patrick; Altshuler, David; Stein, Lincoln D; Krishnan, Lalitha; Smith, Albert Vernon; Tello-Ruiz, Marcela K; Thorisson, Gudmundur A; Chakravarti, Aravinda; Chen, Peter E; Cutler, David J; Kashuk, Carl S; Lin, Shin; Abecasis, Gonçalo R; Guan, Weihua; Li, Yun; Munro, Heather M; Qin, Zhaohui Steve; Thomas, Daryl J; McVean, Gilean; Auton, Adam; Bottolo, Leonardo; Cardin, Niall; Eyheramendy, Susana; Freeman, Colin; Marchini, Jonathan; Myers, Simon; Spencer, Chris; Stephens, Matthew; Donnelly, Peter; Cardon, Lon R; Clarke, Geraldine; Evans, David M; Morris, Andrew P; Weir, Bruce S; Tsunoda, Tatsuhiko; Johnson, Todd A; Mullikin, James C; Sherry, Stephen T; Feolo, Michael; Skol, Andrew; Zhang, Houcan; Zeng, Changqing; Zhao, Hui; Matsuda, Ichiro; Fukushima, Yoshimitsu; Macer, Darryl R; Suda, Eiko; Rotimi, Charles N; Adebamowo, Clement A; Ajayi, Ike; Aniagwu, Toyin; Marshall, Patricia A; Nkwodimmah, Chibuzor; Royal, Charmaine D M; Leppert, Mark F; Dixon, Missy; Peiffer, Andy; Qiu, Renzong; Kent, Alastair; Kato, Kazuto; Niikawa, Norio; Adewole, Isaac F; Knoppers, Bartha M; Foster, Morris W; Clayton, Ellen Wright; Watkin, Jessica; Gibbs, Richard A; Belmont, John W; Muzny, Donna; Nazareth, Lynne; Sodergren, Erica; Weinstock, George M; Wheeler, David A; Yakub, Imtaz; Gabriel, Stacey B; Onofrio, Robert C; Richter, Daniel J; Ziaugra, Liuda; Birren, Bruce W; Daly, Mark J; Altshuler, David; Wilson, Richard K; Fulton, Lucinda L; Rogers, Jane; Burton, John; Carter, Nigel P; Clee, Christopher M; Griffiths, Mark; Jones, Matthew C; McLay, Kirsten; Plumb, Robert W; Ross, Mark T; Sims, Sarah K; Willey, David L; Chen, Zhu; Han, Hua; Kang, Le; Godbout, Martin; Wallenburg, John C; L'Archevêque, Paul; Bellemare, Guy; Saeki, Koji; Wang, Hongguang; An, Daochang; Fu, Hongbo; Li, Qing; Wang, Zhen; Wang, Renwu; Holden, Arthur L; Brooks, Lisa D; McEwen, Jean E; Guyer, Mark S; Wang, Vivian Ota; Peterson, Jane L; Shi, Michael; Spiegel, Jack; Sung, Lawrence M; Zacharia, Lynn F; Collins, Francis S; Kennedy, Karen; Jamieson, Ruth; Stewart, John

    2007-10-18

    With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

  13. Mode Selection Rules for a Two-Delay System with Positive and Negative Feedback Loops

    Science.gov (United States)

    Takahashi, Kin'ya; Kobayashi, Taizo

    2018-04-01

    The mode selection rules for a two-delay system, which has negative feedback with a short delay time t1 and positive feedback with a long delay time t2, are studied numerically and theoretically. We find two types of mode selection rules depending on the strength of the negative feedback. When the strength of the negative feedback |α1| (α1 0), 2m + 1-th harmonic oscillation is well sustained in a neighborhood of t1/t2 = even/odd, i.e., relevant condition. In a neighborhood of the irrelevant condition given by t1/t2 = odd/even or t1/t2 = odd/odd, higher harmonic oscillations are observed. However, if |α1| is slightly less than α2, a different mode selection rule works, where the condition t1/t2 = odd/even is relevant and the conditions t1/t2 = odd/odd and t1/t2 = even/odd are irrelevant. These mode selection rules are different from the mode selection rule of the normal two-delay system with two positive feedback loops, where t1/t2 = odd/odd is relevant and the others are irrelevant. The two types of mode selection rules are induced by individually different mechanisms controlling the Hopf bifurcation, i.e., the Hopf bifurcation controlled by the "boosted bifurcation process" and by the "anomalous bifurcation process", which occur for |α1| below and above the threshold value αth, respectively.

  14. Organo-Selenium Coatings Inhibit Gram-Negative and Gram-Positive Bacterial Attachment to Ophthalmic Scleral Buckle Material.

    Science.gov (United States)

    Tran, Phat; Arnett, Avery; Jarvis, Courtney; Mosley, Thomas; Tran, Khien; Hanes, Rob; Webster, Dan; Mitchell, Kelly; Dominguez, Leo; Hamood, Abdul; Reid, Ted W

    2017-09-01

    Biofilm formation is a problem for solid and sponge-type scleral buckles. This can lead to complications that require removal of the buckle, and result in vision loss due to related ocular morbidity, primarily infection, or recurrent retinal detachment. We investigate the ability of a covalent organo-selenium coating to inhibit biofilm formation on a scleral buckle. Sponge and solid Labtican brand scleral buckles were coated with organo-selenium coupled to a silyation reagent. Staphylococcus aureus biofilm formation was monitored by a standard colony-forming unit assay and the confocal laser scanning microscopy, while Pseudomonas aeruginosa biofilm formation was examined by scanning electron microscopy. Stability studies were done, by soaking in phosphate buffer saline (PBS) at room temperature for 2 months. Toxicity against human corneal epithelial cell was examined by growing the cells in the presence of organo-selenium-coated scleral buckles. The organo-selenium coating inhibited biofilm formation by gram-negative and gram-positive bacteria. The buckle coatings also were shown to be fully active after soaking in PBS for 2 months. The organo-selenium coatings had no effect on the viability of human corneal epithelial cells. Organo-selenium can be used to covalently coat a scleral buckle, which is stable and inhibits biofilm formation for gram-negative and gram-positive bacteria. The organo-selenium buckle coating was stable and nontoxic to cell culture. This technology provides a means to inhibit bacterial attachment to devices attached to the eye, without damage to ocular cells.

  15. Positive Selection of γδ CTL by TL Antigen Expressed in the Thymus

    Science.gov (United States)

    Tsujimura, Kunio; Takahashi, Toshitada; Morita, Akimichi; Hasegawa-Nishiwaki, Hitomi; Iwase, Shigeru; Obata, Yuichi

    1996-01-01

    To elucidate the function of the mouse TL antigen in the thymus, we have derived two TL transgenic mouse strains by introducing Tla a -3 of A strain origin with its own promoter onto a C3H background with no expression of TL in the thymus. These transgenic mouse strains, both of which express high levels of Tlaa-3-TL antigen in their thymus, were analyzed for their T cell function with emphasis on cytotoxic T lymphocyte (CTL) generation. A T cell response against TL was induced in Tg.Tlaa-3-1, Tg.Tlaa-3-2, and control C3H mice by skin grafts from H-2K b/T3 b transgenic mice, Tg.Con.3-1, expressing T3b-TL ubiquitously. Spleen cells from mice that had rejected the T3b-TL positive skin grafts were restimulated in vitro with Tg.Con.3-1 irradiated spleen cells. In mixed lymphocyte cultures (MLC), approximately 20% and 15% of Thy-1+ T cells derived from Tg.Tlaa-3-1 and Tg.Tlaa-3-2, respectively, expressed TCRγδ, whereas almost all those from C3H expressed TCRαβ. The MLC from Tg.Tlaa-3-2 and C3H demonstrated high CTL activity against TL, while those from Tg.Tlaa-3-1 had little or none. The generation of γδ CTL recognizing TL in Tg.Tlaa-3-2, but not C3H mice, was confirmed by the establishment of CTL clones. A total of 14 γδ CTL clones were established from Tg.Tlaa-3-2, whereas none were obtained from C3H. Of the 14 γδ CTL clones, 8 were CD8+ and 6 were CD4−CD8− double negative. The CTL activity of all these clones was TL specific and inhibited by anti-TL, but not by anti-H-2 antibodies, demonstrating that they recognize TL directly without antigen presentation by H-2. The CTL activity was blocked by antibodies to TCRγδ and CD3, and also by antibodies to CD8α and CD8β in CD8+ clones, showing that the activity was mediated by TCRγδ and coreceptors. The thymic origin of these γδ CTL clones was indicated by the expression of Thy-1 and Ly-1 (CD5), and also CD8αβ heterodimers in CD8+ clones on their surfaces and by the usage of TCR Vγ4 chains in 12 of

  16. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells

    Science.gov (United States)

    Lagadinou, Eleni D.; Sach, Alexander; Callahan, Kevin; Rossi, Randall M.; Neering, Sarah J.; Minhajuddin, Mohammad; Ashton, John M.; Pei, Shanshan; Grose, Valerie; O’Dwyer, Kristen M.; Liesveld, Jane L.; Brookes, Paul S.; Becker, Michael W.; Jordan, Craig T.

    2013-01-01

    Summary Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally-defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly over-express BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation. PMID:23333149

  17. Influence of position and stimulation parameters on intracortical inhibition and facilitation in human tongue motor cortex

    DEFF Research Database (Denmark)

    Kothari, Mohit; Svensson, Peter; Nielsen, Jørgen Feldbæk

    Paired-pulse transcranial magnetic stimulation (ppTMS) can be used to assess short-interval intracortical inhibitory (SICI) and facilitatory (ICF) networks. The aim of the study was to examine the influence of body positions (recline and supine), inter-stimulus intervals (ISI) between the test...... recorded from contralateral tongue muscles. In study 1, single pulse and three ppTMS ISIs: 2, 10, 15 ms were applied 8 times each in three blocks (TS: 120%, 140% and 160% of resting motor threshold (rMT); CS: 80% of rMT) in two different body positions (recline and supine) randomly. In study 2, single...... pulse and four ppTMS ISIs: 2, 2.5, 3, 3.5 ms were applied 8 times each in randomized order in two blocks (CS: 70% and 80% of rMT; TS: 120% of rMT). There was a significant effect of body position (P=0.049), TS intensities (P

  18. Signatures of positive selection in Toll-like receptor (TLR genes in mammals

    Directory of Open Access Journals (Sweden)

    Areal Helena

    2011-12-01

    Full Text Available Abstract Background Toll-like receptors (TLRs are a major class of pattern recognition receptors (PRRs expressed in the cell surface or membrane compartments of immune and non-immune cells. TLRs are encoded by a multigene family and represent the first line of defense against pathogens by detecting foreigner microbial molecular motifs, the pathogen-associated molecular patterns (PAMPs. TLRs are also important by triggering the adaptive immunity in vertebrates. They are characterized by the presence of leucine-rich repeats (LRRs in the ectodomain, which are associated with the PAMPs recognition. The direct recognition of different pathogens by TLRs might result in different evolutionary adaptations important to understand the dynamics of the host-pathogen interplay. Ten mammal TLR genes, viral (TLR3, 7, 8, 9 and non-viral (TLR1-6, 10, were selected to identify signatures of positive selection that might have been imposed by interacting pathogens and to clarify if viral and non-viral TLRs might display different patterns of molecular evolution. Results By using Maximum Likelihood approaches, evidence of positive selection was found in all the TLRs studied. The number of positively selected codons (PSC ranged between 2-26 codons (0.25%-2.65% with the non-viral TLR4 as the receptor with higher percentage of positively selected codons (2.65%, followed by the viral TLR8 (2.50%. The results indicated that viral and non-viral TLRs are similarly under positive selection. Almost all TLRs have at least one PSC located in the LRR ectodomain which underlies the importance of the pathogen recognition by this region. Conclusions Our results are not in line with previous studies on primates and birds that identified more codons under positive selection in non-viral TLRs. This might be explained by the fact that both primates and birds are homogeneous groups probably being affected by only a restricted number of related viruses with equivalent motifs to be

  19. Determination of the energetics of the UDP-glucose pyrophosphorylase reaction by positional isotope exchange inhibition

    International Nuclear Information System (INIS)

    Hester, L.S.; Raushel, F.M.

    1987-01-01

    A method has been developed for obtaining qualitative information about enzyme-catalyzed reactions by measuring the inhibitory effects of added substrates on positional isotope exchange rates. It has been demonstrated for ordered kinetic mechanisms that an increase in the concentration of the second substrate to add to the enzyme will result in a linear increase in the ratio of the chemical and positional isotope exchange rates. The slopes and intercepts from these plots can be used to determine the partitioning ratios of binary and ternary enzyme complexes. The method has been applied to the reaction catalyzed by UDP-glucose pyrophosphorylase. A positional isotope exchange reaction was measured within oxygen-18-labeled UTP as a function of variable glucose 1-phosphate concentration in the forward reaction. In the reverse reaction, a positional isotope exchange reaction was measured within oxygen-18-labeled UDP-glucose as a function of increasing pyrophosphate concentration. The results have been interpreted to indicate that the interconversion of the ternary central complexes is fast relative to product dissociation in either direction. In the forward direction, the release of UDP-glucose is slower than the release of pyrophosphate. The release of glucose 1-phosphate is slower than the release of UTP in the reverse reaction

  20. Sardinians genetic background explained by runs of homozygosity and genomic regions under positive selection.

    Directory of Open Access Journals (Sweden)

    Cornelia Di Gaetano

    Full Text Available The peculiar position of Sardinia in the Mediterranean sea has rendered its population an interesting biogeographical isolate. The aim of this study was to investigate the genetic population structure, as well as to estimate Runs of Homozygosity and regions under positive selection, using about 1.2 million single nucleotide polymorphisms genotyped in 1077 Sardinian individuals. Using four different methods--fixation index, inflation factor, principal component analysis and ancestry estimation--we were able to highlight, as expected for a genetic isolate, the high internal homogeneity of the island. Sardinians showed a higher percentage of genome covered by RoHs>0.5 Mb (F(RoH%0.5 when compared to peninsular Italians, with the only exception of the area surrounding Alghero. We furthermore identified 9 genomic regions showing signs of positive selection and, we re-captured many previously inferred signals. Other regions harbor novel candidate genes for positive selection, like TMEM252, or regions containing long non coding RNA. With the present study we confirmed the high genetic homogeneity of Sardinia that may be explained by the shared ancestry combined with the action of evolutionary forces.

  1. Gene transfer preferentially selects MHC class I positive tumour cells and enhances tumour immunogenicity.

    Science.gov (United States)

    Hacker, Ulrich T; Schildhauer, Ines; Barroso, Margarita Céspedes; Kofler, David M; Gerner, Franz M; Mysliwietz, Josef; Buening, Hildegard; Hallek, Michael; King, Susan B S

    2006-05-01

    The modulated expression of MHC class I on tumour tissue is well documented. Although the effect of MHC class I expression on the tumorigenicity and immunogenicity of MHC class I negative tumour cell lines has been rigorously studied, less is known about the validity of gene transfer and selection in cell lines with a mixed MHC class I phenotype. To address this issue we identified a C26 cell subline that consists of distinct populations of MHC class I (H-2D/K) positive and negative cells. Transient transfection experiments using liposome-based transfer showed a lower transgene expression in MHC class I negative cells. In addition, MHC class I negative cells were more sensitive to antibiotic selection. This led to the generation of fully MHC class I positive cell lines. In contrast to C26 cells, all transfectants were rejected in vivo and induced protection against the parental tumour cells in rechallenge experiments. Tumour cell specificity of the immune response was demonstrated in in vitro cytokine secretion and cytotoxicity assays. Transfectants expressing CD40 ligand and hygromycin phosphotransferase were not more immunogenic than cells expressing hygromycin resistance alone. We suggest that the MHC class I positive phenotype of the C26 transfectants had a bearing on their immunogenicity, because selected MHC class I positive cells were more immunogenic than parental C26 cells and could induce specific anti-tumour immune responses. These data demonstrate that the generation of tumour cell transfectants can lead to the selection of subpopulations that show an altered phenotype compared to the parental cell line and display altered immunogenicity independent of selection marker genes or other immune modulatory genes. Our results show the importance of monitoring gene transfer in the whole tumour cell population, especially for the evaluation of in vivo therapies targeted to heterogeneous tumour cell populations.

  2. Evidence for positive selection on the leptin gene in Cetacea and Pinnipedia.

    Directory of Open Access Journals (Sweden)

    Li Yu

    Full Text Available The leptin gene has received intensive attention and scientific investigation for its importance in energy homeostasis and reproductive regulation in mammals. Furthermore, study of the leptin gene is of crucial importance for public health, particularly for its role in obesity, as well as for other numerous physiological roles that it plays in mammals. In the present work, we report the identification of novel leptin genes in 4 species of Cetacea, and a comparison with 55 publicly available leptin sequences from mammalian genome assemblies and previous studies. Our study provides evidence for positive selection in the suborder Odontoceti (toothed whales of the Cetacea and the family Phocidae (earless seals of the Pinnipedia. We also detected positive selection in several leptin gene residues in these two lineages. To test whether leptin and its receptor evolved in a coordinated manner, we analyzed 24 leptin receptor gene (LPR sequences from available mammalian genome assemblies and other published data. Unlike the case of leptin, our analyses did not find evidence of positive selection for LPR across the Cetacea and Pinnipedia lineages. In line with this, positively selected sites identified in the leptin genes of these two lineages were located outside of leptin receptor binding sites, which at least partially explains why co-evolution of leptin and its receptor was not observed in the present study. Our study provides interesting insights into current understanding of the evolution of mammalian leptin genes in response to selective pressures from life in an aquatic environment, and leads to a hypothesis that new tissue specificity or novel physiologic functions of leptin genes may have arisen in both odontocetes and phocids. Additional data from other species encompassing varying life histories and functional tests of the adaptive role of the amino acid changes identified in this study will help determine the factors that promote the adaptive

  3. Positive selection in the SLC11A1 gene in the family Equidae.

    Science.gov (United States)

    Bayerova, Zuzana; Janova, Eva; Matiasovic, Jan; Orlando, Ludovic; Horin, Petr

    2016-05-01

    Immunity-related genes are a suitable model for studying effects of selection at the genomic level. Some of them are highly conserved due to functional constraints and purifying selection, while others are variable and change quickly to cope with the variation of pathogens. The SLC11A1 gene encodes a transporter protein mediating antimicrobial activity of macrophages. Little is known about the patterns of selection shaping this gene during evolution. Although it is a typical evolutionarily conserved gene, functionally important polymorphisms associated with various diseases were identified in humans and other species. We analyzed the genomic organization, genetic variation, and evolution of the SLC11A1 gene in the family Equidae to identify patterns of selection within this important gene. Nucleotide SLC11A1 sequences were shown to be highly conserved in ten equid species, with more than 97 % sequence identity across the family. Single nucleotide polymorphisms (SNPs) were found in the coding and noncoding regions of the gene. Seven codon sites were identified to be under strong purifying selection. Codons located in three regions, including the glycosylated extracellular loop, were shown to be under diversifying selection. A 3-bp indel resulting in a deletion of the amino acid 321 in the predicted protein was observed in all horses, while it has been maintained in all other equid species. This codon comprised in an N-glycosylation site was found to be under positive selection. Interspecific variation in the presence of predicted N-glycosylation sites was observed.

  4. Evidence of Positive Selection of Aquaporins Genes from Pontoporia blainvillei during the Evolutionary Process of Cetaceans.

    Directory of Open Access Journals (Sweden)

    Simone Lima São Pedro

    Full Text Available Marine mammals are well adapted to their hyperosmotic environment. Several morphological and physiological adaptations for water conservation and salt excretion are known to be present in cetaceans, being responsible for regulating salt balance. However, most previous studies have focused on the unique renal physiology of marine mammals, but the molecular bases of these mechanisms remain poorly explored. Many genes have been identified to be involved in osmotic regulation, including the aquaporins. Considering that aquaporin genes were potentially subject to strong selective pressure, the aim of this study was to analyze the molecular evolution of seven aquaporin genes (AQP1, AQP2, AQP3, AQP4, AQP6, AQP7, and AQP9 comparing the lineages of cetaceans and terrestrial mammals.Our results demonstrated strong positive selection in cetacean-specific lineages acting only in the gene for AQP2 (amino acids 23, 83, 107,179, 180, 181, 182, whereas no selection was observed in terrestrial mammalian lineages. We also analyzed the changes in the 3D structure of the aquaporin 2 protein. Signs of strong positive selection in AQP2 sites 179, 180, 181, and 182 were unexpectedly identified only in the baiji lineage, which was the only river dolphin examined in this study. Positive selection in aquaporins AQP1 (45, AQP4 (74, AQP7 (342, 343, 356 was detected in cetaceans and artiodactyls, suggesting that these events are not related to maintaining water and electrolyte homeostasis in seawater.Our results suggest that the AQP2 gene might reflect different selective pressures in maintaining water balance in cetaceans, contributing to the passage from the terrestrial environment to the aquatic. Further studies are necessary, especially those including other freshwater dolphins, who exhibit osmoregulatory mechanisms different from those of marine cetaceans for the same essential task of maintaining serum electrolyte balance.

  5. Selective inhibition of Sarcocystis neurona calcium-dependent protein kinase 1 for equine protozoal myeloencephalitis therapy.

    Science.gov (United States)

    Ojo, Kayode K; Dangoudoubiyam, Sriveny; Verma, Shiv K; Scheele, Suzanne; DeRocher, Amy E; Yeargan, Michelle; Choi, Ryan; Smith, Tess R; Rivas, Kasey L; Hulverson, Matthew A; Barrett, Lynn K; Fan, Erkang; Maly, Dustin J; Parsons, Marilyn; Dubey, Jitender P; Howe, Daniel K; Van Voorhis, Wesley C

    2016-12-01

    Sarcocystis neurona is the most frequent cause of equine protozoal myeloencephalitis, a debilitating neurological disease of horses that can be difficult to treat. We identified SnCDPK1, the S. neurona homologue of calcium-dependent protein kinase 1 (CDPK1), a validated drug target in Toxoplasma gondii. SnCDPK1 shares the glycine "gatekeeper" residue of the well-characterized T. gondii enzyme, which allows the latter to be targeted by bumped kinase inhibitors. This study presents detailed molecular and phenotypic evidence that SnCDPK1 can be targeted for rational drug development. Recombinant SnCDPK1 was tested against four bumped kinase inhibitors shown to potently inhibit both T. gondii (Tg) CDPK1 and T. gondii tachyzoite growth. SnCDPK1 was inhibited by low nanomolar concentrations of these BKIs and S. neurona growth was inhibited at 40-120nM concentrations. Thermal shift assays confirmed these bumped kinase inhibitors bind CDPK1 in S. neurona cell lysates. Treatment with bumped kinase inhibitors before or after invasion suggests that bumped kinase inhibitors interfere with S. neurona mammalian host cell invasion in the 0.5-2.5μM range but interfere with intracellular division at 2.5μM. In vivo proof-of-concept experiments were performed in a murine model of S. neurona infection. The experimental infected groups treated for 30days with compound BKI-1553 (n=10 mice) had no signs of disease, while the infected control group had severe signs and symptoms of infection. Elevated antibody responses were found in 100% of control infected animals, but only 20% of BKI-1553 treated infected animals. Parasites were found in brain tissues of 100% of the control infected animals, but only in 10% of the BKI-1553 treated animals. The bumped kinase inhibitors used in these assays have been chemically optimized for potency, selectivity and pharmacokinetic properties, and hence are good candidates for treatment of equine protozoal myeloencephalitis. Copyright © 2016

  6. Influence of position and stimulation parameters on intracortical inhibition and facilitation in human tongue motor cortex

    DEFF Research Database (Denmark)

    Kothari, Mohit; Svensson, Peter; Nielsen, Jørgen Feldbæk

    2014-01-01

    Paired-pulse transcranial magnetic stimulation (ppTMS) can be used to assess short-interval intracortical inhibitory (SICI) and facilitatory (ICF) networks. Many methodological parameters may however influence the outcome. The aim of the study was to examine the influence of body positions (recline...... motor cortex and motor evoked potentials (MEPs) were recorded from contralateral tongue muscles. In study 1, single pulse and three ppTMS ISIs: 2, 10, 15 ms were applied 8 times each in three blocks (TS: 120%, 140% and 160% of resting motor threshold (rMT); CS: 80% of rMT) in two different body...... positions (recline and supine) randomly. In study 2, single pulse and four ppTMS ISIs: 2, 2.5, 3, 3.5 ms were applied 8 times each in randomized order in two blocks (CS: 70% and 80% of rMT; TS: 120% of rMT). There was a significant effect of body position (P=0.049), TS intensities (P

  7. Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha

    International Nuclear Information System (INIS)

    Jang, Eun Hyang; Jang, Soon Young; Cho, In-Hye; Hong, Darong; Jung, Bom; Park, Min-Ju; Kim, Jong-Ho

    2015-01-01

    Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. - Highlights: • Hispolon decreased ERα expression at both mRNA and protein levels. • Hispolon decreased ERα transcriptional activity. • Hispolon treatment inhibited expression of ERα target gene pS2. • Shikonin is a candidate chemotherapeutic target in the treatment of human breast cancer

  8. Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Eun Hyang; Jang, Soon Young; Cho, In-Hye [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Hong, Darong [Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Jung, Bom; Park, Min-Ju [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Kim, Jong-Ho, E-mail: jonghokim@khu.ac.kr [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of)

    2015-08-07

    Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. - Highlights: • Hispolon decreased ERα expression at both mRNA and protein levels. • Hispolon decreased ERα transcriptional activity. • Hispolon treatment inhibited expression of ERα target gene pS2. • Shikonin is a candidate chemotherapeutic target in the treatment of human breast cancer.

  9. Inhibition selectivity of grapefruit juice components on human cytochromes P450.

    Science.gov (United States)

    Tassaneeyakul, W; Guo, L Q; Fukuda, K; Ohta, T; Yamazoe, Y

    2000-06-15

    Five compounds including furanocoumarin monomers (bergamottin, 6', 7'-dihydroxybergamottin (DHB)), furanocoumarin dimers (4-¿¿6-hydroxy-71-¿(1-hydroxy-1-methyl)ethyl-4-methyl-6-(7-oxo-7H- furo¿3,2-g1benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimethyl- 2-octenyl]oxy]-7H-furo[3,2-g]¿1benzopyran-7-one (GF-I-1) and 4-¿¿6-hydroxy-7¿¿4-methyl-1-(1-methylethenyl)-6-(7-oxo-7H-furo¿3, 2-g1benzopyran-4-yl)-4-hexenylŏxy-3, 7-dimethyl-2-octenylŏxy-7H-furo¿3,2-g1benzopyran-7-one (GF-I-4)), and a sesquiterpene nootkatone have been isolated from grapefruit juice and screened for their inhibitory effects toward human cytochrome P450 (P450) forms using selective substrate probes. Addition of ethyl acetate extract of grapefruit juice into an incubation mixture resulted in decreased activities of CYP3A4, CYP1A2, CYP2C9, and CYP2D6. All four furanocoumarins clearly inhibited CYP3A4-catalyzed nifedipine oxidation in concentration- and time-dependent manners, suggesting that these compounds are mechanism-based inhibitors of CYP3A4. Of the furanocoumarins investigated, furanocoumarin dimers, GF-I-1 and GF-I-4, were the most potent inhibitors of CYP3A4. Inhibitor concentration required for half-maximal rate of inactivation (K(I)) values for bergamottin, DHB, GF-I-1, and GF-I-4 were calculated, respectively, as 40.00, 5. 56, 0.31, and 0.13 microM, whereas similar values were observed on their inactivation rate constant at infinite concentration of inhibitor (k(inact), 0.05-0.08 min(-1)). Apparent selectivity toward CYP3A4 does occur with the furanocoumarin dimers. In contrast, bergamottin showed rather stronger inhibitory effect on CYP1A2, CYP2C9, CYP2C19, and CYP2D6 than on CYP3A4. DHB inhibited CYP3A4 and CYP1A2 activities at nearly equivalent potencies. Among P450 forms investigated, CYP2E1 was the least sensitive to the inhibitory effect of furanocoumarin components. A sesquiterpene nootkatone has no significant effect on P450 activities investigated except for CYP2A6 and CYP2C19

  10. Dynamic modulation of corticospinal excitability and short-latency afferent inhibition during onset and maintenance phase of selective finger movement.

    Science.gov (United States)

    Cho, Hyun Joo; Panyakaew, Pattamon; Thirugnanasambandam, Nivethida; Wu, Tianxia; Hallett, Mark

    2016-06-01

    During highly selective finger movement, corticospinal excitability is reduced in surrounding muscles at the onset of movement but this phenomenon has not been demonstrated during maintenance of movement. Sensorimotor integration may play an important role in selective movement. We sought to investigate how corticospinal excitability and short-latency afferent inhibition changes in active and surrounding muscles during onset and maintenance of selective finger movement. Using transcranial magnetic stimulation (TMS) and paired peripheral stimulation, input-output recruitment curve and short-latency afferent inhibition (SAI) were measured in the first dorsal interosseus and abductor digiti minimi muscles during selective index finger flexion. Motor surround inhibition was present only at the onset phase, but not at the maintenance phase of movement. SAI was reduced at onset but not at the maintenance phase of movement in both active and surrounding muscles. Our study showed dynamic changes in corticospinal excitability and sensorimotor modulation for active and surrounding muscles in different movement states. SAI does not appear to contribute to motor surround inhibition at the movement onset phase. Also, there seems to be different inhibitory circuit(s) other than SAI for the movement maintenance phase in order to delineate the motor output selectively when corticospinal excitability is increased in both active and surrounding muscles. This study enhances our knowledge of dynamic changes in corticospinal excitability and sensorimotor interaction in different movement states to understand normal and disordered movements. Published by Elsevier Ireland Ltd.

  11. Nasal continuous positive airway pressure inhibits gastroesophageal reflux in newborn lambs.

    Directory of Open Access Journals (Sweden)

    Djamal Djeddi

    Full Text Available BACKGROUND: Using esophageal pHmetry, nasal CPAP (nCPAP has been shown to decrease acid gastroesophageal reflux (GER in adult humans. Although both GER (mainly non-acid and nCPAP use are very frequent in newborns, the effect of nCPAP on GER in early life is unknown. Having recently shown that the newborn lamb is a unique model for studying neonatal GER, our main objective was to assess the effect of nCPAP on GER in newborn lambs. METHODS: Eight newborn lambs, aged 2-3 days, were studied. Continuous esophageal pH-Impedance monitoring and polysomnography were performed for six hours during both spontaneous breathing and nCPAP application at 6 cmH2O (nCPAP(6, in a randomized order. Results were compared in the two experimental conditions, as well as without CPAP during the following 6 hours. RESULTS: i nCPAP(6 virtually abolished GER [mean ± SD reflux number for 6 h = 9.1 ± 8.6 without nCPAP(6 vs. 0.6 ± 1 with nCPAP(6, P<0.05]; ii GER number was also reduced during the 6 h-period following nCPAP(6 application (18 ± 16 without nCPAP(6 vs. 7 ± 8.1 with nCPAP(6, P<0.05; iii nCPAP(6 decreased the depth and duration of lower esophageal sphincter relaxation. CONCLUSIONS: nCPAP inhibits GER in the newborn lamb. Further clinical studies using different levels of nasal CPAP are needed to confirm this result in human infants.

  12. Effect of antiviral treatment and host susceptibility on positive selection in hepatitis C virus (HCV).

    Science.gov (United States)

    Jiménez-Hernández, Nuria; Sentandreu, Vicente; Castro, José A; Torres-Puente, Manuela; Bracho, Alma; García-Robles, Inmaculada; Ortega, Enrique; Del Olmo, Juan; Carnicer, Fernando; González-Candelas, Fernando; Moya, Andrés

    2008-02-01

    We have conducted a large sequence study of the E1-E2 and NS5A regions of the HCV, subtypes 1a and b, both in patients previously treated with interferon, and untreated patients, who later responded, or not, to a combination therapy based on interferon plus ribavirin. We have examined the role played by the number of positively selected sites on disease progression and its relationship with several variables such as patients' age, sex and their risk of acquiring the disease. We have detected three groups of patients that respond or not to combination therapy: responders of intermediate age, older non-responders and young non-responders, they possess an increasing average number of positively selected sites in the E1-E2 region, respectively. We conclude that the host's genetic factors play an important role in whether the disease is contained or becomes chronic.

  13. A synbio approach for selection of highly expressed gene variants in Gram-positive bacteria

    DEFF Research Database (Denmark)

    Ferro, Roberto; Rennig, Maja; Hernández Rollán, Cristina

    2018-01-01

    with a long history in food fermentation. We have developed a synbio approach for increasing gene expression in two Gram-positive bacteria. First of all, the gene of interest was coupled to an antibiotic resistance gene to create a growth-based selection system. We then randomised the translation initiation...... region (TIR) preceding the gene of interest and selected clones that produced high protein titres, as judged by their ability to survive on high concentrations of antibiotic. Using this approach, we were able to significantly increase production of two industrially relevant proteins; sialidase in B....... subtilis and tyrosine ammonia lyase in L. lactis. Gram-positive bacteria are widely used to produce industrial enzymes. High titres are necessary to make the production economically feasible. The synbio approach presented here is a simple and inexpensive way to increase protein titres, which can be carried...

  14. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits adhesion of human endometriotic epithelial and stromal cells through suppression of integrin-mediated mechanisms.

    Science.gov (United States)

    Lee, JeHoon; Banu, Sakhila K; Burghardt, Robert C; Starzinski-Powitz, Anna; Arosh, Joe A

    2013-03-01

    Endometriosis is a chronic gynecological disease of reproductive age women characterized by the presence of functional endometrial tissues outside the uterine cavity. Interactions between the endometriotic cells and the peritoneal extracellular matrix proteins (ECM) are crucial mechanisms that allow adhesion of the endometriotic cells into peritoneal mesothelia. Prostaglandin E2 (PGE2) plays an important role in the pathogenesis of endometriosis. In previous studies, we have reported that selective inhibition of PGE2 receptors PTGER2 and PTGER4 decreases survival and invasion of human endometriotic epithelial and stromal cells through multiple mechanisms. Results of the present study indicates that selective inhibition of PTGER2- and PTGER4-mediated PGE2 signaling 1) decreases the expression and/or activity of specific integrin receptor subunits Itgb1 (beta1) and Itgb3 (beta3) but not Itgb5 (beta5), Itga1 (alpha1), Itga2 (alpha2), Itga5 (alpha5), and Itgav (alphav); 2) decreases integrin-signaling components focal adhesion kinase or protein kinase 2 (PTK2) and talin proteins; 3) inhibits interactions between Itgb1/Itgb3 subunits, PTK2, and talin and PTGER2/PTGER4 proteins through beta-arrestin-1 and Src kinase protein complex in human endometriotic epithelial cells 12Z and stromal cells 22B; and 4) decreases adhesion of 12Z and 22B cells to ECM collagen I, collagen IV, fibronectin, and vitronectin in a substrate-specific manner. These novel findings provide an important molecular framework for further evaluation of selective inhibition of PTGER2 and PTGER4 as potential nonsteroidal therapy to expand the spectrum of currently available treatment options for endometriosis in child-bearing age women.

  15. Selective albumin-binding surfaces modified with a thrombin-inhibiting peptide.

    Science.gov (United States)

    Freitas, Sidónio C; Maia, Sílvia; Figueiredo, Ana C; Gomes, Paula; Pereira, Pedro J B; Barbosa, Mário A; Martins, M Cristina L

    2014-03-01

    Blood-contacting medical devices have been associated with severe clinical complications, such as thrombus formation, triggered by the activation of the coagulation cascade due to the adsorption of certain plasma proteins on the surface of biomaterials. Hence, the coating of such surfaces with antithrombotic agents has been used to increase biomaterial haemocompatibility. Biomaterial-induced clotting may also be decreased by albumin adsorption from blood plasma in a selective and reversible way, since this protein is not involved in the coagulation cascade. In this context, this paper reports that the immobilization of the thrombin inhibitor D-Phe-Pro-D-Arg-D-Thr-CONH2 (fPrt) onto nanostructured surfaces induces selective and reversible adsorption of albumin, delaying the clotting time when compared to peptide-free surfaces. fPrt, synthesized with two glycine residues attached to the N-terminus (GGfPrt), was covalently immobilized onto self-assembled monolayers (SAMs) having different ratios of carboxylate-hexa(ethylene glycol)- and tri(ethylene glycol)-terminated thiols (EG6-COOH/EG3) that were specifically designed to control GGfPrt orientation, exposure and density at the molecular level. In solution, GGfPrt was able to inactivate the enzymatic activity of thrombin and to delay plasma clotting time in a concentration-dependent way. After surface immobilization, and independently of its concentration, GGfPrt lost its selectivity to thrombin and its capacity to inhibit thrombin enzymatic activity against the chromogenic substrate n-p-tosyl-Gly-Pro-Arg-p-nitroanilide. Nevertheless, surfaces with low concentrations of GGfPrt could delay the capacity of adsorbed thrombin to cleave fibrinogen. In contrast, GGfPrt immobilized in high concentrations was found to induce the procoagulant activity of the adsorbed thrombin. However, all surfaces containing GGfPrt have a plasma clotting time similar to the negative control (empty polystyrene wells), showing resistance to

  16. De novo transcriptome assembly and positive selection analysis of an individual deep-sea fish.

    Science.gov (United States)

    Lan, Yi; Sun, Jin; Xu, Ting; Chen, Chong; Tian, Renmao; Qiu, Jian-Wen; Qian, Pei-Yuan

    2018-05-24

    High hydrostatic pressure and low temperatures make the deep sea a harsh environment for life forms. Actin organization and microtubules assembly, which are essential for intracellular transport and cell motility, can be disrupted by high hydrostatic pressure. High hydrostatic pressure can also damage DNA. Nucleic acids exposed to low temperatures can form secondary structures that hinder genetic information processing. To study how deep-sea creatures adapt to such a hostile environment, one of the most straightforward ways is to sequence and compare their genes with those of their shallow-water relatives. We captured an individual of the fish species Aldrovandia affinis, which is a typical deep-sea inhabitant, from the Okinawa Trough at a depth of 1550 m using a remotely operated vehicle (ROV). We sequenced its transcriptome and analyzed its molecular adaptation. We obtained 27,633 protein coding sequences using an Illumina platform and compared them with those of several shallow-water fish species. Analysis of 4918 single-copy orthologs identified 138 positively selected genes in A. affinis, including genes involved in microtubule regulation. Particularly, functional domains related to cold shock as well as DNA repair are exposed to positive selection pressure in both deep-sea fish and hadal amphipod. Overall, we have identified a set of positively selected genes related to cytoskeleton structures, DNA repair and genetic information processing, which shed light on molecular adaptation to the deep sea. These results suggest that amino acid substitutions of these positively selected genes may contribute crucially to the adaptation of deep-sea animals. Additionally, we provide a high-quality transcriptome of a deep-sea fish for future deep-sea studies.

  17. Growth of non-Campylobacter, oxidase-positive bacteria on selective Campylobacter agar.

    OpenAIRE

    Moskowitz, L B; Chester, B

    1982-01-01

    A total of 67 oxidase-positive, gram-negative bacteria were tested for growth on selective Campylobacter agar (Blaser formulation, BBL Microbiology Systems, Cockeysville, Md.) at 42 degrees C under microaerophilic conditions. Although the growth of most of these bacteria was prevented, all strains of Achromobacter xylosoxidans, Pseudomonas aeruginosa, Pseudomonas putrefaciens, Pseudomonas alcaligenes, and Pseudomonas pseudoalcaligenes grew as well as Campylobacter fetus subsp. jejuni.

  18. DISCRIMINATIVE MODEL OF CERTAIN MOTOR INDICATORS OF FOOTBALL PLAYERS AS SELECTION CRITERIA FOR TEAM POSITION

    Directory of Open Access Journals (Sweden)

    Goran Vučković

    2013-07-01

    Full Text Available Well-designed and implemented selection is one of the important prerequisites for achieving the expected results in the modern competitive sport at all levels. The aim of this work was to determine how the selection was made for Serbian League players, on the basis of their certain motor parameters and the positions in the team. A sample of 25 senior players of a football team competing in the Serbian League is divided into four sub-samples, based on team positions. For assessment of motor characteristics following tests were used: long jump (LJ, Abalac test (AT; 10 seconds push-ups (PU, 30 seconds trunk bends (TB, 20 meter flying start running (20FSR, 20 meter high start running (20HSR, 50 meter high start running (50HSR and Cooper test (CT . Based on the obtained results it can be concluded that there are significant differences for variable 20FSR and variable CT (F = 3754, 9835, p = .027, .000, respectively. Three canonical discriminant functions were singled out, where the first explained even 84.6%, the second 14.5% and the third only 1% of the total variance, or in summary first two functions explained 99.0% of the variance. It can be concluded that the selected players, in terms of the position in the team, distinguished first by performing on the Cooper test, followed by the result of 20 meter flying start running, 20 meter high start running, 50 meter high start running, trunk bends, and finally by Abalac test, push-ups and long jump. Observed as a function of certain motor characteristics, it could be concluded that in the selection of players in terms of the playing position confidence level was 72.0% in general level, with the most reliable for goalkeepers (100%, midfielders (71.4% and defensive players (70.0%, while the smallest was at strikers (50%.

  19. High amino acid diversity and positive selection at a putative coral immunity gene (tachylectin-2

    Directory of Open Access Journals (Sweden)

    Hellberg Michael E

    2010-05-01

    Full Text Available Abstract Background Genes involved in immune functions, including pathogen recognition and the activation of innate defense pathways, are among the most genetically variable known, and the proteins that they encode are often characterized by high rates of amino acid substitutions, a hallmark of positive selection. The high levels of variation characteristic of immunity genes make them useful tools for conservation genetics. To date, highly variable immunity genes have yet to be found in corals, keystone organisms of the world's most diverse marine ecosystem, the coral reef. Here, we examine variation in and selection on a putative innate immunity gene from Oculina, a coral genus previously used as a model for studies of coral disease and bleaching. Results In a survey of 244 Oculina alleles, we find high nonsynonymous variation and a signature of positive selection, consistent with a putative role in immunity. Using computational protein structure prediction, we generate a structural model of the Oculina protein that closely matches the known structure of tachylectin-2 from the Japanese horseshoe crab (Tachypleus tridentatus, a protein with demonstrated function in microbial recognition and agglutination. We also demonstrate that at least three other genera of anthozoan cnidarians (Acropora, Montastrea and Nematostella possess proteins structurally similar to tachylectin-2. Conclusions Taken together, the evidence of high amino acid diversity, positive selection and structural correspondence to the horseshoe crab tachylectin-2 suggests that this protein is 1 part of Oculina's innate immunity repertoire, and 2 evolving adaptively, possibly under selective pressure from coral-associated microorganisms. Tachylectin-2 may serve as a candidate locus to screen coral populations for their capacity to respond adaptively to future environmental change.

  20. Positive selection and propeptide repeats promote rapid interspecific divergence of a gastropod sperm protein.

    Science.gov (United States)

    Hellberg, M E; Moy, G W; Vacquier, V D

    2000-03-01

    Male-specific proteins have increasingly been reported as targets of positive selection and are of special interest because of the role they may play in the evolution of reproductive isolation. We report the rapid interspecific divergence of cDNA encoding a major acrosomal protein of unknown function (TMAP) of sperm from five species of teguline gastropods. A mitochondrial DNA clock (calibrated by congeneric species divided by the Isthmus of Panama) estimates that these five species diverged 2-10 MYA. Inferred amino acid sequences reveal a propeptide that has diverged rapidly between species. The mature protein has diverged faster still due to high nonsynonymous substitution rates (> 25 nonsynonymous substitutions per site per 10(9) years). cDNA encoding the mature protein (89-100 residues) shows evidence of positive selection (Dn/Ds > 1) for 4 of 10 pairwise species comparisons. cDNA and predicted secondary-structure comparisons suggest that TMAP is neither orthologous nor paralogous to abalone lysin, and thus marks a second, phylogenetically independent, protein subject to strong positive selection in free-spawning marine gastropods. In addition, an internal repeat in one species (Tegula aureotincta) produces a duplicated cleavage site which results in two alternatively processed mature proteins differing by nine amino acid residues. Such alternative processing may provide a mechanism for introducing novel amino acid sequence variation at the amino-termini of proteins. Highly divergent TMAP N-termini from two other tegulines (Tegula regina and Norrisia norrisii) may have originated by such a mechanism.

  1. Positive Selection Driving Cytoplasmic Genome Evolution of the Medicinally Important Ginseng Plant Genus Panax.

    Science.gov (United States)

    Jiang, Peng; Shi, Feng-Xue; Li, Ming-Rui; Liu, Bao; Wen, Jun; Xiao, Hong-Xing; Li, Lin-Feng

    2018-01-01

    Panax L. (the ginseng genus) is a shade-demanding group within the family Araliaceae and all of its species are of crucial significance in traditional Chinese medicine. Phylogenetic and biogeographic analyses demonstrated that two rounds of whole genome duplications accompanying with geographic and ecological isolations promoted the diversification of Panax species. However, contributions of the cytoplasmic genomes to the adaptive evolution of Panax species remained largely uninvestigated. In this study, we sequenced the chloroplast and mitochondrial genomes of 11 accessions belonging to seven Panax species. Our results show that heterogeneity in nucleotide substitution rate is abundant in both of the two cytoplasmic genomes, with the mitochondrial genome possessing more variants at the total level but the chloroplast showing higher sequence polymorphisms at the genic regions. Genome-wide scanning of positive selection identified five and 12 genes from the chloroplast and mitochondrial genomes, respectively. Functional analyses further revealed that these selected genes play important roles in plant development, cellular metabolism and adaptation. We therefore conclude that positive selection might be one of the potential evolutionary forces that shaped nucleotide variation pattern of these Panax species. In particular, the mitochondrial genes evolved under stronger selective pressure compared to the chloroplast genes.

  2. Red Queen Processes Drive Positive Selection on Major Histocompatibility Complex (MHC Genes.

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    Maciej Jan Ejsmond

    2015-11-01

    Full Text Available Major Histocompatibility Complex (MHC genes code for proteins involved in the incitation of the adaptive immune response in vertebrates, which is achieved through binding oligopeptides (antigens of pathogenic origin. Across vertebrate species, substitutions of amino acids at sites responsible for the specificity of antigen binding (ABS are positively selected. This is attributed to pathogen-driven balancing selection, which is also thought to maintain the high polymorphism of MHC genes, and to cause the sharing of allelic lineages between species. However, the nature of this selection remains controversial. We used individual-based computer simulations to investigate the roles of two phenomena capable of maintaining MHC polymorphism: heterozygote advantage and host-pathogen arms race (Red Queen process. Our simulations revealed that levels of MHC polymorphism were high and driven mostly by the Red Queen process at a high pathogen mutation rate, but were low and driven mostly by heterozygote advantage when the pathogen mutation rate was low. We found that novel mutations at ABSs are strongly favored by the Red Queen process, but not by heterozygote advantage, regardless of the pathogen mutation rate. However, while the strong advantage of novel alleles increased the allele turnover rate, under a high pathogen mutation rate, allelic lineages persisted for a comparable length of time under Red Queen and under heterozygote advantage. Thus, when pathogens evolve quickly, the Red Queen is capable of explaining both positive selection and long coalescence times, but the tension between the novel allele advantage and persistence of alleles deserves further investigation.

  3. Positive selection on D-lactate dehydrogenases of Lactobacillus delbrueckii subspecies bulgaricus.

    Science.gov (United States)

    Zhang, Jifeng; Gong, Guangyu; Wang, Xiao; Zhang, Hao; Tian, Weidong

    2015-08-01

    Lactobacillus delbrueckii has been widely used for yogurt fermentation. It has genes encoding both D- and L-type lactate dehydrogenases (LDHs) that catalyse the production of L(+) or D(-) stereoisomer of lactic acid. D-lactic acid is the primary lactate product by L. delbrueckii, yet it cannot be metabolised by human intestine. Since it has been domesticated for long time, an interesting question arises regarding to whether the selection pressure has affected the evolution of both L-LDH and D-LDH genes in the genome. To answer this question, in this study the authors first investigated the evolution of these two genes by constructing phylogenetic trees. They found that D-LDH-based phylogenetic tree could better represent the phylogenetic relationship in the acidophilus complex than L-LDH-based tree. They next investigated the evolutions of LDH genes of L. delbrueckii at amino acid level, and found that D-LDH gene in L. delbrueckii is positively selected, possibly a consequence of long-term domestication. They further identified four amino acids that are under positive selection. One of them, V261, is located at the centre of three catalytic active sites, indicating likely functional effects on the enzyme activity. The selection from the domestication process thus provides direction for future engineering of D-LDH.

  4. Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Fortanet, Jorge Garcia; Chen, Christine Hiu-Tung; Chen, Ying-Nan P.; Chen, Zhouliang; Deng, Zhan; Firestone, Brant; Fekkes, Peter; Fodor, Michelle; Fortin, Pascal D.; Fridrich, Cary; Grunenfelder, Denise; Ho, Samuel; Kang, Zhao B.; Karki, Rajesh; Kato, Mitsunori; Keen, Nick; LaBonte, Laura R.; Larrow, Jay; Lenoir, Francois; Liu, Gang; Liu, Shumei; Lombardo, Franco; Majumdar, Dyuti; Meyer, Matthew J.; Palermo, Mark; Perez, Lawrence; Pu, Minying; Ramsey, Timothy; Sellers, William R.; Shultz, Michael D.; Stams, Travis; Towler, Christopher; Wang, Ping; Williams, Sarah L.; Zhang, Ji-Hu; LaMarche, Matthew J. (Novartis)

    2016-09-08

    SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein–ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.

  5. Selective inhibition of miR-92 in hippocampal neurons alters contextual fear memory.

    Science.gov (United States)

    Vetere, Gisella; Barbato, Christian; Pezzola, Silvia; Frisone, Paola; Aceti, Massimiliano; Ciotti, MariaTeresa; Cogoni, Carlo; Ammassari-Teule, Martine; Ruberti, Francesca

    2014-12-01

    Post-transcriptional gene regulation mediated by microRNAs (miRNAs) is implicated in memory formation; however, the function of miR-92 in this regulation is uncharacterized. The present study shows that training mice in contextual fear conditioning produces a transient increase in miR-92 levels in the hippocampus and decreases several miR-92 gene targets, including: (i) the neuronal Cl(-) extruding K(+) Cl(-) co-transporter 2 (KCC2) protein; (ii) the cytoplasmic polyadenylation protein (CPEB3), an RNA-binding protein regulator of protein synthesis in neurons; and (iii) the transcription factor myocyte enhancer factor 2D (MEF2D), one of the MEF2 genes which negatively regulates memory-induced structural plasticity. Selective inhibition of endogenous miR-92 in CA1 hippocampal neurons, by a sponge lentiviral vector expressing multiple sequences imperfectly complementary to mature miR-92 under the control of the neuronal specific synapsin promoter, leads to up-regulation of KCC2, CPEB3 and MEF2D, impairs contextual fear conditioning, and prevents a memory-induced increase in the spine density. Taken together, the results indicate that neuronal-expressed miR-92 is an endogenous fine regulator of contextual fear memory in mice. © 2014 Wiley Periodicals, Inc.

  6. Hydrocortisone selectively inhibits IgE-dependent arachidonic acid release from rat peritoneal mast cells

    International Nuclear Information System (INIS)

    Heiman, A.S.; Crews, F.T.

    1984-01-01

    Purified rat mst cells were used to study the effects of antiinflammatory steroids on the release of [1-14C]-arachidonic acid ([1-14C]AA) and metabolites. Mast cell were incubated overnight with glucocorticoids, [1-14C]AA incorporated into cellular phospholipids and the release of [1-14C]AA, and metabolites determined using a variety of secretagogues. Release of [1-14C]AA and metabolites by concanavalin A, the antigen ovalbumin and anti-immunoglobulin E antibody was markedly reduced by glucocorticoid treatment. Neither the total incorporation of [1-14C]AA nor the distribution into phospholipids was altered by hydrocortisone pretreatment. Glucocorticoid pretreatment did not alter [1-14C]AA release stimulated by somatostatin, compound 48/80, or the calcium ionophore, A23187. These data indicate that antiinflammatory steroids selectively inhibit immunoglobulin dependent release of arachidonic acid from rat mast cells. These findings question the role of lipomodulin and macrocortin as general phospholipase inhibitors and suggest that they may be restricted to immunoglobulin stimuli

  7. Protease inhibitors and indoleamines selectively inhibit cholinesterases in the histopathologic structures of Alzheimer disease.

    Science.gov (United States)

    Wright, C I; Guela, C; Mesulam, M M

    1993-01-01

    Neurofibrillary tangles and amyloid plaques express acetylcholinesterase and butyrylcholinesterase activity in Alzheimer disease. We previously reported that traditional acetylcholinesterase inhibitors such as BW284C51, tacrine, and physostigmine were more potent inhibitors of the acetylcholinesterase in normal axons and cell bodies than of the acetylcholinesterase in plaques and tangles. We now report that the reverse pattern is seen with indoleamines (such as serotonin and its precursor 5-hydroxytryptophan), carboxypeptidase inhibitor, and the nonspecific protease inhibitor bacitracin. These substances are more potent inhibitors of the cholinesterases in plaques and tangles than of those in normal axons and cell bodies. These results show that the enzymatic properties of plaque and tangle-associated cholinesterases diverge from those of normal axons and cell bodies. The selective susceptibility to bacitracin and carboxypeptidase inhibitor indicates that the catalytic sites of plaque and tangle-bound cholinesterases are more closely associated with peptidase or protease-like properties than the catalytic sites of cholinesterases in normal axons and cell bodies. This shift in enzymatic affinity may lead to the abnormal protein processing that is thought to play a major role in the pathogenesis of Alzheimer disease. The availability of pharmacological and dietary means for altering brain indoleamines raises therapeutic possibilities for inhibiting the abnormal cholinesterase activity associated with Alzheimer disease. Images PMID:8421706

  8. Circle Solutions, a philosophy and pedagogy for learning positive relationships: What promotes and inhibits sustainable outcomes?

    Directory of Open Access Journals (Sweden)

    Florence McCarthy

    2013-04-01

    Full Text Available Educators are increasingly aware that the efficacy of social and emotional learning (SEL is dependent on implementation factors, not just program content. These include the philosophy underpinning an intervention, the beliefs as well as the skills of facilitators, and the classroom/whole school context in which the intervention takes place. This article outlines the philosophy and pedagogy of Circle Solutions and presents findings from research where 18 undergraduate students supported and developed ‘Circle Time’ in 8 Greater Western Sydney primary schools for a university module on community service. The study indicates that when there is full teacher participation within the principles of the Circle philosophy, together with activeschool support that promotes relational values, the learning outcomes for positive relationship building are more sustainable.

  9. Evaluation of an Improved Branch-Site Likelihood Method for Detecting Positive Selection at the Molecular Level

    DEFF Research Database (Denmark)

    Zhang, Jianzhi; Nielsen, Rasmus; Yang, Ziheng

    2005-01-01

    of interest, while test 2 had acceptable false-positive rates and appeared robust against violations of model assumptions. As test 2 is a direct test of positive selection on the lineages of interest, it is referred to as the branch-site test of positive selection and is recommended for use in real data......Detecting positive Darwinian selection at the DNA sequence level has been a subject of considerable interest. However, positive selection is difficult to detect because it often operates episodically on a few amino acid sites, and the signal may be masked by negative selection. Several methods have...... been developed to test positive selection that acts on given branches (branch methods) or on a subset of sites (site methods). Recently, Yang, Z., and R. Nielsen (2002. Codon-substitution models for detecting molecular adaptation at individual sites along specific lineages. Mol. Biol. Evol. 19...

  10. Barriers Inhibiting Inquiry-Based Science Teaching and Potential Solutions: Perceptions of Positively Inclined Early Adopters

    Science.gov (United States)

    Fitzgerald, Michael; Danaia, Lena; McKinnon, David H.

    2017-07-01

    In recent years, calls for the adoption of inquiry-based pedagogies in the science classroom have formed a part of the recommendations for large-scale high school science reforms. However, these pedagogies have been problematic to implement at scale. This research explores the perceptions of 34 positively inclined early-adopter teachers in relation to their implementation of inquiry-based pedagogies. The teachers were part of a large-scale Australian high school intervention project based around astronomy. In a series of semi-structured interviews, the teachers identified a number of common barriers that prevented them from implementing inquiry-based approaches. The most important barriers identified include the extreme time restrictions on all scales, the poverty of their common professional development experiences, their lack of good models and definitions for what inquiry-based teaching actually is, and the lack of good resources enabling the capacity for change. Implications for expectations of teachers and their professional learning during educational reform and curriculum change are discussed.

  11. Ancient and recent positive selection transformed opioid cis-regulation in humans.

    Directory of Open Access Journals (Sweden)

    Matthew V Rockman

    2005-12-01

    Full Text Available Changes in the cis-regulation of neural genes likely contributed to the evolution of our species' unique attributes, but evidence of a role for natural selection has been lacking. We found that positive natural selection altered the cis-regulation of human prodynorphin, the precursor molecule for a suite of endogenous opioids and neuropeptides with critical roles in regulating perception, behavior, and memory. Independent lines of phylogenetic and population genetic evidence support a history of selective sweeps driving the evolution of the human prodynorphin promoter. In experimental assays of chimpanzee-human hybrid promoters, the selected sequence increases transcriptional inducibility. The evidence for a change in the response of the brain's natural opioids to inductive stimuli points to potential human-specific characteristics favored during evolution. In addition, the pattern of linked nucleotide and microsatellite variation among and within modern human populations suggests that recent selection, subsequent to the fixation of the human-specific mutations and the peopling of the globe, has favored different prodynorphin cis-regulatory alleles in different parts of the world.

  12. Widespread Positive Selection Drives Differentiation of Centromeric Proteins in the Drosophila melanogaster subgroup.

    Science.gov (United States)

    Beck, Emily A; Llopart, Ana

    2015-11-25

    Rapid evolution of centromeric satellite repeats is thought to cause compensatory amino acid evolution in interacting centromere-associated kinetochore proteins. Cid, a protein that mediates kinetochore/centromere interactions, displays particularly high amino acid turnover. Rapid evolution of both Cid and centromeric satellite repeats led us to hypothesize that the apparent compensatory evolution may extend to interacting partners in the Condensin I complex (i.e., SMC2, SMC4, Cap-H, Cap-D2, and Cap-G) and HP1s. Missense mutations in these proteins often result in improper centromere formation and aberrant chromosome segregation, thus selection for maintained function and coevolution among proteins of the complex is likely strong. Here, we report evidence of rapid evolution and recurrent positive selection in seven centromere-associated proteins in species of the Drosophila melanogaster subgroup, and further postulate that positive selection on these proteins could be a result of centromere drive and compensatory changes, with kinetochore proteins competing for optimal spindle attachment.

  13. Detecting Signatures of Positive Selection along Defined Branches of a Population Tree Using LSD.

    Science.gov (United States)

    Librado, Pablo; Orlando, Ludovic

    2018-06-01

    Identifying the genomic basis underlying local adaptation is paramount to evolutionary biology, and bears many applications in the fields of conservation biology, crop, and animal breeding, as well as personalized medicine. Although many approaches have been developed to detect signatures of positive selection within single populations and population pairs, the increasing wealth of high-throughput sequencing data requires improved methods capable of handling multiple, and ideally large number of, populations in a single analysis. In this study, we introduce LSD (levels of exclusively shared differences), a fast and flexible framework to perform genome-wide selection scans, along the internal and external branches of a given population tree. We use forward simulations to demonstrate that LSD can identify branches targeted by positive selection with remarkable sensitivity and specificity. We illustrate a range of potential applications by analyzing data from the 1000 Genomes Project and uncover a list of adaptive candidates accompanying the expansion of anatomically modern humans out of Africa and their spread to Europe.

  14. A synbio approach for selection of highly expressed gene variants in Gram-positive bacteria.

    Science.gov (United States)

    Ferro, Roberto; Rennig, Maja; Hernández-Rollán, Cristina; Daley, Daniel O; Nørholm, Morten H H

    2018-03-08

    The market for recombinant proteins is on the rise, and Gram-positive strains are widely exploited for this purpose. Bacillus subtilis is a profitable host for protein production thanks to its ability to secrete large amounts of proteins, and Lactococcus lactis is an attractive production organism with a long history in food fermentation. We have developed a synbio approach for increasing gene expression in two Gram-positive bacteria. First of all, the gene of interest was coupled to an antibiotic resistance gene to create a growth-based selection system. We then randomised the translation initiation region (TIR) preceding the gene of interest and selected clones that produced high protein titres, as judged by their ability to survive on high concentrations of antibiotic. Using this approach, we were able to significantly increase production of two industrially relevant proteins; sialidase in B. subtilis and tyrosine ammonia lyase in L. lactis. Gram-positive bacteria are widely used to produce industrial enzymes. High titres are necessary to make the production economically feasible. The synbio approach presented here is a simple and inexpensive way to increase protein titres, which can be carried out in any laboratory within a few days. It could also be implemented as a tool for applications beyond TIR libraries, such as screening of synthetic, homologous or domain-shuffled genes.

  15. Prostaglandin E 2 (PgE 2 ) Inhibition By Crude Extracts Of Selected ...

    African Journals Online (AJOL)

    This study was undertaken to assess anti-inflammatory activity of crude extracts of Cassine transvaalensis Burtt-Davy, Clerodendrum uncinatum Schinz and Commiphora glandulosa Schinz using COX inhibition assay. Water extract of C. transvaalensis root bark (125mg/ml) exhibited a (90%) PGE2 inhibition in ...

  16. Inhibition of various gram-positive and gram-negative bacteria growth on selenium nanoparticle coated paper towels.

    Science.gov (United States)

    Wang, Qi; Larese-Casanova, Philip; Webster, Thomas J

    2015-01-01

    There are wide spread bacterial contamination issues on various paper products, such as paper towels hanging in sink splash zones or those used to clean surfaces, filter papers used in water and air purifying systems, and wrappings used in the food industry; such contamination may lead to the potential spread of bacteria and consequent severe health concerns. In this study, selenium nanoparticles were coated on normal paper towel surfaces through a quick precipitation method, introducing antibacterial properties to the paper towels in a healthy way. Their effectiveness at preventing biofilm formation was tested in bacterial assays involving Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus epidermidis. The results showed significant and continuous bacteria inhibition with about a 90% reduction from 24 to 72 hours for gram-positive bacteria including S. aureus and S. epidermidis. The selenium coated paper towels also showed significant inhibition of gram-negative bacteria like P. aeruginosa and E. coli growth at about 57% and 84%, respectively, after 72 hours of treatment. Therefore, this study established a promising selenium-based antibacterial strategy to prevent bacterial growth on paper products, which may lead to the avoidance of bacteria spreading and consequent severe health concerns.

  17. Selective Inhibition of Steroidogenic Enzymes by Ketoconazole in Rat Ovary Cells

    Directory of Open Access Journals (Sweden)

    Michael Gal

    2014-01-01

    Full Text Available Objective Ketoconazole (KCZ is an anti-fungal agent extensively used for clinical applications related to its inhibitory effects on adrenal and testicular steroidogenesis. Much less information is available on the effects of KCZ on synthesis of steroid hormones in the ovary. The present study aimed to characterize the in situ effects of KCZ on steroidogenic enzymes in primary rat ovary cells. Methods Following the induction of folliculogenesis in gonadotropin treated rats, freshly prepared ovarian cells were incubated in suspension for up to four hours while radiolabeled steroid substrates were added and time dependent generation of their metabolic products was analyzed by thin layer chromatography (TLC. Results KCZ inhibits the P450 steroidogenic enzymes in a selective and dose dependent manner, including cholesterol side-chain cleavage cytochrome P450 (CYP11A1/P450scc, the 17α-hydroxylase activity of CYP17A1/P450c17, and CYP19A1/P450arom, with IC 50 values of 0.3, 1.8, and 0.3 μg/mL (0.56, 3.36, and 0.56 μM, respectively. Unaffected by KCZ, at 10 μg/mL, were the 17,20 lyase activity of CYP17A1, as well as five non-cytochrome steroidogenic enzymes including 3β-hydroxysteroid dehydrogenase-δ 5-4 isomerase type 1 (3βHSD1, 5α-reductase, 20α-hydroxysteroid dehydrogenase (20α-HSD, 3α-hydroxysteroid dehydrogenase (3α-HSD, and 17β-hydroxysteroid dehydrogenase type 1 (17HSD1. Conclusion These findings map the effects of KCZ on the ovarian pathways of progestin, androgen, and estrogen synthesis. Hence, the drug may have a potential use as an acute and reversible modulator of ovarian steroidogenesis in pathological circumstances.

  18. Betulinic acid selectively increases protein degradation and enhances prostate cancer-specific apoptosis: possible role for inhibition of deubiquitinase activity.

    Directory of Open Access Journals (Sweden)

    Teresita Reiner

    Full Text Available Inhibition of the ubiquitin-proteasome system (UPS of protein degradation is a valid anti-cancer strategy and has led to the approval of bortezomib for the treatment of multiple myeloma. However, the alternative approach of enhancing the degradation of oncoproteins that are frequently overexpressed in cancers is less developed. Betulinic acid (BA is a plant-derived small molecule that can increase apoptosis specifically in cancer but not in normal cells, making it an attractive anti-cancer agent. Our results in prostate cancer suggested that BA inhibited multiple deubiquitinases (DUBs, which resulted in the accumulation of poly-ubiquitinated proteins, decreased levels of oncoproteins, and increased apoptotic cell death. In normal fibroblasts, however, BA did not inhibit DUB activity nor increased total poly-ubiquitinated proteins, which was associated with a lack of effect on cell death. In the TRAMP transgenic mouse model of prostate cancer, treatment with BA (10 mg/kg inhibited primary tumors, increased apoptosis, decreased angiogenesis and proliferation, and lowered androgen receptor and cyclin D1 protein. BA treatment also inhibited DUB activity and increased ubiquitinated proteins in TRAMP prostate cancer but had no effect on apoptosis or ubiquitination in normal mouse tissues. Overall, our data suggests that BA-mediated inhibition of DUBs and induction of apoptotic cell death specifically in prostate cancer but not in normal cells and tissues may provide an effective non-toxic and clinically selective agent for chemotherapy.

  19. Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants.

    Directory of Open Access Journals (Sweden)

    Wei Zhang

    2017-05-01

    Full Text Available The recent Middle East respiratory syndrome coronavirus (MERS-CoV, Ebola and Zika virus outbreaks exemplify the continued threat of (re-emerging viruses to human health, and our inability to rapidly develop effective therapeutic countermeasures. Many viruses, including MERS-CoV and the Crimean-Congo hemorrhagic fever virus (CCHFV encode deubiquitinating (DUB enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub and interferon stimulated gene 15 (ISG15 from cellular proteins to suppress host antiviral innate immune responses. A variety of viral DUBs (vDUBs, including the MERS-CoV papain-like protease, are responsible for cleaving the viral replicase polyproteins during replication, and are thereby critical components of the viral replication cycle. Together, this makes vDUBs highly attractive antiviral drug targets. However, structural similarity between the catalytic cores of vDUBs and human DUBs complicates the development of selective small molecule vDUB inhibitors. We have thus developed an alternative strategy to target the vDUB activity through a rational protein design approach. Here, we report the use of phage-displayed ubiquitin variant (UbV libraries to rapidly identify potent and highly selective protein-based inhibitors targeting the DUB domains of MERS-CoV and CCHFV. UbVs bound the vDUBs with high affinity and specificity to inhibit deubiquitination, deISGylation and in the case of MERS-CoV also viral replicative polyprotein processing. Co-crystallization studies further revealed critical molecular interactions between UbVs and MERS-CoV or CCHFV vDUBs, accounting for the observed binding specificity and high affinity. Finally, expression of UbVs during MERS-CoV infection reduced infectious progeny titers by more than four orders of magnitude, demonstrating the remarkable potency of UbVs as antiviral agents. Our results thereby establish a strategy to produce protein-based inhibitors

  20. Bayes Empirical Bayes Inference of Amino Acid Sites Under Positive Selection

    DEFF Research Database (Denmark)

    Yang, Ziheng; Wong, Wendy Shuk Wan; Nielsen, Rasmus

    2005-01-01

    , with > 1 indicating positive selection. Statistical distributions are used to model the variation in among sites, allowing a subset of sites to have > 1 while the rest of the sequence may be under purifying selection with ... probabilities that a site comes from the site class with > 1. Current implementations, however, use the naive EB (NEB) approach and fail to account for sampling errors in maximum likelihood estimates of model parameters, such as the proportions and ratios for the site classes. In small data sets lacking...... information, this approach may lead to unreliable posterior probability calculations. In this paper, we develop a Bayes empirical Bayes (BEB) approach to the problem, which assigns a prior to the model parameters and integrates over their uncertainties. We compare the new and old methods on real and simulated...

  1. Design and optimization of selective azaindole amide M1 positive allosteric modulators.

    Science.gov (United States)

    Davoren, Jennifer E; O'Neil, Steven V; Anderson, Dennis P; Brodney, Michael A; Chenard, Lois; Dlugolenski, Keith; Edgerton, Jeremy R; Green, Michael; Garnsey, Michelle; Grimwood, Sarah; Harris, Anthony R; Kauffman, Gregory W; LaChapelle, Erik; Lazzaro, John T; Lee, Che-Wah; Lotarski, Susan M; Nason, Deane M; Obach, R Scott; Reinhart, Veronica; Salomon-Ferrer, Romelia; Steyn, Stefanus J; Webb, Damien; Yan, Jiangli; Zhang, Lei

    2016-01-15

    Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Selective inhibition of influenza virus protein synthesis by inhibitors of DNA function

    International Nuclear Information System (INIS)

    Minor, P.D.; Dimmock, N.J.

    1977-01-01

    Various known inhibitors of cellular DNA function were shown to inhibit cellular RNA synthesis and influenza (fowl plague) virus multiplication. The drugs were investigated for their effect upon the synthesis of influenza virus proteins. According to this effect they could be classified with previously studied compounds as follows: Group I (ethidium bromide, proflavine, and N-nitroquinoline-N-oxide) inhibited both viral and cellular protein synthesis; Group II (nogalomycin, daunomycin and α-amanitin) inhibited viral but not cellular protein synthesis, and all viral proteins were inhibited coordinately; Group III (mithramycin, echinomycin, and actinomycin D) inhibited all viral but not cellular protein synthesis at high concentrations, but at a lower critical concentration inhibited the synthesis of viral haemagglutinin, neuraminidase, and M protein preferentially; Group IV(uv irradiation and camptothecin) inhibited the synthesis of viral haemagglutinin, neuraminidase, and M protein, but not other viral proteins, even at high doses. The mode of action of these inhibitors is discussed in relation to the mechanism of the nuclear events upon which influenza virus multiplication is dependent

  3. Item-cued directed forgetting of related words and pictures in children and adults: selective rehearsal versus cognitive inhibition.

    Science.gov (United States)

    Lehman, E B; McKinley-Pace, M; Leonard, A M; Thompson, D; Johns, K

    2001-01-01

    The main purpose of this study was to compare the relative importance of selective rehearsal and cognitive inhibition in accounting for developmental changes in the directed-forgetting paradigm developed by R. A. Bjork (1972). In two experiments, children in Grades 2 and 5 and college students were asked to remember some words or pictures and to forget others when items were categorically related. Their memory for both items and the associated remember or forget cues was then tested with recall and recognition. Fifth graders recognized more of the forget-cued words than college students did. The pattern of results suggested that age differences in rehearsal and source monitoring (i.e., remembering whether a word had been cued remember or forget) were better explanatory mechanisms for children's forgetting inefficiencies than retrieval inhibition was. The results are discussed in terms of a multiple process view of inhibition.

  4. Positive selection on the nonhomologous end-joining factor Cernunnos-XLF in the human lineage

    Directory of Open Access Journals (Sweden)

    Jurka Jerzy

    2006-06-01

    Full Text Available Abstract Background Cernunnos-XLF is a nonhomologous end-joining factor that is mutated in patients with a rare immunodeficiency with microcephaly. Several other microcephaly-associated genes such as ASPM and microcephalin experienced recent adaptive evolution apparently linked to brain size expansion in humans. In this study we investigated whether Cernunnos-XLF experienced similar positive selection during human evolution. Results We obtained or reconstructed full-length coding sequences of chimpanzee, rhesus macaque, canine, and bovine Cernunnos-XLF orthologs from sequence databases and sequence trace archives. Comparison of coding sequences revealed an excess of nonsynonymous substitutions consistent with positive selection on Cernunnos-XLF in the human lineage. The hotspots of adaptive evolution are concentrated around a specific structural domain, whose analogue in the structurally similar XRCC4 protein is involved in binding of another nonhomologous end-joining factor, DNA ligase IV. Conclusion Cernunnos-XLF is a microcephaly-associated locus newly identified to be under adaptive evolution in humans, and possibly played a role in human brain expansion. We speculate that Cernunnos-XLF may have contributed to the increased number of brain cells in humans by efficient double strand break repair, which helps to prevent frequent apoptosis of neuronal progenitors and aids mitotic cell cycle progression. Reviewers This article was reviewed by Chris Ponting and Richard Emes (nominated by Chris Ponting, Kateryna Makova, Gáspár Jékely and Eugene V. Koonin.

  5. Transcriptome profile and unique genetic evolution of positively selected genes in yak lungs.

    Science.gov (United States)

    Lan, DaoLiang; Xiong, XianRong; Ji, WenHui; Li, Jian; Mipam, Tserang-Donko; Ai, Yi; Chai, ZhiXin

    2018-04-01

    The yak (Bos grunniens), which is a unique bovine breed that is distributed mainly in the Qinghai-Tibetan Plateau, is considered a good model for studying plateau adaptability in mammals. The lungs are important functional organs that enable animals to adapt to their external environment. However, the genetic mechanism underlying the adaptability of yak lungs to harsh plateau environments remains unknown. To explore the unique evolutionary process and genetic mechanism of yak adaptation to plateau environments, we performed transcriptome sequencing of yak and cattle (Bos taurus) lungs using RNA-Seq technology and a subsequent comparison analysis to identify the positively selected genes in the yak. After deep sequencing, a normal transcriptome profile of yak lung that containing a total of 16,815 expressed genes was obtained, and the characteristics of yak lungs transcriptome was described by functional analysis. Furthermore, Ka/Ks comparison statistics result showed that 39 strong positively selected genes are identified from yak lungs. Further GO and KEGG analysis was conducted for the functional annotation of these genes. The results of this study provide valuable data for further explorations of the unique evolutionary process of high-altitude hypoxia adaptation in yaks in the Tibetan Plateau and the genetic mechanism at the molecular level.

  6. Evidence of positive selection associated with placental loss in tiger sharks.

    Science.gov (United States)

    Swift, Dominic G; Dunning, Luke T; Igea, Javier; Brooks, Edward J; Jones, Catherine S; Noble, Leslie R; Ciezarek, Adam; Humble, Emily; Savolainen, Vincent

    2016-06-14

    All vertebrates initially feed their offspring using yolk reserves. In some live-bearing species these yolk reserves may be supplemented with extra nutrition via a placenta. Sharks belonging to the Carcharhinidae family are all live-bearing, and with the exception of the tiger shark (Galeocerdo cuvier), develop placental connections after exhausting yolk reserves. Phylogenetic relationships suggest the lack of placenta in tiger sharks is due to secondary loss. This represents a dramatic shift in reproductive strategy, and is likely to have left a molecular footprint of positive selection within the genome. We sequenced the transcriptome of the tiger shark and eight other live-bearing shark species. From this data we constructed a time-calibrated phylogenetic tree estimating the tiger shark lineage diverged from the placental carcharhinids approximately 94 million years ago. Along the tiger shark lineage, we identified five genes exhibiting a signature of positive selection. Four of these genes have functions likely associated with brain development (YWHAE and ARL6IP5) and sexual reproduction (VAMP4 and TCTEX1D2). Our results indicate the loss of placenta in tiger sharks may be associated with subsequent adaptive changes in brain development and sperm production.

  7. Influence of needle position on lumbar segmental nerve root block selectivity.

    Science.gov (United States)

    Wolff, André P; Groen, Gerbrand J; Wilder-Smith, Oliver H

    2006-01-01

    In patients with chronic low back pain radiating to the leg, segmental nerve root blocks (SNRBs) are performed to predict surgical outcome and identify the putative symptomatic spinal nerve. Epidural spread may lead to false interpretation, affecting clinical decision making. Systematic fluoroscopic analysis of epidural local anesthetic spread and its relationship to needle tip location has not been published to date. Study aims include assessment of epidural local anesthetic spread and its relationship to needle position during fluoroscopy-assisted blocks. Patients scheduled for L4, L5, and S1 blocks were included in this prospective observational study. Under fluoroscopy and electrostimulation, they received 0.5 mL of a mixture containing lidocaine 5 mg and iohexol 75 mg. X-rays with needle tip and contrast were scored for no epidural spread (grade 0), local spread epidurally (grade 1), or to adjacent nerve roots (grade 2). Sixty-five patients were analyzed for epidural spread, 62 for needle position. Grade 1 epidural spread occurred in 47% of L4 and 28% of L5 blocks and grade 2 spread in 3 blocks (5%; L5 n = 1, S1 n = 2). For lumbar blocks, the needle was most frequently found in the lateral upper half of the intervertebral foramen. Epidural spread occurred more frequently with medial needle positions (P = .06). The findings suggest (P = .06) that the risk of grade 1 and 2 lumbar epidural spread, which results in decreased SNRB selectivity, is greater with medial needle positions in the intervertebral foramen. The variability in anatomic position of the dorsal root ganglion necessitates electrostimulation to guide SNRB in addition to fluoroscopy.

  8. Rejection Positivity Predicts Trial-to-Trial Reaction Times in an Auditory Selective Attention Task: A Computational Analysis of Inhibitory Control

    Directory of Open Access Journals (Sweden)

    Sufen eChen

    2014-08-01

    Full Text Available A series of computer simulations using variants of a formal model of attention (Melara & Algom, 2003 probed the role of rejection positivity (RP, a slow-wave electroencephalographic (EEG component, in the inhibitory control of distraction. Behavioral and EEG data were recorded as participants performed auditory selective attention tasks. Simulations that modulated processes of distractor inhibition accounted well for reaction-time (RT performance, whereas those that modulated target excitation did not. A model that incorporated RP from actual EEG recordings in estimating distractor inhibition was superior in predicting changes in RT as a function of distractor salience across conditions. A model that additionally incorporated momentary fluctuations in EEG as the source of trial-to-trial variation in performance precisely predicted individual RTs within each condition. The results lend support to the linking proposition that RP controls the speed of responding to targets through the inhibitory control of distractors.

  9. A cyclized peptide derived from alpha fetoprotein inhibits the proliferation of ER-positive canine mammary cancer cells.

    Science.gov (United States)

    Torres, Cristian Gabriel; Pino, Ana María; Sierralta, Walter Daniel

    2009-06-01

    The effects of estradiol (E2) and of an AFP-derived cyclized peptide (cP) on the proliferation of primary cultures of cancer cells isolated from spontaneous canine mammary tumors were studied. The cellular response to E2 and cP was related to the expression of estradiol receptor (isoforms alpha and beta). In ER-positive cells, 2 nM estradiol increased cell proliferation and the phosphorylation of ERK1/2; 2 microg/ml cP inhibited all these effects. Estradiol also increased HER2 immunoreactivity in ER-positive cells, an effect that was reverted to its basal values by cP. Estradiol stimulated in these cells the release of MMP2 and MMP9 and the shedding of HB-EGF, effects that the cP did not affect. ER-negative cells were refractory to estradiol or cP. All canine mammary tumor cells in culture responded to treatments analogously to human mammary cancer cells. Our results support the proposal of cP as a new, potentially effective therapeutic agent for the management of mammary cancer.

  10. Examination of Signatures of Recent Positive Selection on Genes Involved in Human Sialic Acid Biology.

    Science.gov (United States)

    Moon, Jiyun M; Aronoff, David M; Capra, John A; Abbot, Patrick; Rokas, Antonis

    2018-03-28

    Sialic acids are nine carbon sugars ubiquitously found on the surfaces of vertebrate cells and are involved in various immune response-related processes. In humans, at least 58 genes spanning diverse functions, from biosynthesis and activation to recycling and degradation, are involved in sialic acid biology. Because of their role in immunity, sialic acid biology genes have been hypothesized to exhibit elevated rates of evolutionary change. Consistent with this hypothesis, several genes involved in sialic acid biology have experienced higher rates of non-synonymous substitutions in the human lineage than their counterparts in other great apes, perhaps in response to ancient pathogens that infected hominins millions of years ago (paleopathogens). To test whether sialic acid biology genes have also experienced more recent positive selection during the evolution of the modern human lineage, reflecting adaptation to contemporary cosmopolitan or geographically-restricted pathogens, we examined whether their protein-coding regions showed evidence of recent hard and soft selective sweeps. This examination involved the calculation of four measures that quantify changes in allele frequency spectra, extent of population differentiation, and haplotype homozygosity caused by recent hard and soft selective sweeps for 55 sialic acid biology genes using publicly available whole genome sequencing data from 1,668 humans from three ethnic groups. To disentangle evidence for selection from confounding demographic effects, we compared the observed patterns in sialic acid biology genes to simulated sequences of the same length under a model of neutral evolution that takes into account human demographic history. We found that the patterns of genetic variation of most sialic acid biology genes did not significantly deviate from neutral expectations and were not significantly different among genes belonging to different functional categories. Those few sialic acid biology genes that

  11. Selective histone deacetylase 6 inhibition prolongs survival in a lethal two-hit model.

    Science.gov (United States)

    Cheng, Xin; Liu, Zhengcai; Liu, Baoling; Zhao, Ting; Li, Yongqing; Alam, Hasan B

    2015-07-01

    Hemorrhagic shock (HS) followed by a subsequent insult ("second hit") often initiates an exaggerated systemic inflammatory response and multiple organ failure. We have previously demonstrated that valproic acid, a pan histone deacetylase inhibitor, could improve survival in a rodent "two-hit" model. In the present study, our goal was to determine whether selective inhibition of histone deacetylase 6 with Tubastatin A (Tub-A) could prolong survival in a two-hit model where HS was followed by sepsis from cecal ligation and puncture (CLP). C57Bl/6J mice were subjected to sublethal HS (30% blood loss) and then randomly divided into two groups (n = 13 per group) such as Tub-A group (treatment) and vehicle (VEH) group (control). The Tub-A group was given an intraperitoneal injection of Tub-A (70 mg/kg) dissolved in dimethyl sulfoxide (DMSO). The VEH group was injected with DMSO (1 μl/g body weight). After 24 h, all mice were subjected CLP followed immediately by another dose of Tub-A or DMSO. Survival was monitored for 10 d. In a parallel study, peritoneal irrigation fluid and liver tissue from Tub-A- or DMSO-treated mice were collected 3 h after CLP. Enzyme-linked immunosorbent assay was performed to quantify activity of the myeloperoxidase and concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) in the peritoneal irrigation fluid. RNA was isolated from the liver tissue, and real-time polymerase chain reaction was performed to measure relative messenger RNA levels of TNF-α and IL-6. Treatment with Tub-A significantly improved survival compared with that of the control (69.2% versus 15.4%). In addition, Tub-A significantly suppressed myeloperoxidase activity (169.9 ± 8.4 ng/mL versus 70.4 ± 17.4 ng/mL; P hit model. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. IL-15 inhibits pre-B cell proliferation by selectively expanding Mac-1+B220+ NK cells

    International Nuclear Information System (INIS)

    Nakajima, Shinsuke; Hida, Shigeaki; Taki, Shinsuke

    2008-01-01

    Natural killer (NK) cells are the cells critical for inhibition of repopulation of allogenic bone marrow cells. However, it is not well known if NK cells affect autologous lymphopoiesis. Here, we observed that NK cells could inhibit pre-B cell proliferation in vitro driven by interleukin (IL)-7 in a manner dependent on IL-15. Interestingly, the great majority of expanding NK cells were Mac-1 + B220 + , a recently identified potent interferon (IFN)-γ producer. Indeed, IFN-γ was produced in those cultures, and pre-B cells lacking IFN-γ receptors, but not those lacking type I IFN receptors, were resistant to such an inhibition. Furthermore, even NK cells from mice lacking β2-microglobulin, which were known to be functionally dampened, inhibited pre-B cell proliferation as well. Thus, activated NK cells, which were expanded selectively by IL-15, could potentially regulate B lymphopoiesis through IFN-γ beyond the selection imposed upon self-recognition

  13. Piperlongumine selectively suppresses ABC-DLBCL through inhibition of NF-κB p65 subunit nuclear import

    Energy Technology Data Exchange (ETDEWEB)

    Niu, Mingshan [Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu (China); Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu (China); Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu (China); Shen, Yangling; Xu, Xiaoyu [Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu (China); Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu (China); Yao, Yao; Fu, Chunling [Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu (China); Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu (China); Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu (China); Yan, Zhiling [Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu (China); Wu, Qingyun [Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu (China); Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu (China); Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu (China); Cao, Jiang; Sang, Wei [Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu (China); Zeng, Lingyu [Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu (China); Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu (China); Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu (China); Li, Zhenyu [Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu (China); Liu, Xuejiao, E-mail: liuxuejiao0923@126.com [Insititute of Nervous System Diseases, Xuzhou Medical College, Xuzhou, Jiangsu (China); and others

    2015-07-10

    Constitutive NF-κB activation is required for survival of activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL). However, current NF-κB targeting strategies lack cancer cell specificity. Here, we identified a novel inhibitor, piperlongumine, features direct binding to NF-κB p65 subunit and suppression of p65 nuclear import. This was accompanied by NF-κB reporter activity suppression and NF-κB target gene downregulation. Moreover, mutation of Cys{sup 38} to Ser in p65 abolished this effect of piperlongumine on inhibition of p65 nuclear import. Furthermore, we show that piperlongumine selectively inhibited proliferation and induced apoptosis of ABC-DLBCL cells. Most notably, it has been reported that piperlongumine did not affect normal cells even at high doses and was nontoxic to animals. Hence, our current study provides new insight into piperlongumine's mechanism of action and novel approach to ABC-DLBCL target therapy. - Highlights: • Current NF-κB targeting strategies lack cancer cell specificity. • Piperlongumine inhibits NF-κB p65 subunit nuclear import via directly binding to p65. • Piperlongumine selectively inhibits proliferation of ABC-DLBCL cells. • This study provides a novel approach to ABC-DLBCL target therapy.

  14. Piperlongumine selectively suppresses ABC-DLBCL through inhibition of NF-κB p65 subunit nuclear import

    International Nuclear Information System (INIS)

    Niu, Mingshan; Shen, Yangling; Xu, Xiaoyu; Yao, Yao; Fu, Chunling; Yan, Zhiling; Wu, Qingyun; Cao, Jiang; Sang, Wei; Zeng, Lingyu; Li, Zhenyu; Liu, Xuejiao

    2015-01-01

    Constitutive NF-κB activation is required for survival of activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL). However, current NF-κB targeting strategies lack cancer cell specificity. Here, we identified a novel inhibitor, piperlongumine, features direct binding to NF-κB p65 subunit and suppression of p65 nuclear import. This was accompanied by NF-κB reporter activity suppression and NF-κB target gene downregulation. Moreover, mutation of Cys 38 to Ser in p65 abolished this effect of piperlongumine on inhibition of p65 nuclear import. Furthermore, we show that piperlongumine selectively inhibited proliferation and induced apoptosis of ABC-DLBCL cells. Most notably, it has been reported that piperlongumine did not affect normal cells even at high doses and was nontoxic to animals. Hence, our current study provides new insight into piperlongumine's mechanism of action and novel approach to ABC-DLBCL target therapy. - Highlights: • Current NF-κB targeting strategies lack cancer cell specificity. • Piperlongumine inhibits NF-κB p65 subunit nuclear import via directly binding to p65. • Piperlongumine selectively inhibits proliferation of ABC-DLBCL cells. • This study provides a novel approach to ABC-DLBCL target therapy

  15. Mitochondrial toxicity of selective COX-2 inhibitors via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria

    DEFF Research Database (Denmark)

    Syed, Muzeeb; Skonberg, Christian; Hansen, Steen Honoré

    2016-01-01

    Cyclooxygenase-2 (COX-2) inhibitors (coxibs) are non-steroidal anti-inflammatory drugs (NSAIDs) designed to selectively inhibit COX-2. However, drugs of this therapeutic class are associated with drug induced liver injury (DILI) and mitochondrial injury is likely to play a role. The effects...... of selective COX-2 inhibitors on inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria were investigated. The order of potency of inhibition of ATP synthesis was: lumiracoxib (IC50: 6.48 ± 2.74 μM)>celecoxib (IC50: 14.92 ± 6.40 μM)>valdecoxib (IC50: 161.4 ± 28.6 μM)>rofecoxib (IC50...... correlation (with r(2)=0.921) was observed between the potency of inhibition of ATP synthesis and the log P values. The in vitro metabolism of coxibs in rat liver mitochondria yielded for each drug substance a major single metabolite and identified a hydroxy metabolite with each of the coxibs...

  16. Selective inhibition of endogenous antioxidants with Auranofin causes mitochondrial oxidative stress which can be countered by selenium supplementation.

    Science.gov (United States)

    Radenkovic, Filip; Holland, Olivia; Vanderlelie, Jessica J; Perkins, Anthony V

    2017-12-15

    Auranofin is a thiol-reactive gold (I)-containing compound with potential asa chemotherapeutic. Auranofin has the capacity to selectively inhibit endogenous antioxidant enzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx), resulting in oxidative stress and the initiation of a pro-apoptotic cascade. The effect of Auranofin exposure on TrxR and GPx, and the potential for cellular protection through selenium supplementation was examined in the non-cancerous human cell line Swan-71. Auranofin exposure resulted in a concentration dependent differential inhibition of selenoprotein antioxidants. Significant inhibition of TrxR was observed at 20nM Auranofin with inhibition of GPx from 10µM. Significant increases in reactive oxygen species (ROS) were associated with antioxidant inhibition at Auranofin concentrations of 100nM (TrxR inhibition) and 10µM (TrxR and GPx inhibition), respectively. Evaluation of mitochondrial respiration demonstrated significant reductions in routine and maximal respiration at both 100nM and 10μM Auranofin. Auranofin treatment at concentrations of 10μM and higher concentrations resulted in a ∼68% decrease in cellular viability and was associated with elevations in pro-apoptotic markers cytochrome c flux control factor (FCFc) at concentration of 100nM and mitochondrial Bax at 10μM. The supplementation of selenium (100nM) prior to treatment had a generalized protective affect through the restoration of antioxidant activity with a significant increase in TrxR and GPx activity, a significant reduction in ROS and associated improvement in mitochondrial respiration and cellular viability (10µM ∼48% increase). Selenium supplementation reduced the FCFc at low doses of Auranofin (selenium exposure. Therefore, Auranofin dose and the selenium status of patients are important considerations in the therapeutic use of Auranofin as an agent of chemosensitization. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  17. Device for the selective positioning of a component on a tube plate

    International Nuclear Information System (INIS)

    1974-01-01

    The invention relates to a device for the selective positioning of a component on a tube plate. It particularly applies to the positioning of a guide tube head successively opposite all the tubes of the tube bundle of a nuclear reactor steam generator. The large number of tubes in the tube bundle of the steam generator in a pressure water nuclear power station must be checked periodically for any likely corrosion. This check is effected with a Foucault current probe which is inserted in each tube in turn and is connected to a probe signal processing unit. The probe is placed in a flexible guide tube brought in turn in front of each tube of the bundle to be checked. The invention concerns a device to move the opening of a tube guide for a Foucault current detector over the entire surface of the tube plate, thereby providing access to all the tubes whilst limiting the interventions to a single positioning and a single withdrawal of the apparatus for testing all the bundle. Between the two interventions at the beginning and end of the operation, all displacements are remote controlled from outside the dangerous radioacive area [fr

  18. Evidence for positive selection and recombination hotspots in Deformed wing virus (DWV).

    Science.gov (United States)

    Dalmon, A; Desbiez, C; Coulon, M; Thomasson, M; Le Conte, Y; Alaux, C; Vallon, J; Moury, B

    2017-01-25

    Deformed wing virus (DWV) is considered one of the most damaging pests in honey bees since the spread of its vector, Varroa destructor. In this study, we sequenced the whole genomes of two virus isolates and studied the evolutionary forces that act on DWV genomes. The isolate from a Varroa-tolerant bee colony was characterized by three recombination breakpoints between DWV and the closely related Varroa destructor virus-1 (VDV-1), whereas the variant from the colony using conventional Varroa management was similar to the originally described DWV. From the complete sequence dataset, nine independent DWV-VDV-1 recombination breakpoints were detected, and recombination hotspots were found in the 5' untranslated region (5' UTR) and the conserved region encoding the helicase. Partial sequencing of the 5' UTR and helicase-encoding region in 41 virus isolates suggested that most of the French isolates were recombinants. By applying different methods based on the ratio between non-synonymous (dN) and synonymous (dS) substitution rates, we identified four positions that showed evidence of positive selection. Three of these positions were in the putative leader protein (Lp), and one was in the polymerase. These findings raise the question of the putative role of the Lp in viral evolution.

  19. Selective inhibition of the demethylation at C-14 in ergosterol biosynthesis by the fungicide, Denmert (S-1358)

    International Nuclear Information System (INIS)

    Kato, Toshiro; Kawase, Yasuo

    1976-01-01

    A direct evidence of the inhibitory effect in a cell-free system of S. cerevisiae was experimentally studied, and the site of action of Denmert (S-n-butyl S'-p-tert-butylbenzyl N-3-pyridyldithiocarbon-imidate) in sterol biosynthesis was examined. 14 C-labeled lanosterol and 14-desmethyl-lanosterol were biosynthetically prepared. DL-mevalonate-2- 14 C was incubated with yeast cell-free homogenates for 3 hr at 28 deg C while being shaked vigorously in atmospheric oxygen. The resultant 14 C-labeled sterol was extracted and chromatographed on a silicic acid-Hyflo Super Cel column. 4,4-dimethyl sterol thus obtained was acetylated with acetic anhydride and pyridine. The separation of lanosteryl acetate and 14-desmethyl lanosteryl acetate was accomplished on alumina thin-layer plates. After the saponification of each steryl acetate, the quantity of the sterol was assessed by gas chromatography with cholesterol as an internal standard. The incubation of the 14 C-labeled sterol was achieved under the same conditions as those for the DL-mevalonate-2- 14 C except the addition of the substrate which was dispersed in 0.1M phosphate buffer. Denmert inhibited the conversion of 14 C-labeled lanosterol to 4-desmethyl sterol, while the conversion of 14 C-labeled 14-desmethyl lanosterol to 4-desmethyl sterol was hardly affected by the fungicide. Therefore, Denmert is a potent selective inhibitor of the demethylation at the C-14 position in ergosterol biosynthesis. The fungicide, triarimol, exhibited the same effect on sterol biosynthesis as that of Denmert. (Iwakiri, K.)

  20. The monoamine oxidase inhibition properties of selected structural analogues of methylene blue

    International Nuclear Information System (INIS)

    Delport, Anzelle; Harvey, Brian H.; Petzer, Anél; Petzer, Jacobus P.

    2017-01-01

    The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, the present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC 50 = 0.0037 μM), Nile blue (IC 50 = 0.0077 μM) and 1,9-dimethyl methylene blue (IC 50 = 0.018 μM) exhibiting higher potency inhibition compared to MB (IC 50 = 0.07 μM). Nile blue also represents a potent MAO-B inhibitor with an IC 50 value of 0.012 μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST. - Highlights: • MB analogues, cresyl violet and Nile blue, are high potency MAO-A inhibitors. • Nile blue also represents a potent MAO-B inhibitor. • Potent MAO-A inhibition should alert to potential serotonin toxicity.

  1. Selective attentional enhancement and inhibition of fronto-posterior connectivity by the basal ganglia during attention switching.

    Science.gov (United States)

    van Schouwenburg, Martine R; den Ouden, Hanneke E M; Cools, Roshan

    2015-06-01

    The prefrontal cortex and the basal ganglia interact to selectively gate a desired action. Recent studies have shown that this selective gating mechanism of the basal ganglia extends to the domain of attention. Here, we investigate the nature of this action-like gating mechanism for attention using a spatial attention-switching paradigm in combination with functional neuroimaging and dynamic causal modeling. We show that the basal ganglia guide attention by focally releasing inhibition of task-relevant representations, while simultaneously inhibiting task-irrelevant representations by selectively modulating prefrontal top-down connections. These results strengthen and specify the role of the basal ganglia in attention. Moreover, our findings have implications for psychological theorizing by suggesting that inhibition of unattended sensory regions is not only a consequence of mutual suppression, but is an active process, subserved by the basal ganglia. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. Enteric Micromotor Can Selectively Position and Spontaneously Propel in the Gastrointestinal Tract.

    Science.gov (United States)

    Li, Jinxing; Thamphiwatana, Soracha; Liu, Wenjuan; Esteban-Fernández de Ávila, Berta; Angsantikul, Pavimol; Sandraz, Elodie; Wang, Jianxing; Xu, Tailin; Soto, Fernando; Ramez, Valentin; Wang, Xiaolei; Gao, Weiwei; Zhang, Liangfang; Wang, Joseph

    2016-09-22

    The gastrointestinal (GI) tract, which hosts hundreds of bacteria species, becomes the most exciting organ for the emerging microbiome research. Some of these GI microbes are hostile and cause a variety of diseases. These bacteria colonize in different segments of the GI tract dependent on the local physicochemical and biological factors. Therefore, selectively locating therapeutic or imaging agents to specific GI segments is of significant importance for studying gut microbiome and treating various GI-related diseases. Herein, we demonstrate an enteric micromotor system capable of precise positioning and controllable retention in desired segments of the GI tract. These motors, consisting of magnesium-based tubular micromotors coated with an enteric polymer layer, act as a robust nanobiotechnology tool for site-specific GI delivery. The micromotors can deliver payload to a particular location via dissolution of their enteric coating to activate their propulsion at the target site toward localized tissue penetration and retention.

  3. Augmenting the Genetic Toolbox for Sulfolobus islandicus with a Stringent Positive Selectable Marker for Agmatine Prototrophy

    Science.gov (United States)

    Cooper, Tara E.; Krause, David J.

    2013-01-01

    Sulfolobus species have become the model organisms for studying the unique biology of the crenarchaeal division of the archaeal domain. In particular, Sulfolobus islandicus provides a powerful opportunity to explore natural variation via experimental functional genomics. To support these efforts, we further expanded genetic tools for S. islandicus by developing a stringent positive selection for agmatine prototrophs in strains in which the argD gene, encoding arginine decarboxylase, has been deleted. Strains with deletions in argD were shown to be auxotrophic for agmatine even in nutrient-rich medium, but growth could be restored by either supplementation of exogenous agmatine or reintroduction of a functional copy of the argD gene from S. solfataricus P2 into the ΔargD host. Using this stringent selection, a robust targeted gene knockout system was established via an improved next generation of the MID (marker insertion and unmarked target gene deletion) method. Application of this novel system was validated by targeted knockout of the upsEF genes involved in UV-inducible cell aggregation formation. PMID:23835176

  4. Genes under positive selection in a model plant pathogenic fungus, Botrytis.

    Science.gov (United States)

    Aguileta, Gabriela; Lengelle, Juliette; Chiapello, Hélène; Giraud, Tatiana; Viaud, Muriel; Fournier, Elisabeth; Rodolphe, François; Marthey, Sylvain; Ducasse, Aurélie; Gendrault, Annie; Poulain, Julie; Wincker, Patrick; Gout, Lilian

    2012-07-01

    The rapid evolution of particular genes is essential for the adaptation of pathogens to new hosts and new environments. Powerful methods have been developed for detecting targets of selection in the genome. Here we used divergence data to compare genes among four closely related fungal pathogens adapted to different hosts to elucidate the functions putatively involved in adaptive processes. For this goal, ESTs were sequenced in the specialist fungal pathogens Botrytis tulipae and Botrytis ficariarum, and compared with genome sequences of Botrytis cinerea and Sclerotinia sclerotiorum, responsible for diseases on over 200 plant species. A maximum likelihood-based analysis of 642 predicted orthologs detected 21 genes showing footprints of positive selection. These results were validated by resequencing nine of these genes in additional Botrytis species, showing they have also been rapidly evolving in other related species. Twenty of the 21 genes had not previously been identified as pathogenicity factors in B. cinerea, but some had functions related to plant-fungus interactions. The putative functions were involved in respiratory and energy metabolism, protein and RNA metabolism, signal transduction or virulence, similarly to what was detected in previous studies using the same approach in other pathogens. Mutants of B. cinerea were generated for four of these genes as a first attempt to elucidate their functions. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Signatures of positive selection in African Butana and Kenana dairy zebu cattle.

    Science.gov (United States)

    Bahbahani, Hussain; Salim, Bashir; Almathen, Faisal; Al Enezi, Fahad; Mwacharo, Joram M; Hanotte, Olivier

    2018-01-01

    Butana and Kenana are two types of zebu cattle found in Sudan. They are unique amongst African indigenous zebu cattle because of their high milk production. Aiming to understand their genome structure, we genotyped 25 individuals from each breed using the Illumina BovineHD Genotyping BeadChip. Genetic structure analysis shows that both breeds have an admixed genome composed of an even proportion of indicine (0.75 ± 0.03 in Butana, 0.76 ± 0.006 in Kenana) and taurine (0.23 ± 0.009 in Butana, 0.24 ± 0.006 in Kenana) ancestries. We also observe a proportion of 0.02 to 0.12 of European taurine ancestry in ten individuals of Butana that were sampled from cattle herds in Tamboul area suggesting local crossbreeding with exotic breeds. Signatures of selection analyses (iHS and Rsb) reveal 87 and 61 candidate positive selection regions in Butana and Kenana, respectively. These regions span genes and quantitative trait loci (QTL) associated with biological pathways that are important for adaptation to marginal environments (e.g., immunity, reproduction and heat tolerance). Trypanotolerance QTL are intersecting candidate regions in Kenana cattle indicating selection pressure acting on them, which might be associated with an unexplored level of trypanotolerance in this cattle breed. Several dairy traits QTL are overlapping the identified candidate regions in these two zebu cattle breeds. Our findings underline the potential to improve dairy production in the semi-arid pastoral areas of Africa through breeding improvement strategy of indigenous local breeds.

  6. Kinetics and selectivity of permanganate chemiluminescence: a study of hydroxyl and amino disubstituted benzene positional isomers.

    Science.gov (United States)

    Slezak, Teo; Smith, Zoe M; Adcock, Jacqui L; Hindson, Christopher M; Barnett, Neil W; Nesterenko, Pavel N; Francis, Paul S

    2011-11-30

    Examination of the chemiluminescence reactions of dihydroxybenzenes, aminophenols and phenylenediamines with acidic potassium permanganate has provided a new understanding of the relationships between analyte structure, reaction conditions, kinetics of the light-producing pathway and emission intensity, with broad implications for this widely utilised chemiluminescence detection system. Using a permanganate reagent prepared in a polyphosphate solution and adjusted to pH 2.5, large differences in the rate of reaction with different positional isomers were observed, with the meta-substituted forms reacting far slower and therefore exhibiting much lower chemiluminescence intensities in flow analysis systems. The preliminary partial reduction of permanganate to form significant concentrations of Mn(III) increased the rate of reaction with all analytes tested, resulting in comparable or (in the case of aminophenol and phenylenediamine) even greater emission intensities for the meta-isomers, demonstrating the opportunity to tune the selectivity of the reagent towards certain classes of compound or even specific positional isomers of the same compound. Using more acidic permanganate reagents, in which polyphosphates are not required, the discrepancy between the chemiluminescence intensities was still observed, but was less prominent due to the generally faster rates of reaction. The enhancement of these chemiluminescence reactions by on-line addition of formic acid or formaldehyde can in part also be attributed to the generation of significant pools of the key Mn(III) precursor to the emitting species. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Biased small-molecule ligands for selective inhibition of HIV-1 cell entry via CCR5

    DEFF Research Database (Denmark)

    Berg, Christian; Spiess, Katja; von Lüttichau, Hans Rudolf

    2016-01-01

    Since the discovery of HIV's use of CCR5 as the primary coreceptor in fusion, the focus on developing small-molecule receptor antagonists for inhibition hereof has only resulted in one single drug, Maraviroc. We therefore investigated the possibility of using small-molecule CCR5 agonists as HIV-1...

  8. Phosphoenolpyruvate carboxylase from C4 leaves is selectively targeted for inhibition by anionic phospholipids

    NARCIS (Netherlands)

    Monreal, J.A.; McLoughlin, F.; Echevarría, C.; García-Mauriño, S.; Testerink, C.

    2010-01-01

    Phosphoenolpyruvate carboxylase (PEPC; EC 4.1.1.31) is an enzyme playing a crucial role in photosynthesis of C4 plants. Here, we identify anionic phospholipids as novel regulators that inhibit C4 PEPC activity and provide evidence that the enzyme partially localizes to membranes.

  9. The Effect of Perceptual Load on Attention-Induced Motion Blindness: The Efficiency of Selective Inhibition

    Science.gov (United States)

    Hay, Julia L.; Milders, Maarten M.; Sahraie, Arash; Niedeggen, Michael

    2006-01-01

    Recent visual marking studies have shown that the carry-over of distractor inhibition can impair the ability of singletons to capture attention if the singleton and distractors share features. The current study extends this finding to first-order motion targets and distractors, clearly separated in time by a visual cue (the letter X). Target…

  10. Modeling intentional inhibition of actions

    NARCIS (Netherlands)

    Thilakarathne, D.J.; Treur, J.

    2015-01-01

    Inspired by cognitive and neurological literature on action ownership and action awareness, in this paper a computational cognitive model for intentional inhibition (i.e.; the capacity to voluntarily suspend or inhibit an action) is introduced. The interplay between (positive) potential selection of

  11. The monoamine oxidase inhibition properties of selected structural analogues of methylene blue

    Energy Technology Data Exchange (ETDEWEB)

    Delport, Anzelle [Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520 (South Africa); Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520 (South Africa); Harvey, Brian H. [Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520 (South Africa); Pharmacology, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520 (South Africa); Petzer, Anél [Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520 (South Africa); Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520 (South Africa); Petzer, Jacobus P., E-mail: jacques.petzer@nwu.ac.za [Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520 (South Africa); Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520 (South Africa)

    2017-06-15

    The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, the present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC{sub 50} = 0.0037 μM), Nile blue (IC{sub 50} = 0.0077 μM) and 1,9-dimethyl methylene blue (IC{sub 50} = 0.018 μM) exhibiting higher potency inhibition compared to MB (IC{sub 50} = 0.07 μM). Nile blue also represents a potent MAO-B inhibitor with an IC{sub 50} value of 0.012 μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST. - Highlights: • MB analogues, cresyl violet and Nile blue, are high potency MAO-A inhibitors. • Nile blue also represents a potent MAO-B inhibitor. • Potent MAO-A inhibition should alert to potential serotonin toxicity.

  12. Positive selection in octopus haemocyanin indicates functional links to temperature adaptation.

    Science.gov (United States)

    Oellermann, Michael; Strugnell, Jan M; Lieb, Bernhard; Mark, Felix C

    2015-07-05

    Octopods have successfully colonised the world's oceans from the tropics to the poles. Yet, successful persistence in these habitats has required adaptations of their advanced physiological apparatus to compensate impaired oxygen supply. Their oxygen transporter haemocyanin plays a major role in cold tolerance and accordingly has undergone functional modifications to sustain oxygen release at sub-zero temperatures. However, it remains unknown how molecular properties evolved to explain the observed functional adaptations. We thus aimed to assess whether natural selection affected molecular and structural properties of haemocyanin that explains temperature adaptation in octopods. Analysis of 239 partial sequences of the haemocyanin functional units (FU) f and g of 28 octopod species of polar, temperate, subtropical and tropical origin revealed natural selection was acting primarily on charge properties of surface residues. Polar octopods contained haemocyanins with higher net surface charge due to decreased glutamic acid content and higher numbers of basic amino acids. Within the analysed partial sequences, positive selection was present at site 2545, positioned between the active copper binding centre and the FU g surface. At this site, methionine was the dominant amino acid in polar octopods and leucine was dominant in tropical octopods. Sites directly involved in oxygen binding or quaternary interactions were highly conserved within the analysed sequence. This study has provided the first insight into molecular and structural mechanisms that have enabled octopods to sustain oxygen supply from polar to tropical conditions. Our findings imply modulation of oxygen binding via charge-charge interaction at the protein surface, which stabilize quaternary interactions among functional units to reduce detrimental effects of high pH on venous oxygen release. Of the observed partial haemocyanin sequence, residue 2545 formed a close link between the FU g surface and the

  13. Positive evolutionary selection of an HD motif on Alzheimer precursor protein orthologues suggests a functional role.

    Science.gov (United States)

    Miklós, István; Zádori, Zoltán

    2012-02-01

    HD amino acid duplex has been found in the active center of many different enzymes. The dyad plays remarkably different roles in their catalytic processes that usually involve metal coordination. An HD motif is positioned directly on the amyloid beta fragment (Aβ) and on the carboxy-terminal region of the extracellular domain (CAED) of the human amyloid precursor protein (APP) and a taxonomically well defined group of APP orthologues (APPOs). In human Aβ HD is part of a presumed, RGD-like integrin-binding motif RHD; however, neither RHD nor RXD demonstrates reasonable conservation in APPOs. The sequences of CAEDs and the position of the HD are not particularly conserved either, yet we show with a novel statistical method using evolutionary modeling that the presence of HD on CAEDs cannot be the result of neutral evolutionary forces (pHD motif is underrepresented in the proteomes of all species of the animal kingdom. Position migration can be explained by high probability occurrence of multiple copies of HD on intermediate sequences, from which only one is kept by selective evolutionary forces, in a similar way as in the case of the "transcription binding site turnover." CAED of all APP orthologues and homologues are predicted to bind metal ions including Amyloid-like protein 1 (APLP1) and Amyloid-like protein 2 (APLP2). Our results suggest that HDs on the CAEDs are most probably key components of metal-binding domains, which facilitate and/or regulate inter- or intra-molecular interactions in a metal ion-dependent or metal ion concentration-dependent manner. The involvement of naturally occurring mutations of HD (Tottori (D7N) and English (H6R) mutations) in early onset Alzheimer's disease gives additional support to our finding that HD has an evolutionary preserved function on APPOs.

  14. Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation.

    Science.gov (United States)

    Scannevin, Robert H; Alexander, Richard; Haarlander, Tara Mezzasalma; Burke, Sharon L; Singer, Monica; Huo, Cuifen; Zhang, Yue-Mei; Maguire, Diane; Spurlino, John; Deckman, Ingrid; Carroll, Karen I; Lewandowski, Frank; Devine, Eric; Dzordzorme, Keli; Tounge, Brett; Milligan, Cindy; Bayoumy, Shariff; Williams, Robyn; Schalk-Hihi, Celine; Leonard, Kristi; Jackson, Paul; Todd, Matthew; Kuo, Lawrence C; Rhodes, Kenneth J

    2017-10-27

    Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability of this therapeutic approach. This discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Selective inhibition of phosphodiesterase 5 enhances glutamatergic synaptic plasticity and memory in mice.

    Science.gov (United States)

    Uthayathas, Subramaniam; Parameshwaran, Kodeeswaran; Karuppagounder, Senthilkumar S; Ahuja, Manuj; Dhanasekaran, Muralikrishnan; Suppiramaniam, Vishnu

    2013-11-01

    Phosphodiesterases (PDEs) belong to a family of proteins that control metabolism of cyclic nucleotides. Targeting PDE5, for enhancing cellular function, is one of the therapeutic strategies for male erectile dysfunction. We have investigated whether in vivo inhibition of PDE5, which is expressed in several brain regions, will enhance memory and synaptic transmission in the hippocampus of healthy mice. We have found that acute administration of sildenafil, a specific PDE5 inhibitor, enhanced hippocampus-dependent memory tasks. To elucidate the underlying mechanism in the memory enhancement, effects of sildenafil on long-term potentiation (LTP) were measured. The level of LTP was significantly elevated, with concomitant increases in basal synaptic transmission, in mice treated with sildenafil (1 mg/kg/day) for 15 days compared to control mice. These results suggest that moderate PDE5 inhibition enhances memory by increasing synaptic plasticity and transmission in the hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

  16. Selective chemical binding enhances cesium tolerance in plants through inhibition of cesium uptake.

    Science.gov (United States)

    Adams, Eri; Chaban, Vitaly; Khandelia, Himanshu; Shin, Ryoung

    2015-03-05

    High concentrations of cesium (Cs(+)) inhibit plant growth but the detailed mechanisms of Cs(+) uptake, transport and response in plants are not well known. In order to identify small molecules with a capacity to enhance plant tolerance to Cs(+), chemical library screening was performed using Arabidopsis. Of 10,000 chemicals tested, five compounds were confirmed as Cs(+) tolerance enhancers. Further investigation and quantum mechanical modelling revealed that one of these compounds reduced Cs(+) concentrations in plants and that the imidazole moiety of this compound bound specifically to Cs(+). Analysis of the analogous compounds indicated that the structure of the identified compound is important for the effect to be conferred. Taken together, Cs(+) tolerance enhancer isolated here renders plants tolerant to Cs(+) by inhibiting Cs(+) entry into roots via specific binding to the ion thus, for instance, providing a basis for phytostabilisation of radiocesium-contaminated farmland.

  17. Thinking about a Limited Future Enhances the Positivity of Younger and Older Adults’ Recall: Support for Socioemotional Selectivity Theory

    OpenAIRE

    Barber, Sarah J.; Opitz, Philipp C.; Martins, Bruna; Sakaki, Michiko; Mather, Mara

    2016-01-01

    Compared with younger adults, older adults have a relative preference to attend to and remember positive over negative information. This is known as the “positivity effect,” and researchers have typically evoked socioemotional selectivity theory to explain it. According to socioemotional selectivity theory, as people get older they begin to perceive their time left in life as more limited. These reduced time horizons prompt older adults to prioritize achieving emotional gratification and thus...

  18. Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

    Directory of Open Access Journals (Sweden)

    Cara J. Valvona

    2018-03-01

    Full Text Available Medulloblastoma is the most common malignant paediatric brain tumour and current therapies often leave patients with severe neurological disabilities. Four major molecular groups of medulloblastoma have been identified (Wnt, Shh, Group 3 and Group 4, which include additional, recently defined subgroups with different prognosis and genetic characteristics. Lactate dehydrogenase A (LDHA is a key enzyme in the aerobic glycolysis pathway, an abnormal metabolic pathway commonly observed in cancers, associated with tumour progression and metastasis. Studies indicate MBs have a glycolytic phenotype; however, LDHA has not yet been explored as a therapeutic target for medulloblastoma. LDHA expression was examined in medulloblastoma subgroups and cell lines. The effects of LDHA inhibition by oxamate or LDHA siRNA on medulloblastoma cell line metabolism, migration and proliferation were examined. LDHA was significantly overexpressed in Group 3 and Wnt MBs compared to non-neoplastic cerebellum. Furthermore, we found that oxamate significantly attenuated glycolysis, proliferation and motility in medulloblastoma cell lines, but LDHA siRNA did not. We established that aerobic glycolysis is a potential therapeutic target for medulloblastoma, but broader LDH inhibition (LDHA, B, and C may be more appropriate than LDHA inhibition alone.

  19. Selective inhibition of precursor incorporation into ribosomal RNA in gamma-irradiated Tetrahymena pyriformis

    International Nuclear Information System (INIS)

    Ernst, S.G.; Oleinick, N.L.; Rustad, R.C.; Greenblatt, R.M.

    1979-01-01

    Sublethal doses of γ radiation are known to inhibit total RNA synthesis in the ciliate protozoan Tetrahymena. To determine if the synthesis of a particular class of RNA is preferentially inhibited, pulse-labeled RNA was isolated from normal exponentially growing cells, irradiated cells, and cells in which total RNA synthesis had recovered to the pre-irradiation level. The RNAs were analyzed by SDS-polyacrylamide gel electrphoresis and oligo(dT)-cellulose column chromatography. Inhibition of RNA synthesis primarily involves ribosomal RNA. However, radiation does not cause a delay in the processing of precursor rRNA or a preferential loss of either of the mature rRNAs. Following irradiation, poly(A)-containing RNA [poly(A+)RNA] is synthesized at a rate up to three times greater than the control rate. The elevated poly(A+)RNA synthesis occurs during the period of depressed rRNA synthesis and even after rRNA synthesis has recovered to its pre-irradiation rate. While the sizes of the total cellular ribonucleoside triphosphate pools are depressed in the irradiated cells, these pools probably do not represent the actual compartments containing the precursors for RNA synthesis, and the observed changes cannot explain the modifications in macromolecular synthesis in irradiated Tetrahymena. (Auth.)

  20. Electrochemical activation and inhibition of neuromuscular systems through modulation of ion concentrations with ion-selective membranes

    Science.gov (United States)

    Song, Yong-Ak; Melik, Rohat; Rabie, Amr N.; Ibrahim, Ahmed M. S.; Moses, David; Tan, Ara; Han, Jongyoon; Lin, Samuel J.

    2011-12-01

    Conventional functional electrical stimulation aims to restore functional motor activity of patients with disabilities resulting from spinal cord injury or neurological disorders. However, intervention with functional electrical stimulation in neurological diseases lacks an effective implantable method that suppresses unwanted nerve signals. We have developed an electrochemical method to activate and inhibit a nerve by electrically modulating ion concentrations in situ along the nerve. Using ion-selective membranes to achieve different excitability states of the nerve, we observe either a reduction of the electrical threshold for stimulation by up to approximately 40%, or voluntary, reversible inhibition of nerve signal propagation. This low-threshold electrochemical stimulation method is applicable in current implantable neuroprosthetic devices, whereas the on-demand nerve-blocking mechanism could offer effective clinical intervention in disease states caused by uncontrolled nerve activation, such as epilepsy and chronic pain syndromes.

  1. Comparative Genomics of Smut Pathogens: Insights From Orphans and Positively Selected Genes Into Host Specialization

    Directory of Open Access Journals (Sweden)

    Juliana Benevenuto

    2018-04-01

    Full Text Available Host specialization is a key evolutionary process for the diversification and emergence of new pathogens. However, the molecular determinants of host range are poorly understood. Smut fungi are biotrophic pathogens that have distinct and narrow host ranges based on largely unknown genetic determinants. Hence, we aimed to expand comparative genomics analyses of smut fungi by including more species infecting different hosts and to define orphans and positively selected genes to gain further insights into the genetics basis of host specialization. We analyzed nine lineages of smut fungi isolated from eight crop and non-crop hosts: maize, barley, sugarcane, wheat, oats, Zizania latifolia (Manchurian rice, Echinochloa colona (a wild grass, and Persicaria sp. (a wild dicot plant. We assembled two new genomes: Ustilago hordei (strain Uhor01 isolated from oats and U. tritici (strain CBS 119.19 isolated from wheat. The smut genomes were of small sizes, ranging from 18.38 to 24.63 Mb. U. hordei species experienced genome expansions due to the proliferation of transposable elements and the amount of these elements varied among the two strains. Phylogenetic analysis confirmed that Ustilago is not a monophyletic genus and, furthermore, detected misclassification of the U. tritici specimen. The comparison between smut pathogens of crop and non-crop hosts did not reveal distinct signatures, suggesting that host domestication did not play a dominant role in shaping the evolution of smuts. We found that host specialization in smut fungi likely has a complex genetic basis: different functional categories were enriched in orphans and lineage-specific selected genes. The diversification and gain/loss of effector genes are probably the most important determinants of host specificity.

  2. Functional divergence caused by ancient positive selection of a Drosophila hybrid incompatibility locus.

    Directory of Open Access Journals (Sweden)

    Daniel A Barbash

    2004-06-01

    Full Text Available Interspecific hybrid lethality and sterility are a consequence of divergent evolution between species and serve to maintain the discrete identities of species. The evolution of hybrid incompatibilities has been described in widely accepted models by Dobzhansky and Muller where lineage-specific functional divergence is the essential characteristic of hybrid incompatibility genes. Experimentally tractable models are required to identify and test candidate hybrid incompatibility genes. Several Drosophila melanogaster genes involved in hybrid incompatibility have been identified but none has yet been shown to have functionally diverged in accordance with the Dobzhansky-Muller model. By introducing transgenic copies of the X-linked Hybrid male rescue (Hmr gene into D. melanogaster from its sibling species D. simulans and D. mauritiana, we demonstrate that Hmr has functionally diverged to cause F1 hybrid incompatibility between these species. Consistent with the Dobzhansky-Muller model, we find that Hmr has diverged extensively in the D. melanogaster lineage, but we also find extensive divergence in the sibling-species lineage. Together, these findings implicate over 13% of the amino acids encoded by Hmr as candidates for causing hybrid incompatibility. The exceptional level of divergence at Hmr cannot be explained by neutral processes because we use phylogenetic methods and population genetic analyses to show that the elevated amino-acid divergence in both lineages is due to positive selection in the distant past-at least one million generations ago. Our findings suggest that multiple substitutions driven by natural selection may be a general phenomenon required to generate hybrid incompatibility alleles.

  3. New evidence for positive selection helps explain the paternal age effect observed in achondroplasia

    Science.gov (United States)

    Shinde, Deepali N.; Elmer, Dominik P.; Calabrese, Peter; Boulanger, Jérôme; Arnheim, Norman; Tiemann-Boege, Irene

    2013-01-01

    There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome average. Moreover, these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones, known as the paternal age effect (PAE). The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single-nucleotide substitution (c.1138G>A) in FGFR3. To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline, we examined the spatial distribution of the c.1138G>A substitution in a testis from an 80-year-old unaffected man. Using a technology based on bead-emulsion amplification, we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false-positive rate lower than 2.7 × 10−6. We observed that most mutations are clustered in a few pieces with 95% of all mutations occurring in 27% of the total testis. Using computational simulations, we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site. Instead, we determined that the observed mutation distribution fits a germline selection model, where mutant spermatogonial stem cells have a proliferative advantage over unmutated cells. Combined with data on several other PAE mutations, our results support the idea that the PAE, associated with a number of Mendelian disorders, may be explained primarily by a selective mechanism. PMID:23740942

  4. Selective inhibition of CYP2C8 by fisetin and its methylated metabolite, geraldol, in human liver microsomes.

    Science.gov (United States)

    Shrestha, Riya; Kim, Ju-Hyun; Nam, Wongshik; Lee, Hye Suk; Lee, Jae-Mok; Lee, Sangkyu

    2018-04-01

    Fisetin is a flavonol compound commonly found in edible vegetables and fruits. It has anti-tumor, antioxidant, and anti-inflammatory effects. Geraldol, the O-methyl metabolite of fisetin in mice, is reported to suppress endothelial cell migration and proliferation. Although the in vivo and in vitro effects of fisetin and its metabolites are frequently reported, studies on herb-drug interactions have not yet been performed. This study was designed to investigate the inhibitory effect of fisetin and geraldol on eight isoforms of human cytochrome P450 (CYP) by using cocktail assay and LC-MS/MS analysis. The selective inhibition of CYP2C8-catalyzed paclitaxel hydroxylation by fisetin and geraldol were confirmed in pooled human liver microsomes (HLMs). In addition, an IC 50 shift assay under different pre-incubation conditions confirmed that fisetin and geraldol shows a reversible concentration-dependent, but not mechanism-based, inhibition of CYP2C8. Moreover, Michaelis-Menten, Lineweaver-burk plots, Dixon and Eadie-Hofstee showed a non-competitive inhibition mode with an equilibrium dissociation constant of 4.1 μM for fisetin and 11.5 μM for geraldol, determined from secondary plot of the Lineweaver-Burk plot. In conclusion, our results indicate that fisetin showed selective reversible and non-competitive inhibition of CYP2C8 more than its main metabolite, geraldol, in HLMs. Copyright © 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  5. Counting on dis-inhibition: a circuit motif for interval counting and selectivity in the anuran auditory system.

    Science.gov (United States)

    Naud, Richard; Houtman, Dave; Rose, Gary J; Longtin, André

    2015-11-01

    Information can be encoded in the temporal patterning of spikes. How the brain reads these patterns is of general importance and represents one of the greatest challenges in neuroscience. We addressed this issue in relation to temporal pattern recognition in the anuran auditory system. Many species of anurans perform mating decisions based on the temporal structure of advertisement calls. One important temporal feature is the number of sound pulses that occur with a species-specific interpulse interval. Neurons representing this pulse count have been recorded in the anuran inferior colliculus, but the mechanisms underlying their temporal selectivity are incompletely understood. Here, we construct a parsimonious model that can explain the key dynamical features of these cells with biologically plausible elements. We demonstrate that interval counting arises naturally when combining interval-selective inhibition with pulse-per-pulse excitation having both fast- and slow-conductance synapses. Interval-dependent inhibition is modeled here by a simple architecture based on known physiology of afferent nuclei. Finally, we consider simple implementations of previously proposed mechanistic explanations for these counting neurons and show that they do not account for all experimental observations. Our results demonstrate that tens of millisecond-range temporal selectivities can arise from simple connectivity motifs of inhibitory neurons, without recourse to internal clocks, spike-frequency adaptation, or appreciable short-term plasticity. Copyright © 2015 the American Physiological Society.

  6. Direction selectivity in the larval zebrafish tectum is mediated by asymmetric inhibition

    Directory of Open Access Journals (Sweden)

    Abhinav eGrama

    2012-09-01

    Full Text Available The extraction of the direction of motion is an important computation performed by many sensory systems and in particular, the mechanism by which direction selective ganglion cells (DS-RGCs in the retina acquire their selective properties, has been studied extensively. However, whether DS-RGCs simply relay this information to downstream areas or whether additional and potentially de-novo processing occurs in these recipient structures is a matter of great interest. Neurons in the larval zebrafish tectum, the largest retino-recipent area in this animal, show direction selective responses to moving visual stimuli but how these properties are acquired is still unknown. In order to study this, we first used two-photon calcium imaging to classify the population responses of tectal cells to bars moving at different speeds and in different directions. Subsequently, we performed in-vivo whole cell electrophysiology on these direction selective tectal neurons and we found that their inhibitory inputs were strongly biased towards the null direction of motion, whereas the excitatory inputs showed little selectivity. In addition, we found that excitatory currents evoked by a stimulus moving in the preferred direction occurred before the inhibitory currents whereas a stimulus moving in the null direction evoked currents in the reverse temporal order. The membrane potential modulations resulting from these currents were enhanced by the spike generation mechanism to generate amplified direction selectivity in the spike output. Thus our results implicate a local inhibitory circuit in generating direction selectivity in tectal neurons.

  7. Selecting Candidates for Key Leadership Positions in Program Executive Offices Ground Combat Systems and Combat Service and Combat Service Support

    Science.gov (United States)

    2016-10-14

    start or continue a profitable growth pattern and boost morale and motivation, a poor decision may bring the company to the brink of financial...HON Frank Kendall issued a memorandum titled “Key Leadership Positions and Qualification Criteria” (Kendall, 2013). This memorandum provides a...Chief Developmental Tester • Program Lead, Business Financial Manager SELECTING CANDIDATES FOR KEY LEADERSHIP POSITIONS 4

  8. Differential positive selection of malaria resistance genes in three indigenous populations of Peninsular Malaysia.

    Science.gov (United States)

    Liu, Xuanyao; Yunus, Yushimah; Lu, Dongsheng; Aghakhanian, Farhang; Saw, Woei-Yuh; Deng, Lian; Ali, Mohammad; Wang, Xu; Nor, Fadzilah Mohd; Ghazali, Fadzilah; Rahman, Thuhairah Abdul; Shaari, Shahrul Azlin; Salleh, Mohd Zaki; Phipps, Maude E; Ong, Rick Twee-Hee; Xu, Shuhua; Teo, Yik-Ying; Hoh, Boon-Peng

    2015-04-01

    The indigenous populations from Peninsular Malaysia, locally known as Orang Asli, continue to adopt an agro-subsistence nomadic lifestyle, residing primarily within natural jungle habitats. Leading a hunter-gatherer lifestyle in a tropical jungle environment, the Orang Asli are routinely exposed to malaria. Here we surveyed the genetic architecture of individuals from four Orang Asli tribes with high-density genotyping across more than 2.5 million polymorphisms. These tribes reside in different geographical locations in Peninsular Malaysia and belong to three main ethno-linguistic groups, where there is minimal interaction between the tribes. We first dissect the genetic diversity and admixture between the tribes and with neighboring urban populations. Later, by implementing five metrics, we investigated the genome-wide signatures for positive natural selection of these Orang Asli, respectively. Finally, we searched for evidence of genomic adaptation to the pressure of malaria infection. We observed that different evolutionary responses might have emerged in the different Orang Asli communities to mitigate malaria infection.

  9. Source apportionment and location by selective wind sampling and Positive Matrix Factorization.

    Science.gov (United States)

    Venturini, Elisa; Vassura, Ivano; Raffo, Simona; Ferroni, Laura; Bernardi, Elena; Passarini, Fabrizio

    2014-10-01

    In order to determine the pollution sources in a suburban area and identify the main direction of their origin, PM2.5 was collected with samplers coupled with a wind select sensor and then subjected to Positive Matrix Factorization (PMF) analysis. In each sample, soluble ions, organic carbon, elemental carbon, levoglucosan, metals, and Polycyclic Aromatic Hydrocarbons (PAHs) were determined. PMF results identified six main sources affecting the area: natural gas home appliances, motor vehicles, regional transport, biomass combustion, manufacturing activities, and secondary aerosol. The connection of factor temporal trends with other parameters (i.e., temperature, PM2.5 concentration, and photochemical processes) confirms factor attributions. PMF analysis indicated that the main source of PM2.5 in the area is secondary aerosol. This should be mainly due to regional contributions, owing to both the secondary nature of the source itself and the higher concentration registered in inland air masses. The motor vehicle emission source contribution is also important. This source likely has a prevalent local origin. The most toxic determined components, i.e., PAHs, Cd, Pb, and Ni, are mainly due to vehicular traffic. Even if this is not the main source in the study area, it is the one of greatest concern. The application of PMF analysis to PM2.5 collected with this new sampling technique made it possible to obtain more detailed results on the sources affecting the area compared to a classical PMF analysis.

  10. Silencing, positive selection and parallel evolution: busy history of primate cytochromes C.

    Science.gov (United States)

    Pierron, Denis; Opazo, Juan C; Heiske, Margit; Papper, Zack; Uddin, Monica; Chand, Gopi; Wildman, Derek E; Romero, Roberto; Goodman, Morris; Grossman, Lawrence I

    2011-01-01

    Cytochrome c (cyt c) participates in two crucial cellular processes, energy production and apoptosis, and unsurprisingly is a highly conserved protein. However, previous studies have reported for the primate lineage (i) loss of the paralogous testis isoform, (ii) an acceleration and then a deceleration of the amino acid replacement rate of the cyt c somatic isoform, and (iii) atypical biochemical behavior of human cyt c. To gain insight into the cause of these major evolutionary events, we have retraced the history of cyt c loci among primates. For testis cyt c, all primate sequences examined carry the same nonsense mutation, which suggests that silencing occurred before the primates diversified. For somatic cyt c, maximum parsimony, maximum likelihood, and Bayesian phylogenetic analyses yielded the same tree topology. The evolutionary analyses show that a fast accumulation of non-synonymous mutations (suggesting positive selection) occurred specifically on the anthropoid lineage root and then continued in parallel on the early catarrhini and platyrrhini stems. Analysis of evolutionary changes using the 3D structure suggests they are focused on the respiratory chain rather than on apoptosis or other cyt c functions. In agreement with previous biochemical studies, our results suggest that silencing of the cyt c testis isoform could be linked with the decrease of primate reproduction rate. Finally, the evolution of cyt c in the two sister anthropoid groups leads us to propose that somatic cyt c evolution may be related both to COX evolution and to the convergent brain and body mass enlargement in these two anthropoid clades.

  11. Potent and Selective Peptide-based Inhibition of the G Protein Gαq*

    Science.gov (United States)

    Charpentier, Thomas H.; Waldo, Gary L.; Lowery-Gionta, Emily G.; Krajewski, Krzysztof; Strahl, Brian D.; Kash, Thomas L.; Harden, T. Kendall; Sondek, John

    2016-01-01

    In contrast to G protein-coupled receptors, for which chemical and peptidic inhibitors have been extensively explored, few compounds are available that directly modulate heterotrimeric G proteins. Active Gαq binds its two major classes of effectors, the phospholipase C (PLC)-β isozymes and Rho guanine nucleotide exchange factors (RhoGEFs) related to Trio, in a strikingly similar fashion: a continuous helix-turn-helix of the effectors engages Gαq within its canonical binding site consisting of a groove formed between switch II and helix α3. This information was exploited to synthesize peptides that bound active Gαq in vitro with affinities similar to full-length effectors and directly competed with effectors for engagement of Gαq. A representative peptide was specific for active Gαq because it did not bind inactive Gαq or other classes of active Gα subunits and did not inhibit the activation of PLC-β3 by Gβ1γ2. In contrast, the peptide robustly prevented activation of PLC-β3 or p63RhoGEF by Gαq; it also prevented G protein-coupled receptor-promoted neuronal depolarization downstream of Gαq in the mouse prefrontal cortex. Moreover, a genetically encoded form of this peptide flanked by fluorescent proteins inhibited Gαq-dependent activation of PLC-β3 at least as effectively as a dominant-negative form of full-length PLC-β3. These attributes suggest that related, cell-penetrating peptides should effectively inhibit active Gαq in cells and that these and genetically encoded sequences may find application as molecular probes, drug leads, and biosensors to monitor the spatiotemporal activation of Gαq in cells. PMID:27742837

  12. Acute inhibition of selected membrane-proximal mouse T cell receptor signaling by mitochondrial antagonists.

    Directory of Open Access Journals (Sweden)

    Kwangmi Kim

    2009-11-01

    Full Text Available T cells absorb nanometric membrane vesicles, prepared from plasma membrane of antigen presenting cells, via dual receptor/ligand interactions of T cell receptor (TCR with cognate peptide/major histocompatibility complex (MHC plus lymphocyte function-associated antigen 1 (LFA-1 with intercellular adhesion molecule 1. TCR-mediated signaling for LFA-1 activation is also required for the vesicle absorption. Exploiting those findings, we had established a high throughput screening (HTS platform and screened a library for isolation of small molecules inhibiting the vesicle absorption. Follow-up studies confirmed that treatments (1 hour with various mitochondrial antagonists, including a class of anti-diabetic drugs (i.e., Metformin and Phenformin, resulted in ubiquitous inhibition of the vesicle absorption without compromising viability of T cells. Further studies revealed that the mitochondrial drug treatments caused impairment of specific membrane-proximal TCR signaling event(s. Thus, activation of Akt and PLC-gamma1 and entry of extracellular Ca(2+ following TCR stimulation were attenuated while polymerization of monomeric actins upon TCR triggering progressed normally after the treatments. Dynamic F-actin rearrangement concurring with the vesicle absorption was also found to be impaired by the drug treatments, implying that the inhibition by the drug treatments of downstream signaling events (and the vesicle absorption could result from lack of directional relocation of signaling and cell surface molecules. We also assessed the potential application of mitochondrial antagonists as immune modulators by probing effects of the long-term drug treatments (24 hours on viability of resting primary T cells and cell cycle progression of antigen-stimulated T cells. This study unveils a novel regulatory mechanism for T cell immunity in response to environmental factors having effects on mitochondrial function.

  13. Potent and Selective Peptide-based Inhibition of the G Protein Gαq.

    Science.gov (United States)

    Charpentier, Thomas H; Waldo, Gary L; Lowery-Gionta, Emily G; Krajewski, Krzysztof; Strahl, Brian D; Kash, Thomas L; Harden, T Kendall; Sondek, John

    2016-12-02

    In contrast to G protein-coupled receptors, for which chemical and peptidic inhibitors have been extensively explored, few compounds are available that directly modulate heterotrimeric G proteins. Active Gα q binds its two major classes of effectors, the phospholipase C (PLC)-β isozymes and Rho guanine nucleotide exchange factors (RhoGEFs) related to Trio, in a strikingly similar fashion: a continuous helix-turn-helix of the effectors engages Gα q within its canonical binding site consisting of a groove formed between switch II and helix α3. This information was exploited to synthesize peptides that bound active Gα q in vitro with affinities similar to full-length effectors and directly competed with effectors for engagement of Gα q A representative peptide was specific for active Gα q because it did not bind inactive Gα q or other classes of active Gα subunits and did not inhibit the activation of PLC-β3 by Gβ 1 γ 2 In contrast, the peptide robustly prevented activation of PLC-β3 or p63RhoGEF by Gα q ; it also prevented G protein-coupled receptor-promoted neuronal depolarization downstream of Gα q in the mouse prefrontal cortex. Moreover, a genetically encoded form of this peptide flanked by fluorescent proteins inhibited Gα q -dependent activation of PLC-β3 at least as effectively as a dominant-negative form of full-length PLC-β3. These attributes suggest that related, cell-penetrating peptides should effectively inhibit active Gα q in cells and that these and genetically encoded sequences may find application as molecular probes, drug leads, and biosensors to monitor the spatiotemporal activation of Gα q in cells. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Glucagon Amyloid-like Fibril Morphology Is Selected via Morphology-Dependent Growth Inhibition

    DEFF Research Database (Denmark)

    Andersen, C.B.; Otzen, D.; Christiansen, Gunna

    2007-01-01

    Protein Structure and Biophysics, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Malov, Denmark, Centre for Insoluble Protein Structures (inSPIN), Department of Life Sciences, Aalborg University, Sohngaardsholmsvej 49, DK-9000 Aalborg, Denmark, and Institute of Medical Microbiology and Immunology...... twisted fibril seeds cannot grow at high concentrations. We conclude that there exists a morphology-dependent mechanism for inhibition of glucagon fibril growth. Light scattering experiments indicate that glucagon is mainly monomeric below 1 mg/mL and increasingly trimeric above this concentration. We...

  15. Growth inhibition of selected microorganisms by an association of dairy starter cultures and probiotics

    Directory of Open Access Journals (Sweden)

    Beniamino T. Cenci-Goga

    2015-05-01

    Full Text Available Several growth curves for selected pathogens and hygiene indicators alone and vs selected dairy starter cultures (LAB and commercial probiotics have been performed. All strains for LAB and commercial probiotics were inoculated as pure cultures into skim milk to get an initial cocci:bacilli:enterocci ratio of 2:1:1 and a concentration of approximately 107 cfu mL–1 until challenge vs selected pathogens and hygiene indicators. Selected pathogens came from the collection of the Laboratorio di Ispezione degli Alimenti di O.A. or were reference strains (Escherichia coli, CSH26 K12, Staphylococcus aureus 27R, Salmonella Derby 27, Pseudomonas fluorescens ATCC 13525, Listeria innocua ATCC 33090. Each strain was inoculated into skim milk to get an initial concentration of approximately 106 cfu mL–1. Growth curves in skim milk for the following challenges were studied: i sterility control; ii association LAB; iii association of LAB vs each selected pathogen or hygiene indicator; iv selected pathogen or hygiene indicator alone. The challenges were carried out in BHI broth and in skim milk at 37°C. The highest reduction was observed in milk but in general the association of LAB and the probiotic was able to limit the growth of pathogens and hygiene indicators.

  16. Transcriptome-based phylogeny of endemic Lake Baikal amphipod species flock: fast speciation accompanied by frequent episodes of positive selection.

    Science.gov (United States)

    Naumenko, Sergey A; Logacheva, Maria D; Popova, Nina V; Klepikova, Anna V; Penin, Aleksey A; Bazykin, Georgii A; Etingova, Anna E; Mugue, Nikolai S; Kondrashov, Alexey S; Yampolsky, Lev Y

    2017-01-01

    Endemic species flocks inhabiting ancient lakes, oceanic islands and other long-lived isolated habitats are often interpreted as adaptive radiations. Yet molecular evidence for directional selection during species flocks radiation is scarce. Using partial transcriptomes of 64 species of Lake Baikal (Siberia, Russia) endemic amphipods and two nonendemic outgroups, we report a revised phylogeny of this species flock and analyse evidence for positive selection within the endemic lineages. We confirm two independent invasions of amphipods into Baikal and demonstrate that several morphological features of Baikal amphipods, such as body armour and reduction in appendages and sensory organs, evolved in several lineages in parallel. Radiation of Baikal amphipods has been characterized by short phylogenetic branches and frequent episodes of positive selection which tended to be more frequent in the early phase of the second invasion of amphipods into Baikal when the most intensive diversification occurred. Notably, signatures of positive selection are frequent in genes encoding mitochondrial membrane proteins with electron transfer chain and ATP synthesis functionality. In particular, subunits of both the membrane and substrate-level ATP synthases show evidence of positive selection in the plankton species Macrohectopus branickii, possibly indicating adaptation to active plankton lifestyle and to survival under conditions of low temperature and high hydrostatic pressures known to affect membranes functioning. Other functional categories represented among genes likely to be under positive selection include Ca-binding muscle-related proteins, possibly indicating adaptation to Ca-deficient low mineralization Baikal waters. © 2016 John Wiley & Sons Ltd.

  17. Systematic detection of positive selection in the human-pathogen interactome and lasting effects on infectious disease susceptibility.

    Directory of Open Access Journals (Sweden)

    Erik Corona

    Full Text Available Infectious disease has shaped the natural genetic diversity of humans throughout the world. A new approach to capture positive selection driven by pathogens would provide information regarding pathogen exposure in distinct human populations and the constantly evolving arms race between host and disease-causing agents. We created a human pathogen interaction database and used the integrated haplotype score (iHS to detect recent positive selection in genes that interact with proteins from 26 different pathogens. We used the Human Genome Diversity Panel to identify specific populations harboring pathogen-interacting genes that have undergone positive selection. We found that human genes that interact with 9 pathogen species show evidence of recent positive selection. These pathogens are Yersenia pestis, human immunodeficiency virus (HIV 1, Zaire ebolavirus, Francisella tularensis, dengue virus, human respiratory syncytial virus, measles virus, Rubella virus, and Bacillus anthracis. For HIV-1, GWAS demonstrate that some naturally selected variants in the host-pathogen protein interaction networks continue to have functional consequences for susceptibility to these pathogens. We show that selected human genes were enriched for HIV susceptibility variants (identified through GWAS, providing further support for the hypothesis that ancient humans were exposed to lentivirus pandemics. Human genes in the Italian, Miao, and Biaka Pygmy populations that interact with Y. pestis show significant signs of selection. These results reveal some of the genetic footprints created by pathogens in the human genome that may have left lasting marks on susceptibility to infectious disease.

  18. Stressing the ubiquitin-proteasome system without 20S proteolytic inhibition selectively kills cervical cancer cells.

    Directory of Open Access Journals (Sweden)

    Ravi K Anchoori

    Full Text Available Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate, and for specific signaling pathways, notably HPV E6-targeted degradation of p53 and PDZ proteins. Natural compounds with antioxidant properties including flavonoids and triterpenoids hold promise as anticancer agents by interfering with ubiquitin-dependent protein degradation. An increasing body of evidence indicates that their α-β unsaturated carbonyl system is the molecular determinant for inhibition of ubiquitin-mediated protein degradation up-stream of the catalytic sites of the 20S proteasome. Herein we report the identification and characterization of a new class of chalcone-based, potent and cell permeable chemical inhibitors of ubiquitin-dependent protein degradation, and a lead compound RAMB1. RAMB1 inhibits ubiquitin-dependent protein degradation without compromising the catalytic activities of the 20S proteasome, a mechanism distinct from that of Bortezomib. Treatment of cervical cancer cells with RAMB1 triggers unfolded protein responses, including aggresome formation and Hsp90 stabilization, and increases p53 steady state levels. RAMB1 treatment results in activation of lysosomal-dependent degradation pathways as a mechanism to compensate for increasing levels of poly-ubiquitin enriched toxic aggregates. Importantly, RAMB1 synergistically triggers cell death of cervical cancer cells when combined with the lysosome inhibitor Chloroquine.

  19. Mathematical Optimization Algorithm for Minimizing the Cost Function of GHG Emission in AS/RS Using Positive Selection Based Clonal Selection Principle

    Science.gov (United States)

    Mahalakshmi; Murugesan, R.

    2018-04-01

    This paper regards with the minimization of total cost of Greenhouse Gas (GHG) efficiency in Automated Storage and Retrieval System (AS/RS). A mathematical model is constructed based on tax cost, penalty cost and discount cost of GHG emission of AS/RS. A two stage algorithm namely positive selection based clonal selection principle (PSBCSP) is used to find the optimal solution of the constructed model. In the first stage positive selection principle is used to reduce the search space of the optimal solution by fixing a threshold value. In the later stage clonal selection principle is used to generate best solutions. The obtained results are compared with other existing algorithms in the literature, which shows that the proposed algorithm yields a better result compared to others.

  20. The modulation of inhibition of return by object-internal structure: implications for theories of object-based attentional selection.

    Science.gov (United States)

    Reppa, Irene; Leek, E Charles

    2003-06-01

    Recently, Vecera, Behrmann, and McGoldrick (2000), using a divided-attention task, reported that targets are detected more accurately when they occur on the same structural part of an object, suggesting that attention can be directed toward object-internal features. We present converging evidence using the object-based inhibition of return (IOR) paradigm as an implicit measure of selection. The results show that IOR is attenuated when cues and targets appear on the same part of an object relative to when they are separated by a part boundary. These findings suggest that object-based mechanisms of selection can operate over shape representations that make explicit information about object-internal structure.

  1. Purine salvage in the apicomplexan Sarcocystis neurona, and generation of hypoxanthine-xanthine-guanine phosphoribosyltransferase-deficient clones for positive-negative selection of transgenic parasites.

    Science.gov (United States)

    Dangoudoubiyam, Sriveny; Zhang, Zijing; Howe, Daniel K

    2014-09-01

    Sarcocystis neurona is an apicomplexan parasite that causes severe neurological disease in horses and marine mammals. The Apicomplexa are all obligate intracellular parasites that lack purine biosynthesis pathways and rely on the host cell for their purine requirements. Hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT) and adenosine kinase (AK) are key enzymes that function in two complementary purine salvage pathways in apicomplexans. Bioinformatic searches of the S. neurona genome revealed genes encoding HXGPRT, AK and all of the major purine salvage enzymes except purine nucleoside phosphorylase. Wild-type S. neurona were able to grow in the presence of mycophenolic acid (MPA) but were inhibited by 6-thioxanthine (6-TX), suggesting that the pathways involving either HXGPRT or AK are functional in this parasite. Prior work with Toxoplasma gondii demonstrated the utility of HXGPRT as a positive-negative selection marker. To enable the use of HXGPRT in S. neurona, the SnHXGPRT gene sequence was determined and a gene-targeting plasmid was transfected into S. neurona. SnHXGPRT-deficient mutants were selected with 6-TX, and single-cell clones were obtained. These Sn∆HXG parasites were susceptible to MPA and could be complemented using the heterologous T. gondii HXGPRT gene. In summary, S. neurona possesses both purine salvage pathways described in apicomplexans, thus allowing the use of HXGPRT as a positive-negative drug selection marker in this parasite.

  2. Intraocular lens power selection and positioning with and without intraoperative aberrometry.

    Science.gov (United States)

    Hatch, Kathryn M; Woodcock, Emily C; Talamo, Jonathan H

    2015-04-01

    To determine the value of intraoperative aberrometry in cases of toric intraocular lens (IOL) implantation and positioning. In this non-randomized retrospective comparative trial, two groups of eyes underwent cataract extraction with toric IOL implantation: the aberrometry group (n = 37 eyes), where toric IOL power and alignment were determined before surgery with automated keratometry, standard optical biometry, and an online calculator and then refined using intraoperative aberrometry, and the toric calculator group (n = 27 eyes), where IOL selection was performed in a similar manner but without intraoperative aberrometry. The primary outcome measure was mean postoperative residual refractive astigmatism (RRA). Mean RRA measured at follow-up after surgery was 0.46 ± 0.42 and 0.68 ± 0.34 diopters (D) in the aberrometry and toric calculator groups, respectively (P = .0153). A 75% and 57% reduction in cylinder was noted between preoperative keratometric astigmatism and postoperative RRA in the aberrometry and toric calculator groups, respectively (P = .0027). RRA of 0.25 D or less, 0.50 D or less, 0.75 D or less, and 1.00 D or less was seen 38%, 78%, 86%, and 95% of the time, respectively, in the aberrometry group and 22%, 33%, 74%, and 89% of the time, respectively, in the toric calculator group. These data show that the chance of a patient being in a lower postoperative RRA range increased when intraoperative aberrometry was used (P = .0130). Patients undergoing cataract extraction with toric IOL placement aided by intraoperative aberrometry were 2.4 times more likely to have less than 0.50 D of RRA compared to standard methods. Copyright 2015, SLACK Incorporated.

  3. Silencing, positive selection and parallel evolution: busy history of primate cytochromes C.

    Directory of Open Access Journals (Sweden)

    Denis Pierron

    Full Text Available Cytochrome c (cyt c participates in two crucial cellular processes, energy production and apoptosis, and unsurprisingly is a highly conserved protein. However, previous studies have reported for the primate lineage (i loss of the paralogous testis isoform, (ii an acceleration and then a deceleration of the amino acid replacement rate of the cyt c somatic isoform, and (iii atypical biochemical behavior of human cyt c. To gain insight into the cause of these major evolutionary events, we have retraced the history of cyt c loci among primates. For testis cyt c, all primate sequences examined carry the same nonsense mutation, which suggests that silencing occurred before the primates diversified. For somatic cyt c, maximum parsimony, maximum likelihood, and Bayesian phylogenetic analyses yielded the same tree topology. The evolutionary analyses show that a fast accumulation of non-synonymous mutations (suggesting positive selection occurred specifically on the anthropoid lineage root and then continued in parallel on the early catarrhini and platyrrhini stems. Analysis of evolutionary changes using the 3D structure suggests they are focused on the respiratory chain rather than on apoptosis or other cyt c functions. In agreement with previous biochemical studies, our results suggest that silencing of the cyt c testis isoform could be linked with the decrease of primate reproduction rate. Finally, the evolution of cyt c in the two sister anthropoid groups leads us to propose that somatic cyt c evolution may be related both to COX evolution and to the convergent brain and body mass enlargement in these two anthropoid clades.

  4. FLAX OIL FROM TRANSGENIC LINUM USITATISSIMUM SELECTIVELY INHIBITS IN VITRO PROLIFERATION OF HUMAN CANCER CELL LINES.

    Science.gov (United States)

    Gebarowski, Tomasz; Gebczak, Katarzyna; Wiatrak, Benita; Kulma, Anna; Pelc, Katarzyna; Czuj, Tadeusz; Szopa, Jan; Gasiorowski, Kazimierz

    2017-03-01

    Emulsions made of oils from transgenic flaxseeds significantly decreased in vitro proliferation of six tested human cancer cell lines in 48-h cultures, as assessed with the standard sulforhodamine assay. However, the emulsions also increased proliferation rate of normal human dermal fibroblasts and, to a lower extend, of keratinocytes. Both inhibition of in vitro proliferation of human cancer cell lines and stimulation of proliferation of normal dermal fibroblasts and keratinocytes were especially strong with the emulsion type B and with emulsion type M. Oils from seeds of transgenic flax type B and M should be considered as valuable adjunct to standard cytostatic therapy of human cancers and also could be applied to improve the treatment of skin lesions in wound healing.

  5. Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

    Science.gov (United States)

    Kobayashi, Toru; Washiyama, Kazuo; Ikeda, Kazutaka

    2010-01-01

    Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attention-deficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K+ (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentration-dependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A1 adenosine receptors or by intracellularly applied GTPγS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain- and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function. PMID:20393461

  6. Review of the inhibition of biological activities of food-related selected toxins by natural compounds.

    Science.gov (United States)

    Friedman, Mendel; Rasooly, Reuven

    2013-04-23

    There is a need to develop food-compatible conditions to alter the structures of fungal, bacterial, and plant toxins, thus transforming toxins to nontoxic molecules. The term 'chemical genetics' has been used to describe this approach. This overview attempts to survey and consolidate the widely scattered literature on the inhibition by natural compounds and plant extracts of the biological (toxicological) activity of the following food-related toxins: aflatoxin B1, fumonisins, and ochratoxin A produced by fungi; cholera toxin produced by Vibrio cholerae bacteria; Shiga toxins produced by E. coli bacteria; staphylococcal enterotoxins produced by Staphylococcus aureus bacteria; ricin produced by seeds of the castor plant Ricinus communis; and the glycoalkaloid α-chaconine synthesized in potato tubers and leaves. The reduction of biological activity has been achieved by one or more of the following approaches: inhibition of the release of the toxin into the environment, especially food; an alteration of the structural integrity of the toxin molecules; changes in the optimum microenvironment, especially pH, for toxin activity; and protection against adverse effects of the toxins in cells, animals, and humans (chemoprevention). The results show that food-compatible and safe compounds with anti-toxin properties can be used to reduce the toxic potential of these toxins. Practical applications and research needs are suggested that may further facilitate reducing the toxic burden of the diet. Researchers are challenged to (a) apply the available methods without adversely affecting the nutritional quality, safety, and sensory attributes of animal feed and human food and (b) educate food producers and processors and the public about available approaches to mitigating the undesirable effects of natural toxins that may present in the diet.

  7. Orientation selectivity in inhibition-dominated networks of spiking neurons: effect of single neuron properties and network dynamics.

    Science.gov (United States)

    Sadeh, Sadra; Rotter, Stefan

    2015-01-01

    The neuronal mechanisms underlying the emergence of orientation selectivity in the primary visual cortex of mammals are still elusive. In rodents, visual neurons show highly selective responses to oriented stimuli, but neighboring neurons do not necessarily have similar preferences. Instead of a smooth map, one observes a salt-and-pepper organization of orientation selectivity. Modeling studies have recently confirmed that balanced random networks are indeed capable of amplifying weakly tuned inputs and generating highly selective output responses, even in absence of feature-selective recurrent connectivity. Here we seek to elucidate the neuronal mechanisms underlying this phenomenon by resorting to networks of integrate-and-fire neurons, which are amenable to analytic treatment. Specifically, in networks of perfect integrate-and-fire neurons, we observe that highly selective and contrast invariant output responses emerge, very similar to networks of leaky integrate-and-fire neurons. We then demonstrate that a theory based on mean firing rates and the detailed network topology predicts the output responses, and explains the mechanisms underlying the suppression of the common-mode, amplification of modulation, and contrast invariance. Increasing inhibition dominance in our networks makes the rectifying nonlinearity more prominent, which in turn adds some distortions to the otherwise essentially linear prediction. An extension of the linear theory can account for all the distortions, enabling us to compute the exact shape of every individual tuning curve in our networks. We show that this simple form of nonlinearity adds two important properties to orientation selectivity in the network, namely sharpening of tuning curves and extra suppression of the modulation. The theory can be further extended to account for the nonlinearity of the leaky model by replacing the rectifier by the appropriate smooth input-output transfer function. These results are robust and do not

  8. Orientation selectivity in inhibition-dominated networks of spiking neurons: effect of single neuron properties and network dynamics.

    Directory of Open Access Journals (Sweden)

    Sadra Sadeh

    2015-01-01

    Full Text Available The neuronal mechanisms underlying the emergence of orientation selectivity in the primary visual cortex of mammals are still elusive. In rodents, visual neurons show highly selective responses to oriented stimuli, but neighboring neurons do not necessarily have similar preferences. Instead of a smooth map, one observes a salt-and-pepper organization of orientation selectivity. Modeling studies have recently confirmed that balanced random networks are indeed capable of amplifying weakly tuned inputs and generating highly selective output responses, even in absence of feature-selective recurrent connectivity. Here we seek to elucidate the neuronal mechanisms underlying this phenomenon by resorting to networks of integrate-and-fire neurons, which are amenable to analytic treatment. Specifically, in networks of perfect integrate-and-fire neurons, we observe that highly selective and contrast invariant output responses emerge, very similar to networks of leaky integrate-and-fire neurons. We then demonstrate that a theory based on mean firing rates and the detailed network topology predicts the output responses, and explains the mechanisms underlying the suppression of the common-mode, amplification of modulation, and contrast invariance. Increasing inhibition dominance in our networks makes the rectifying nonlinearity more prominent, which in turn adds some distortions to the otherwise essentially linear prediction. An extension of the linear theory can account for all the distortions, enabling us to compute the exact shape of every individual tuning curve in our networks. We show that this simple form of nonlinearity adds two important properties to orientation selectivity in the network, namely sharpening of tuning curves and extra suppression of the modulation. The theory can be further extended to account for the nonlinearity of the leaky model by replacing the rectifier by the appropriate smooth input-output transfer function. These results are

  9. Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway.

    Directory of Open Access Journals (Sweden)

    Desheng Lu

    Full Text Available BACKGROUND: Aberrant activation of Wnt/beta-catenin signaling promotes the development of several cancers. It has been demonstrated that the Wnt signaling pathway is activated in chronic lymphocytic leukemia (CLL cells, and that uncontrolled Wnt/beta-catenin signaling may contribute to the defect in apoptosis that characterizes this malignancy. Thus, the Wnt signaling pathway is an attractive candidate for developing targeted therapies for CLL. METHODOLOGY/PRINCIPAL FINDINGS: The diuretic agent ethacrynic acid (EA was identified as a Wnt inhibitor using a cell-based Wnt reporter assay. In vitro assays further confirmed the inhibitory effect of EA on Wnt/beta-catenin signaling. Cell viability assays showed that EA selectively induced cell death in primary CLL cells. Exposure of CLL cells to EA decreased the expression of Wnt/beta-catenin target genes, including LEF-1, cyclin D1 and fibronectin. Immune co-precipitation experiments demonstrated that EA could directly bind to LEF-1 protein and destabilize the LEF-1/beta-catenin complex. N-acetyl-L-cysteine (NAC, which can react with the alpha, beta-unsaturated ketone in EA, but not other anti-oxidants, prevented the drug's inhibition of Wnt/beta-catenin activation and its ability to induce apoptosis in CLL cells. CONCLUSIONS/SIGNIFICANCE: Our studies indicate that EA selectively suppresses CLL survival due to inhibition of Wnt/beta-catenin signaling. Antagonizing Wnt signaling in CLL with EA or related drugs may represent an effective treatment of this disease.

  10. Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently inhibit feline immunodeficiency virus replication

    NARCIS (Netherlands)

    Horzinek, M.C.; Egberink, H.F.; Clercq, E. de; Vliet, A.L.W. van; Balzarini, J.; Bridger, G.J.; Henson, G.; Schols, D.

    1999-01-01

    Bicyclams are low-molecular-weight anti-human immunodeficiency virus (HIV) agents that have been shown to act as potent and selective CXC chemokine receptor 4 (CXCR4) antagonists. Here, we demonstrate that bicyclams are potent inhibitors of feline immunodeficiency virus (FIV) replication when

  11. Selective cyclooxygenase-1 inhibition improves collateral vascular reactivity in biliary cirrhotic rats

    Directory of Open Access Journals (Sweden)

    Ching-Chih Chang

    2013-10-01

    Conclusion: There was no significant hemodynamic change and renal toxicity after acute administration of COX inhibitor in the FBDL-induced cirrhotic rats. Preincubation of selective COX-1, but not COX-2, inhibitor could enhance collateral vascular response to AVP, indicating that COX-1 plays a major role in the collateral vascular reactivity.

  12. Interference and Inhibition in Tasks of Selective Attention by Persons with and without Mental Retardation

    Science.gov (United States)

    Merrill, Edward C.

    2006-01-01

    Persons with mental retardation often exhibit greater interference in visual selective attention tasks than do persons matched with them on CA. My goal here was to evaluate whether differences in distractor interference between persons with and without mental retardation may be related to differences in negative priming. Fifteen participants with…

  13. Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism.

    OpenAIRE

    Miner, W. D.; Sanger, G. J.

    1986-01-01

    MDL 72222, the selective 5-hydroxytryptamine (5-HT) M-receptor antagonist, prevented or reduced cisplatin-induced emesis in ferrets. It is suggested that cisplatin-induced, and possibly other cytotoxic drug-induced vomiting may involve a 5-HT M-receptor mechanism.

  14. Construction of Expression Vector for Anti-Alpha-Fetoprotein Gene and Its Inhibition Effects on Alpha-Fetoprotein Positive Hepg2 Cells

    Science.gov (United States)

    Wang, Ze; Zhang, Hui

    As research previously demonstrated, suppression of AFP expression or its biological activities might inhibit the proliferation of AFP positive human hepatocellular carcinoma cells. In this study, we constructed an anti-AFP gene vector and transfected it to HepG2 cells. RT-PCR showed AFP gene expression in the transfected cells was reduced. MTT assay suggested the proliferation of the transfected cells was also inhibited comparing with the untransfected cells. This result provides a new insight into AFP as the target for preventing and treating hepatocellular carcinoma.

  15. Adaptive evolution of the spike gene of SARS coronavirus: changes in positively selected sites in different epidemic groups

    Directory of Open Access Journals (Sweden)

    He Shao-Heng

    2006-10-01

    Full Text Available Abstract Background It is believed that animal-to-human transmission of severe acute respiratory syndrome (SARS coronavirus (CoV is the cause of the SARS outbreak worldwide. The spike (S protein is one of the best characterized proteins of SARS-CoV, which plays a key role in SARS-CoV overcoming species barrier and accomplishing interspecies transmission from animals to humans, suggesting that it may be the major target of selective pressure. However, the process of adaptive evolution of S protein and the exact positively selected sites associated with this process remain unknown. Results By investigating the adaptive evolution of S protein, we identified twelve amino acid sites (75, 239, 244, 311, 479, 609, 613, 743, 765, 778, 1148, and 1163 in the S protein under positive selective pressure. Based on phylogenetic tree and epidemiological investigation, SARS outbreak was divided into three epidemic groups: 02–04 interspecies, 03-early-mid, and 03-late epidemic groups in the present study. Positive selection was detected in the first two groups, which represent the course of SARS-CoV interspecies transmission and of viral adaptation to human host, respectively. In contrast, purifying selection was detected in 03-late group. These indicate that S protein experiences variable positive selective pressures before reaching stabilization. A total of 25 sites in 02–04 interspecies epidemic group and 16 sites in 03-early-mid epidemic group were identified under positive selection. The identified sites were different between these two groups except for site 239, which suggests that positively selected sites are changeable between groups. Moreover, it was showed that a larger proportion (24% of positively selected sites was located in receptor-binding domain (RBD than in heptad repeat (HR1-HR2 region in 02–04 interspecies epidemic group (p = 0.0208, and a greater percentage (25% of these sites occurred in HR1–HR2 region than in RBD in 03-early

  16. Molecular size is important for the safety and selective inhibition of intrinsic factor Xase for fucosylated chondroitin sulfate.

    Science.gov (United States)

    Yan, Lufeng; Li, Junhui; Wang, Danli; Ding, Tian; Hu, Yaqin; Ye, Xingqian; Linhardt, Robert J; Chen, Shiguo

    2017-12-15

    Fucosylated chondroitin sulfate from sea cucumber Isostichopus badionotus (FCS-Ib) showed potent anticoagulant activities without selectivity. The present study focused on developing safe FCS-Ib oligomers showing selective inhibition of intrinsic factor Xase (anti-FXase) prepared through partial N-deacetylation-deaminative cleavage. The N-deacetylation degree was regulated by reaction time, controlling the resulting oligomer distribution. Structure analysis confirmed the selectivity of degradation, and 12 high purity fractions with trisaccharide-repeating units were separated. In vitro anticoagulant assays indicated a decrease in molecular weight (Mw) dramatically reduced activated partial thromboplastin time (APTT), thrombin time (TT), AT-dependent anti-FIIa and anti-FXa activities, while the oligomers retained potent anti-FXase activity until they fell below 3kDa. Meanwhile, human FXII activation and platelet aggregation were markedly reduced with decreasing Mw and were moderate when under 12.0kDa. Thus, fragments of 3-12.0kDa should be safe and effective as selective inhibitors of intrinsic tenase complex for application as clinical anticoagulants. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Does marriage inhibit antisocial behavior?: An examination of selection vs causation via a longitudinal twin design.

    Science.gov (United States)

    Burt, S Alexandra; Donnellan, M Brent; Humbad, Mikhila N; Hicks, Brian M; McGue, Matt; Iacono, William G

    2010-12-01

    Previous studies have indicated that marriage is negatively associated with male antisocial behavior. Although often interpreted as a causal association, marriage is not a random event. As such, the association may stem from selection processes, whereby men less inclined toward antisocial behavior are more likely to marry. To evaluate selection vs causation explanations of the association between marriage and desistence from antisocial behavior. Co-twin control analyses in a prospective twin study provided an analogue of the idealized counterfactual model of causation. The co-twin control design uses the unmarried co-twin of a married twin to estimate what the married twin would have looked like had he remained unmarried. Discordant monozygotic (MZ) twins are particularly informative because they share a common genotype and rearing environment. General community study. Two hundred eighty-nine male-male twin pairs (65.1% MZ) from the Minnesota Twin Family Study underwent assessment at 17, 20, 24, and 29 years of age. None of the participants were married at 17 years of age, and 2.6% were married at 20 years of age. By 29 years of age, 58.8% of the participants were or had been married. A tally of criterion C symptoms of DSM-III-R antisocial personality disorder, as assessed via structured clinical interview. Mean differences in antisocial behavior across marital status at age 29 years were present even at 17 and 20 years of age, suggesting a selection process. However, the within-pair effect of marriage was significant for MZ twins, such that the married twin engaged in less antisocial behavior following marriage than his unmarried co-twin. Results were equivalent to those in dizygotic twins and persisted when controlling for prior antisocial behavior. Results indicate an initial selection effect, whereby men with lower levels of antisocial behavior are more likely to marry. However, this tendency to refrain from antisocial behavior appears to be accentuated by the

  18. Caspase inhibition in select olfactory neurons restores innate attraction behavior in aged Drosophila.

    Directory of Open Access Journals (Sweden)

    Takahiro Chihara

    2014-06-01

    Full Text Available Sensory and cognitive performance decline with age. Neural dysfunction caused by nerve death in senile dementia and neurodegenerative disease has been intensively studied; however, functional changes in neural circuits during the normal aging process are not well understood. Caspases are key regulators of cell death, a hallmark of age-related neurodegeneration. Using a genetic probe for caspase-3-like activity (DEVDase activity, we have mapped age-dependent neuronal changes in the adult brain throughout the lifespan of Drosophila. Spatio-temporally restricted caspase activation was observed in the antennal lobe and ellipsoid body, brain structures required for olfaction and visual place memory, respectively. We also found that caspase was activated in an age-dependent manner in specific subsets of Drosophila olfactory receptor neurons (ORNs, Or42b and Or92a neurons. These neurons are essential for mediating innate attraction to food-related odors. Furthermore, age-induced impairments of neural transmission and attraction behavior could be reversed by specific inhibition of caspase in these ORNs, indicating that caspase activation in Or42b and Or92a neurons is responsible for altering animal behavior during normal aging.

  19. BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements.

    Science.gov (United States)

    Bhagwat, Anand S; Roe, Jae-Seok; Mok, Beverly Y L; Hohmann, Anja F; Shi, Junwei; Vakoc, Christopher R

    2016-04-19

    The bromodomain and extraterminal (BET) protein BRD4 can physically interact with the Mediator complex, but the relevance of this association to the therapeutic effects of BET inhibitors in cancer is unclear. Here, we show that BET inhibition causes a rapid release of Mediator from a subset of cis-regulatory elements in the genome of acute myeloid leukemia (AML) cells. These sites of Mediator eviction were highly correlated with transcriptional suppression of neighboring genes, which are enriched for targets of the transcription factor MYB and for functions related to leukemogenesis. A shRNA screen of Mediator in AML cells identified the MED12, MED13, MED23, and MED24 subunits as performing a similar regulatory function to BRD4 in this context, including a shared role in sustaining a block in myeloid maturation. These findings suggest that the interaction between BRD4 and Mediator has functional importance for gene-specific transcriptional activation and for AML maintenance. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Caspase inhibition in select olfactory neurons restores innate attraction behavior in aged Drosophila.

    Science.gov (United States)

    Chihara, Takahiro; Kitabayashi, Aki; Morimoto, Michie; Takeuchi, Ken-ichi; Masuyama, Kaoru; Tonoki, Ayako; Davis, Ronald L; Wang, Jing W; Miura, Masayuki

    2014-06-01

    Sensory and cognitive performance decline with age. Neural dysfunction caused by nerve death in senile dementia and neurodegenerative disease has been intensively studied; however, functional changes in neural circuits during the normal aging process are not well understood. Caspases are key regulators of cell death, a hallmark of age-related neurodegeneration. Using a genetic probe for caspase-3-like activity (DEVDase activity), we have mapped age-dependent neuronal changes in the adult brain throughout the lifespan of Drosophila. Spatio-temporally restricted caspase activation was observed in the antennal lobe and ellipsoid body, brain structures required for olfaction and visual place memory, respectively. We also found that caspase was activated in an age-dependent manner in specific subsets of Drosophila olfactory receptor neurons (ORNs), Or42b and Or92a neurons. These neurons are essential for mediating innate attraction to food-related odors. Furthermore, age-induced impairments of neural transmission and attraction behavior could be reversed by specific inhibition of caspase in these ORNs, indicating that caspase activation in Or42b and Or92a neurons is responsible for altering animal behavior during normal aging.

  1. Prediction of Genes Related to Positive Selection Using Whole-Genome Resequencing in Three Commercial Pig Breeds

    Directory of Open Access Journals (Sweden)

    HyoYoung Kim

    2015-12-01

    Full Text Available Selective sweep can cause genetic differentiation across populations, which allows for the identification of possible causative regions/genes underlying important traits. The pig has experienced a long history of allele frequency changes through artificial selection in the domestication process. We obtained an average of 329,482,871 sequence reads for 24 pigs from three pig breeds: Yorkshire (n = 5, Landrace (n = 13, and Duroc (n = 6. An average read depth of 11.7 was obtained using whole-genome resequencing on an Illumina HiSeq2000 platform. In this study, cross-population extended haplotype homozygosity and cross-population composite likelihood ratio tests were implemented to detect genes experiencing positive selection for the genome-wide resequencing data generated from three commercial pig breeds. In our results, 26, 7, and 14 genes from Yorkshire, Landrace, and Duroc, respectively were detected by two kinds of statistical tests. Significant evidence for positive selection was identified on genes ST6GALNAC2 and EPHX1 in Yorkshire, PARK2 in Landrace, and BMP6, SLA-DQA1, and PRKG1 in Duroc.These genes are reportedly relevant to lactation, reproduction, meat quality, and growth traits. To understand how these single nucleotide polymorphisms (SNPs related positive selection affect protein function, we analyzed the effect of non-synonymous SNPs. Three SNPs (rs324509622, rs80931851, and rs80937718 in the SLA-DQA1 gene were significant in the enrichment tests, indicating strong evidence for positive selection in Duroc. Our analyses identified genes under positive selection for lactation, reproduction, and meat-quality and growth traits in Yorkshire, Landrace, and Duroc, respectively.

  2. Triptolide inhibits proliferation of Epstein–Barr virus-positive B lymphocytes by down-regulating expression of a viral protein LMP1

    International Nuclear Information System (INIS)

    Zhou, Heng; Guo, Wei; Long, Cong; Wang, Huan; Wang, Jingchao; Sun, Xiaoping

    2015-01-01

    Highlights: • Triptolide inhibits proliferation of EBV-positive lymphoma cells in vitro and in vivo. • Triptolide reduces expression of LMP1 by decreasing its transcription level. • Triptolide inhibits ED-L1 promoter activity. - Abstract: Epstein–Barr virus (EBV) infects various types of cells and mainly establishes latent infection in B lymphocytes. The viral latent membrane protein 1 (LMP1) plays important roles in transformation and proliferation of B lymphocytes infected with EBV. Triptolide is a compound of Tripterygium extracts, showing anti-inflammatory, immunosuppressive, and anti-cancer activities. In this study, it is determined whether triptolide inhibits proliferation of Epstein–Barr virus-positive B lymphocytes. The CCK-8 assays were performed to examine cell viabilities of EBV-positive B95-8 and P3HR-1 cells treated by triptolide. The mRNA and protein levels of LMP1 were examined by real time-PCR and Western blotting, respectively. The activities of two LMP1 promoters (ED-L1 and TR-L1) were determined by Dual luciferase reportor assay. The results showed that triptolide inhibited the cell viability of EBV-positive B lymphocytes, and the over-expression of LMP1 attenuated this inhibitory effect. Triptolide decreased the LMP1 expression and transcriptional levels in EBV-positive B cells. The activity of LMP1 promoter ED-L1 in type III latent infection was strongly suppressed by triptolide treatment. In addition, triptolide strongly reduced growth of B95-8 induced B lymphoma in BALB/c nude mice. These results suggest that triptolide decreases proliferation of EBV-induced B lymphocytes possibly by a mechanism related to down-regulation of the LMP1 expression

  3. Triptolide inhibits proliferation of Epstein–Barr virus-positive B lymphocytes by down-regulating expression of a viral protein LMP1

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Heng [Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Guo, Wei [Department of Pathology and Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Long, Cong; Wang, Huan; Wang, Jingchao [Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Sun, Xiaoping, E-mail: xsun6@whu.edu.cn [Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); State Key Laboratory of Virology, Wuhan University, Wuhan 430072 (China)

    2015-01-16

    Highlights: • Triptolide inhibits proliferation of EBV-positive lymphoma cells in vitro and in vivo. • Triptolide reduces expression of LMP1 by decreasing its transcription level. • Triptolide inhibits ED-L1 promoter activity. - Abstract: Epstein–Barr virus (EBV) infects various types of cells and mainly establishes latent infection in B lymphocytes. The viral latent membrane protein 1 (LMP1) plays important roles in transformation and proliferation of B lymphocytes infected with EBV. Triptolide is a compound of Tripterygium extracts, showing anti-inflammatory, immunosuppressive, and anti-cancer activities. In this study, it is determined whether triptolide inhibits proliferation of Epstein–Barr virus-positive B lymphocytes. The CCK-8 assays were performed to examine cell viabilities of EBV-positive B95-8 and P3HR-1 cells treated by triptolide. The mRNA and protein levels of LMP1 were examined by real time-PCR and Western blotting, respectively. The activities of two LMP1 promoters (ED-L1 and TR-L1) were determined by Dual luciferase reportor assay. The results showed that triptolide inhibited the cell viability of EBV-positive B lymphocytes, and the over-expression of LMP1 attenuated this inhibitory effect. Triptolide decreased the LMP1 expression and transcriptional levels in EBV-positive B cells. The activity of LMP1 promoter ED-L1 in type III latent infection was strongly suppressed by triptolide treatment. In addition, triptolide strongly reduced growth of B95-8 induced B lymphoma in BALB/c nude mice. These results suggest that triptolide decreases proliferation of EBV-induced B lymphocytes possibly by a mechanism related to down-regulation of the LMP1 expression.

  4. Pearl millet transformation system using the positive selectable marker gene phosphomannose isomerase

    CSIR Research Space (South Africa)

    O'Kennedy, MM

    2004-04-01

    Full Text Available of the transgene. Similar to results obtained from previous studies with maize and wheat, the manA gene was shown to be a superior selectable marker gene for improving transformation efficiencies when compared to antibiotic or herbicide selectable marker genes....

  5. The Evaluation and Selection of a Fifth Ground Antenna Site for the Global Positioning System.

    Science.gov (United States)

    1987-12-07

    selection was the region between Australia and South America and north of the Antartic . Using the performance results of this study, further study...indicated that the best region for selection was between Australia and South America and north of the Antartic . Using the performance results of this

  6. Structural Basis for Selective Small Molecule Kinase Inhibition of Activated c-Met

    Energy Technology Data Exchange (ETDEWEB)

    Rickert, Keith W.; Patel, Sangita B.; Allison, Timothy J.; Byrne, Noel J.; Darke, Paul L.; Ford, Rachael E.; Guerin, David J.; Hall, Dawn L.; Kornienko, Maria; Lu, Jun; Munshi, Sanjeev K.; Reid, John C.; Shipman, Jennifer M.; Stanton, Elizabeth F.; Wilson, Kevin J.; Young, Jonathon R.; Soisson, Stephen M.; Lumb, Kevin J. (Merck)

    2012-03-15

    The receptor tyrosine kinase c-Met is implicated in oncogenesis and is the target for several small molecule and biologic agents in clinical trials for the treatment of cancer. Binding of the hepatocyte growth factor to the cell surface receptor of c-Met induces activation via autophosphorylation of the kinase domain. Here we describe the structural basis of c-Met activation upon autophosphorylation and the selective small molecule inhibiton of autophosphorylated c-Met. MK-2461 is a potent c-Met inhibitor that is selective for the phosphorylated state of the enzyme. Compound 1 is an MK-2461 analog with a 20-fold enthalpy-driven preference for the autophosphorylated over unphosphorylated c-Met kinase domain. The crystal structure of the unbound kinase domain phosphorylated at Tyr-1234 and Tyr-1235 shows that activation loop phosphorylation leads to the ejection and disorder of the activation loop and rearrangement of helix {alpha}C and the G loop to generate a viable active site. Helix {alpha}C adopts a orientation different from that seen in activation loop mutants. The crystal structure of the complex formed by the autophosphorylated c-Met kinase domain and compound 1 reveals a significant induced fit conformational change of the G loop and ordering of the activation loop, explaining the selectivity of compound 1 for the autophosphorylated state. The results highlight the role of structural plasticity within the kinase domain in imparting the specificity of ligand binding and provide the framework for structure-guided design of activated c-Met inhibitors.

  7. Auditory Selective Attention: an introduction and evidence for distinct facilitation and inhibition mechanisms

    OpenAIRE

    Mikyska, Constanze Elisabeth Anna

    2012-01-01

    Objective Auditory selective attention is a complex brain function that is still not completely understood. The classic example is the so-called “cocktail party effect” (Cherry, 1953), which describes the impressive ability to focus one’s attention on a single voice from a multitude of voices. This means that particular stimuli in the environment are enhanced in contrast to other ones of lower priority that are ignored. To be able to understand how attention can influence the perception and p...

  8. Inference of purifying and positive selection in three subspecies of chimpanzees (Pan troglodytes) from exome sequencing

    DEFF Research Database (Denmark)

    Bataillon, Thomas; Duan, Jinjie; Hvilsom, Christina

    2015-01-01

    of recent gene flow from Western into Eastern chimpanzees. The striking contrast in X-linked vs. autosomal polymorphism and divergence previously reported in Central chimpanzees is also found in Eastern and Western chimpanzees. We show that the direction of selection (DoS) statistic exhibits a strong non......-monotonic relationship with the strength of purifying selection S, making it inappropriate for estimating S. We instead use counts in synonymous vs. non-synonymous frequency classes to infer the distribution of S coefficients acting on non-synonymous mutations in each subspecies. The strength of purifying selection we...... infer is congruent with the differences in effective sizes of each subspecies: Central chimpanzees are undergoing the strongest purifying selection followed by Eastern and Western chimpanzees. Coding indels show stronger selection against indels changing the reading frame than observed in human...

  9. Selective inhibition of aggregation/fibrillation of bovine serum albumin by osmolytes: Mechanistic and energetics insights.

    Directory of Open Access Journals (Sweden)

    Moumita Dasgupta

    Full Text Available Bovine serum albumin (BSA is an important transport protein of the blood and its aggregation/fibrillation would adversely affect its transport ability leading to metabolic disorder. Therefore, understanding the mechanism of fibrillation/aggregation of BSA and design of suitable inhibitor molecules for stabilizing its native conformation, are of utmost importance. The qualitative and quantitative aspects of the effect of osmolytes (proline, hydroxyproline, glycine betaine, sarcosine and sorbitol on heat induced aggregation/fibrillation of BSA at physiological pH (pH 7.4 have been studied employing a combination of fluorescence spectroscopy, Rayleigh scattering, isothermal titration calorimetry (ITC, dynamic light scattering (DLS and transmission electron microscopy (TEM. Formation of fibrils by BSA under the given conditions was confirmed from increase in fluorescence emission intensities of Thioflavin T over a time period of 600 minutes and TEM images. Absence of change in fluorescence emission intensities of 8-Anilinonaphthalene-1-sulfonic acid (ANS in presence of native and aggregated BSA signify the absence of any amorphous aggregates. ITC results have provided important insights on the energetics of interaction of these osmolytes with different stages of the fibrillar aggregates of BSA, thereby suggesting the possible modes/mechanism of inhibition of BSA fibrillation by these osmolytes. The heats of interaction of the osmolytes with different stages of fibrillation of BSA do not follow a trend, suggesting that the interactions of stages of BSA aggregates are osmolyte specific. Among the osmolytes used here, we found glycine betaine to be supporting and promoting the aggregation process while hydroxyproline to be maximally efficient in suppressing the fibrillation process of BSA, followed by sorbitol, sarcosine and proline in the following order of their decreasing potency: Hydroxyproline> Sorbitol> Sarcosine> Proline> Glycine betaine.

  10. Membrane-tethered peptides patterned after the TRP domain (TRPducins) selectively inhibit TRPV1 channel activity.

    Science.gov (United States)

    Valente, Pierluigi; Fernández-Carvajal, Asia; Camprubí-Robles, María; Gomis, Ana; Quirce, Susana; Viana, Félix; Fernández-Ballester, Gregorio; González-Ros, José M; Belmonte, Carlos; Planells-Cases, Rosa; Ferrer-Montiel, Antonio

    2011-05-01

    The transient receptor potential vanilloid 1 (TRPV1) channel is a thermosensory receptor implicated in diverse physiological and pathological processes. The TRP domain, a highly conserved region in the C terminus adjacent to the internal channel gate, is critical for subunit tetramerization and channel gating. Here, we show that cell-penetrating, membrane-anchored peptides patterned after this protein domain are moderate and selective TRPV1 antagonists both in vitro and in vivo, blocking receptor activity in intact rat primary sensory neurons and their peripheral axons with mean decline time of 30 min. The most potent lipopeptide, TRP-p5, blocked all modes of TRPV1 gating with micromolar efficacy (IC(50)100 μM). TRP-p5 did not affect the capsaicin sensitivity of the vanilloid receptor. Our data suggest that TRP-p5 interferes with protein-protein interactions at the level of the TRP domain that are essential for the "conformational" change that leads to gate opening. Therefore, these palmitoylated peptides, which we termed TRPducins, are noncompetitive, voltage-independent, sequence-specific TRPV1 blockers. Our findings indicate that TRPducin-like peptides may embody a novel molecular strategy that can be exploited to generate a selective pharmacological arsenal for the TRP superfamily of ion channels.

  11. Na+/Ca2+ exchanger inhibition exerts a positive inotropic effect in the rat heart, but fails to influence the contractility of the rabbit heart

    OpenAIRE

    Farkas, A S; Acsai, K; Nagy, N; Tóth, A; Fülöp, F; Seprényi, G; Birinyi, P; Nánási, P P; Forster, T; Csanády, M; Papp, J G; Varró, A; Farkas, A

    2008-01-01

    Background and purpose: The Na+/Ca2+ exchanger (NCX) may play a key role in myocardial contractility. The operation of the NCX is affected by the action potential (AP) configuration and the intracellular Na+ concentration. This study examined the effect of selective NCX inhibition by 0.1, 0.3 and 1.0 μM SEA0400 on the myocardial contractility in the setting of different AP configurations and different intracellular Na+ concentrations in rabbit and rat hearts.

  12. P2-2: Effects of Color Preview History on Inter-Trial Inhibition of Selective Attention

    Directory of Open Access Journals (Sweden)

    Eunsam Shin

    2012-10-01

    Full Text Available The distractor previewing effect (DPE refers to the phenomenon that search times for target colors that were previewed (target preview or TP in a preceding target-absent display (TAD are slower than for distractor colors that were previewed (distractor preview, DP in the TAD. The DPE is explained as attentional inhibition for the features associated with TADs. We investigated history effects of this inter-trial inhibition by manipulating color preview history and examined the DPE using RT and the N2pc (an electrophysiological index of attention allocation. The TAD, ranging from 0 to 2, was followed by a target-present display in which participants responded to the shape of a color-oddball. For the 2TADs, a single color (red or green was repeated twice or the two colors were alternated, resulting in TTP, DDP, TDP, and DTP conditions depending on which color (target or distractor in the search display was previewed. The 1TADs resulted in the TP and the DP, and the 0TADs comprised immediate search trials. RTs showed: (a the TP was slower than the DP; (b the TTP and DDP were slowest and fastest, respectively, and between these the DTP was slower than the TDP; (c the TTP-DDP difference doubled the TP-DP difference due to the RT increase in the TTP. The conditions with slower RTs corresponded with late onsets and smaller amplitudes in the N2pc. These results suggest that effects of color preview history are cumulative with weight on more recent events and support the idea of inter-trial inhibition of target selection.

  13. Positive selection in the chromosome 16 VKORC1 genomic region has contributed to the variability of anticoagulant response in humans.

    Directory of Open Access Journals (Sweden)

    Blandine Patillon

    Full Text Available VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2 is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK. This gene was recently suggested to be a putative target of positive selection in East Asian populations. In this study, we genotyped the HGDP-CEPH Panel for six VKORC1 SNPs and downloaded chromosome 16 genotypes from the HGDP-CEPH database in order to characterize the geographic distribution of footprints of positive selection within and around this locus. A unique VKORC1 haplotype carrying the promoter mutation associated with AVK sensitivity showed especially high frequencies in all the 17 HGDP-CEPH East Asian population samples. VKORC1 and 24 neighboring genes were found to lie in a 505 kb region of strong linkage disequilibrium in these populations. Patterns of allele frequency differentiation and haplotype structure suggest that this genomic region has been submitted to a near complete selective sweep in all East Asian populations and only in this geographic area. The most extreme scores of the different selection tests are found within a smaller 45 kb region that contains VKORC1 and three other genes (BCKDK, MYST1 (KAT8, and PRSS8 with different functions. Because of the strong linkage disequilibrium, it is not possible to determine if VKORC1 or one of the three other genes is the target of this strong positive selection that could explain present-day differences among human populations in AVK dose requirement. Our results show that the extended region surrounding a presumable single target of positive selection should be analyzed for genetic variation in a wide range of genetically diverse populations in order to account for other neighboring and confounding selective events and the hitchhiking effect.

  14. Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase.

    Science.gov (United States)

    Keohane, Colleen E; Steele, Andrew D; Fetzer, Christian; Khowsathit, Jittasak; Van Tyne, Daria; Moynié, Lucile; Gilmore, Michael S; Karanicolas, John; Sieber, Stephan A; Wuest, William M

    2018-02-07

    Natural products have served as an inspiration to scientists both for their complex three-dimensional architecture and exquisite biological activity. Promysalin is one such Pseudomonad secondary metabolite that exhibits narrow-spectrum antibacterial activity, originally isolated from the rhizosphere. We herein utilize affinity-based protein profiling (AfBPP) to identify succinate dehydrogenase (Sdh) as the biological target of the natural product. The target was further validated in silico, in vitro, in vivo, and through the selection, and sequencing, of a resistant mutant. Succinate dehydrogenase plays an essential role in primary metabolism of Pseudomonas aeruginosa as the only enzyme that is involved both in the tricarboxylic acid cycle (TCA) and in respiration via the electron transport chain. These findings add credence to other studies that suggest that the TCA cycle is an understudied target in the development of novel therapeutics to combat P. aeruginosa, a significant pathogen in clinical settings.

  15. Inhibition in the Dynamics of Selective Attention: An Integrative Model for Negative Priming

    Directory of Open Access Journals (Sweden)

    Hecke eSchrobsdorff

    2012-11-01

    Full Text Available We introduce a computational model of the negative priming (NP effect that includes perception, memory, attention, decision making, and action. The model is designed to provide a coherent picture across competing theories of NP and to relate psychological experiments to physiological measurements. The model is formulated in terms of an abstract dynamics of activations of features, their binding into object entities or their semantic categorization as well as related memories and implied reactions. The dynamical variables interact in a connectionist network which is shown to be adaptable to a variety of experimental paradigms. We find that selective attention can be modeled by means of inhibitory processes and by a threshold dynamics. Considering the implementation it becomes obvious that the specificity of the experimental paradigm must be taken into account when predicting the nature of the NP effect.

  16. Positive selection in the SLC11A1 gene in the family Equidae

    DEFF Research Database (Denmark)

    Bayerova, Zuzana; Janova, Eva; Matiasovic, Jan

    2016-01-01

    Immunity-related genes are a suitable model for studying effects of selection at the genomic level. Some of them are highly conserved due to functional constraints and purifying selection, while others are variable and change quickly to cope with the variation of pathogens. The SLC11A1 gene encodes...... a transporter protein mediating antimicrobial activity of macrophages. Little is known about the patterns of selection shaping this gene during evolution. Although it is a typical evolutionarily conserved gene, functionally important polymorphisms associated with various diseases were identified in humans...... and other species. We analyzed the genomic organization, genetic variation, and evolution of the SLC11A1 gene in the family Equidae to identify patterns of selection within this important gene. Nucleotide SLC11A1 sequences were shown to be highly conserved in ten equid species, with more than 97 % sequence...

  17. Alkylation of phosphorothioated thrombin binding aptamers improves the selectivity of inhibition of tumor cell proliferation upon anticoagulation.

    Science.gov (United States)

    Yang, Xiantao; Zhu, Yuejie; Wang, Chao; Guan, Zhu; Zhang, Lihe; Yang, Zhenjun

    2017-07-01

    Recently, aptamers have been extensively researched for therapy and diagnostic applications. Thrombin-binding aptamer is a 15nt deoxyribonucleic acid screened by SELEX, it can specifically bind to thrombin and inhibit blood coagulation. Since it is also endowed with excellent antitumor activity, the intrinsic anticoagulation advantage converted to a main potential side effect for its further application in antiproliferative therapy. Site-specific alkylation was conducted through nucleophilic reaction of phosphorothioated TBAs using bromide reagents. Circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR) measurements were used to evaluate anticoagulation activity, and a CCK-8 assay was used to determine cell proliferation activity. The CD spectra of the modified TBAs were weakened, and their affinity for thrombin was dramatically reduced, as reflected by the K D values. On the other hand, their inhibition of A549 cells was retained. Incorporation of different alkyls apparently disrupted the binding of TBA to thrombin while maintaining the antitumor activity. A new modification strategy was established for the use of TBA as a more selective antitumor agent. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Selective inhibition by chloramphenicol of pregnenolone-16 α-carbonitrile-inducible rat liver cytochrome P-450 isozymes

    International Nuclear Information System (INIS)

    Graves, P.E.; Kaminsky, L.S.; Halpert, J.

    1986-01-01

    Pregnenolone-16 α-carbonitrile (PCN) has been shown to induce, in male rats, cytochrome P-450 isozymes responsible for the formation of R-10-hydroxywarfarin and R-dehydrowarfarin. Antibodies to the major PCN-inducible isozyme (PB/PCN-E) inhibit both activities in microsomal preparations. Recently the authors have shown that PCN treatment of female rats also induces the formation of both R-warfarin metabolites. However, in both sexes chloramphenicol (CAP) treatment selectively inhibits only the rate of formation of the R-dehydrowarfarin. A decrease in microsomal P-450 content occurs after in vivo administration of CAP to PCN-treated rats of both sexes. This is in contrast to the lack of effect of CAP on P-450 levels in phenobarbital-treated rats. Covalent binding of 14 C-CAP to microsomal protein in vitro was increased 3 to 4-fold following PCN treatment. Chromatographic evidences suggests the presence of at least two PCN-induced isozymes of similar molecular weights in both male and female rat liver microsomes. These data are consistent with the multiplicity of PCN-inducible P-450 in rat liver

  19. Initiator of carcinogenesis selectively and stably inhibits stem cell differentiation: a concept that initiation of carcinogenesis involves multiple phases

    International Nuclear Information System (INIS)

    Scott, R.E.; Maercklein, P.B.

    1985-01-01

    A concept of carcinogenesis was recently devised in our laboratory that suggests the development of defects in the control of cell differentiation is associated with an early phase of carcinogenesis. To test this proposal directly, the effects of an initiator of carcinogenesis (i.e., UV irradiation) on proadipocyte stem cell differentiation and proliferation was assayed. In this regard, 3T3 T proadipocytes represent a nontransformed mesenchymal stem cell line that possesses the ability to regulate its differentiation at a distinct state in the G 1 phase of the cell cycle as well as the ability to regulate its proliferation at two additional G 1 states. The results establish that a slow dosage of 254 nm UV irradiation selectivity and stably inhibits the differentiation of a high percentage of proadipocyte stem cells without significantly altering their ability to regulate cellular proliferation in growth factor-deficient or nutrient-deficient culture conditions. Differentiation-defect proadipocyte stem cells are demonstrated not to be completely transformed but to show an increased spontaneous transformation rate, as evidenced by the formation of type III foci in high density cell cultures. These data support the role of defects in the control of differentiation in the inhibition of carcinogenesis. These observations support a concept that the initiation of carcinogenesis involves multiple phases

  20. Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin.

    Science.gov (United States)

    Hoepfner, Dominic; McNamara, Case W; Lim, Chek Shik; Studer, Christian; Riedl, Ralph; Aust, Thomas; McCormack, Susan L; Plouffe, David M; Meister, Stephan; Schuierer, Sven; Plikat, Uwe; Hartmann, Nicole; Staedtler, Frank; Cotesta, Simona; Schmitt, Esther K; Petersen, Frank; Supek, Frantisek; Glynne, Richard J; Tallarico, John A; Porter, Jeffrey A; Fishman, Mark C; Bodenreider, Christophe; Diagana, Thierry T; Movva, N Rao; Winzeler, Elizabeth A

    2012-06-14

    With renewed calls for malaria eradication, next-generation antimalarials need be active against drug-resistant parasites and efficacious against both liver- and blood-stage infections. We screened a natural product library to identify inhibitors of Plasmodium falciparum blood- and liver-stage proliferation. Cladosporin, a fungal secondary metabolite whose target and mechanism of action are not known for any species, was identified as having potent, nanomolar, antiparasitic activity against both blood and liver stages. Using postgenomic methods, including a yeast deletion strains collection, we show that cladosporin specifically inhibits protein synthesis by directly targeting P. falciparum cytosolic lysyl-tRNA synthetase. Further, cladosporin is >100-fold more potent against parasite lysyl-tRNA synthetase relative to the human enzyme, which is conferred by the identity of two amino acids within the enzyme active site. Our data indicate that lysyl-tRNA synthetase is an attractive, druggable, antimalarial target that can be selectively inhibited. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Selection of permanent pacing position of cardiac ventricle in patients with complete right bundle branch block

    International Nuclear Information System (INIS)

    Yang Minquan; Zhou Jun; Zhu Yan; Wang Jin; Rong Xin; Zhang Xiaoyi

    2005-01-01

    Objective: To find out the optimal pacing localization by comparing different pacing positions of the right ventricle in brady-cardiacarrhythmia patients with complete right bundle branch block. Methods: DDD type of double lumen permanent pacemaker was implanted in each of the 8 cases of sick sinus syndrome (SSS) and/or III degree atrioventricular block (III degree AVB) with complete right bundle branch block in normal heart function or class I. For each patient, four pacing positions in right ventricle were compared and the QRS pacing durations were recorded. The position with the shortest the QRS duration was chosen as the permanent pacing position. Heart function, chest X-rays and left ventricle ejection fraction (LVEF) were followed up after the operation. Results: In all the 8 cases, the posterior septum of the right ventricle were chosen as the permanent pacing position, with the shorter pacing QRS duration than that of pre-operation (P<0.05) and other pacing positions of the right ventricle. All parameters of this permanent pacing position were within the normal range. During the follow-up of 6-36 months, no abnormity was found in cardiac functions. Conclusion: In brady-cardiacarrhythmia patients with complete right bundle branch block, the implantation of permanent pacemaker should be at the junction region of inlet and outlet tracts, of the posterior septum of the right ventricle with ideal physiological function. (authors)

  2. Selected essential oils inhibit key physiological enzymes and possess intracellular and extracellular antimelanogenic properties in vitro

    Directory of Open Access Journals (Sweden)

    Zaahira Aumeeruddy-Elalfi

    2018-01-01

    Full Text Available Essential oils (EOs extracted from six medicinal herbs and food plants [Cinnamomum zeylanicum (CZ, Psiadia arguta (PA, Psiadia terebinthina (PT, Citrus grandis (CGp, Citrus hystrix (CH, and Citrus reticulata (CR] were studied for any inhibitory potential against key physiological enzymes involved in diabetes (α-glucosidase, skin aging (collagenase and elastase, and neurodegenerative disorders (acetylcholinesterase. Kinetic studies of the active EOs on the aforementioned enzymes were determined using Lineweaver–Burk plots. The intracellular and extracellular antimelanogenic potential of the EOs were evaluated on B16F10 mouse melanocytes. CH and CR were found to significantly inhibit (2.476 ± 0.13 μg/mL and 3.636 ± 0.10 μg/mL, respectively acetylcholinesterase, compared with galantamine (3.989 ± 0.16 μg/mL. CH inhibited collagenase (50% inhibitory concentration 28.71 ± 0.16 μg/mL compared with the control (24.45 ± 0.19 μg/mL. The percentage inhibition in the elastase assay of CH was 63.21% compared to the positive control (75.09%. In addition, CH, CR, CGp, CZ, and PT were found to significantly inhibit α-glucosidase (276.70 ± 0.73 μg/mL, 169.90 ± 0.58 μg/mL, 240.60 ± 6.50 μg/mL, 64.52 ± 0.69 μg/mL, and 313.0 ± 5.0 μg/mL, respectively, compared to acarbose (448.80 ± 0.81 μg/mL. Active EOs showed both uncompetitive and competitive types of inhibition. The EOs also inhibited intracellular (50% inhibitory concentration 15.92 ± 1.06 μg/mL, 23.75 ± 4.47 μg/mL, and 28.99 ± 5.70 μg/mL for CH, CR, and CGp, respectively and extracellular (< 15.625 μg/mL for CH, CR, CGp, and PT melanin production when tested against B16F10 mouse melanocytes. Results from the present study tend to show that EOs extracted from these medicinal plants can inhibit key enzymes and may be potential candidates for cosmetic and pharmaceutical industries.

  3. Effects of selective serotonin reuptake inhibition on neural activity related to risky decisions and monetary rewards in healthy males

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Fisher, Patrick M; Haahr, Mette E

    2014-01-01

    the involvement of the normally functioning 5HT-system in decision-making under risk and processing of monetary rewards. The data suggest that prolonged SSRI treatment might reduce emotional engagement by reducing the impact of risk during decision-making or the impact of reward during outcome evaluation.......Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are commonly prescribed antidepressant drugs targeting the dysfunctional serotonin (5-HT) system, yet little is known about the functional effects of prolonged serotonin reuptake inhibition in healthy individuals. Here we used...... functional MRI (fMRI) to investigate how a three-week fluoxetine intervention influences neural activity related to risk taking and reward processing. Employing a double-blinded parallel-group design, 29 healthy young males were randomly assigned to receive 3 weeks of a daily dose of 40 mg fluoxetine...

  4. Thinking about a limited future enhances the positivity of younger and older adults' recall: Support for socioemotional selectivity theory.

    Science.gov (United States)

    Barber, Sarah J; Opitz, Philipp C; Martins, Bruna; Sakaki, Michiko; Mather, Mara

    2016-08-01

    Compared with younger adults, older adults have a relative preference to attend to and remember positive over negative information. This is known as the "positivity effect," and researchers have typically evoked socioemotional selectivity theory to explain it. According to socioemotional selectivity theory, as people get older they begin to perceive their time left in life as more limited. These reduced time horizons prompt older adults to prioritize achieving emotional gratification and thus exhibit increased positivity in attention and recall. Although this is the most commonly cited explanation of the positivity effect, there is currently a lack of clear experimental evidence demonstrating a link between time horizons and positivity. The goal of the current research was to address this issue. In two separate experiments, we asked participants to complete a writing activity, which directed them to think of time as being either limited or expansive (Experiments 1 and 2) or did not orient them to think about time in a particular manner (Experiment 2). Participants were then shown a series of emotional pictures, which they subsequently tried to recall. Results from both studies showed that regardless of chronological age, thinking about a limited future enhanced the relative positivity of participants' recall. Furthermore, the results of Experiment 2 showed that this effect was not driven by changes in mood. Thus, the fact that older adults' recall is typically more positive than younger adults' recall may index naturally shifting time horizons and goals with age.

  5. Thinking about a Limited Future Enhances the Positivity of Younger and Older Adults’ Recall: Support for Socioemotional Selectivity Theory

    Science.gov (United States)

    Barber, Sarah J.; Opitz, Philipp C.; Martins, Bruna; Sakaki, Michiko; Mather, Mara

    2016-01-01

    Compared with younger adults, older adults have a relative preference to attend to and remember positive over negative information. This is known as the “positivity effect,” and researchers have typically evoked socioemotional selectivity theory to explain it. According to socioemotional selectivity theory, as people get older they begin to perceive their time left in life as more limited. These reduced time horizons prompt older adults to prioritize achieving emotional gratification and thus exhibit increased positivity in attention and recall. Although this is the most commonly cited explanation of the positivity effect, there is currently a lack of clear experimental evidence demonstrating a link between time horizons and positivity. The goal of the current research was to address this issue. In two separate experiments, we asked participants to complete a writing activity, which directed them to think of time as being either limited or expansive (Experiments 1 and 2) or did not orient them to think about time in a particular manner (Experiment 2). Participants were then shown a series of emotional pictures, which they subsequently tried to recall. Results from both studies showed that regardless of chronological age, thinking about a limited future enhanced the relative positivity of participants’ recall. Furthermore, the results of Experiment 2 showed that this effect was not driven by changes in mood. Thus, the fact that older adults’ recall is typically more positive than younger adults’ recall may index naturally shifting time horizons and goals with age. PMID:27112461

  6. Role of maturity timing in selection procedures and in the specialisation of playing positions in youth basketball

    NARCIS (Netherlands)

    te Wierike, Sanne Cornelia Maria; Elferink-Gemser, Marije Titia; Tromp, Eveline Jenny Yvonne; Vaeyens, Roel; Visscher, Chris

    2015-01-01

    This study investigated the role of maturity timing in selection procedures and in the specialisation of playing positions in youth male basketball. Forty-three talented Dutch players (14.66 +/- 1.09years) participated in this study. Maturity timing (age at peak height velocity), anthropometric,

  7. Evolution of species-specific major seminal fluid proteins in placental mammals by gene death and positive selection

    NARCIS (Netherlands)

    Meslin, C.; Laurin, M.; Callebaut, I.; Druart, X.; Monget, P.

    2015-01-01

    The seminal fluid is a complex substance composed of a variety of secreted proteins and has been shown to play an important role in the fertilisation process in mammals and also in Drosophila. Several genes under positive selection have been documented in some rodents and primates. Our study

  8. L-carnitine is an endogenous HDAC inhibitor selectively inhibiting cancer cell growth in vivo and in vitro.

    Science.gov (United States)

    Huang, Hongbiao; Liu, Ningning; Guo, Haiping; Liao, Siyan; Li, Xiaofen; Yang, Changshan; Liu, Shouting; Song, Wenbin; Liu, Chunjiao; Guan, Lixia; Li, Bing; Xu, Li; Zhang, Change; Wang, Xuejun; Dou, Q Ping; Liu, Jinbao

    2012-01-01

    L-carnitine (LC) is generally believed to transport long-chain acyl groups from fatty acids into the mitochondrial matrix for ATP generation via the citric acid cycle. Based on Warburg's theory that most cancer cells mainly depend on glycolysis for ATP generation, we hypothesize that, LC treatment would lead to disturbance of cellular metabolism and cytotoxicity in cancer cells. In this study, Human hepatoma HepG2, SMMC-7721 cell lines, primary cultured thymocytes and mice bearing HepG2 tumor were used. ATP content was detected by HPLC assay. Cell cycle, cell death and cell viability were assayed by flow cytometry and MTS respectively. Gene, mRNA expression and protein level were detected by gene microarray, Real-time PCR and Western blot respectively. HDAC activities and histone acetylation were detected both in test tube and in cultured cells. A molecular docking study was carried out with CDOCKER protocol of Discovery Studio 2.0 to predict the molecular interaction between L-carnitine and HDAC. Here we found that (1) LC treatment selectively inhibited cancer cell growth in vivo and in vitro; (2) LC treatment selectively induces the expression of p21(cip1) gene, mRNA and protein in cancer cells but not p27(kip1); (4) LC increases histone acetylation and induces accumulation of acetylated histones both in normal thymocytes and cancer cells; (5) LC directly inhibits HDAC I/II activities via binding to the active sites of HDAC and induces histone acetylation and lysine-acetylation accumulation in vitro; (6) LC treatment induces accumulation of acetylated histones in chromatin associated with the p21(cip1) gene but not p27(kip1) detected by ChIP assay. These data support that LC, besides transporting acyl group, works as an endogenous HDAC inhibitor in the cell, which would be of physiological and pathological importance.

  9. Positive selection and ancient duplications in the evolution of class B floral homeotic genes of orchids and grasses

    Directory of Open Access Journals (Sweden)

    Koch Marcus A

    2009-04-01

    Full Text Available Abstract Background Positive selection is recognized as the prevalence of nonsynonymous over synonymous substitutions in a gene. Models of the functional evolution of duplicated genes consider neofunctionalization as key to the retention of paralogues. For instance, duplicate transcription factors are specifically retained in plant and animal genomes and both positive selection and transcriptional divergence appear to have played a role in their diversification. However, the relative impact of these two factors has not been systematically evaluated. Class B MADS-box genes, comprising DEF-like and GLO-like genes, encode developmental transcription factors essential for establishment of perianth and male organ identity in the flowers of angiosperms. Here, we contrast the role of positive selection and the known divergence in expression patterns of genes encoding class B-like MADS-box transcription factors from monocots, with emphasis on the family Orchidaceae and the order Poales. Although in the monocots these two groups are highly diverse and have a strongly canalized floral morphology, there is no information on the role of positive selection in the evolution of their distinctive flower morphologies. Published research shows that in Poales, class B-like genes are expressed in stamens and in lodicules, the perianth organs whose identity might also be specified by class B-like genes, like the identity of the inner tepals of their lily-like relatives. In orchids, however, the number and pattern of expression of class B-like genes have greatly diverged. Results The DEF-like genes from Orchidaceae form four well-supported, ancient clades of orthologues. In contrast, orchid GLO-like genes form a single clade of ancient orthologues and recent paralogues. DEF-like genes from orchid clade 2 (OMADS3-like genes are under less stringent purifying selection than the other orchid DEF-like and GLO-like genes. In comparison with orchids, purifying selection

  10. From shunting inhibition to dynamic normalization: Attentional selection and decision-making in brief visual displays.

    Science.gov (United States)

    Smith, Philip L; Sewell, David K; Lilburn, Simon D

    2015-11-01

    Normalization models of visual sensitivity assume that the response of a visual mechanism is scaled divisively by the sum of the activity in the excitatory and inhibitory mechanisms in its neighborhood. Normalization models of attention assume that the weighting of excitatory and inhibitory mechanisms is modulated by attention. Such models have provided explanations of the effects of attention in both behavioral and single-cell recording studies. We show how normalization models can be obtained as the asymptotic solutions of shunting differential equations, in which stimulus inputs and the activity in the mechanism control growth rates multiplicatively rather than additively. The value of the shunting equation approach is that it characterizes the entire time course of the response, not just its asymptotic strength. We describe two models of attention based on shunting dynamics, the integrated system model of Smith and Ratcliff (2009) and the competitive interaction theory of Smith and Sewell (2013). These models assume that attention, stimulus salience, and the observer's strategy for the task jointly determine the selection of stimuli into visual short-term memory (VSTM) and the way in which stimulus representations are weighted. The quality of the VSTM representation determines the speed and accuracy of the decision. The models provide a unified account of a variety of attentional phenomena found in psychophysical tasks using single-element and multi-element displays. Our results show the generality and utility of the normalization approach to modeling attention. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Multimodal Microvascular Imaging Reveals that Selective Inhibition of Class I PI3K Is Sufficient to Induce an Antivascular Response

    Directory of Open Access Journals (Sweden)

    Deepak Sampath

    2013-07-01

    Full Text Available The phosphatidylinositol 3-kinase (PI3K pathway is a central mediator of vascular endothelial growth factor (VEGF-driven angiogenesis. The discovery of small molecule inhibitors that selectively target PI3K or PI3K and mammalian target of rapamycin (mTOR provides an opportunity to pharmacologically determine the contribution of these key signaling nodes in VEGF-A-driven tumor angiogenesis in vivo. This study used an array of microvascular imaging techniques to monitor the antivascular effects of selective class I PI3K, mTOR, or dual PI3K/ mTOR inhibitors in colorectal and prostate cancer xenograft models. Micro-computed tomography (micro-CT angiography, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI, vessel size index (VSI MRI, and DCE ultrasound (DCE-U/S were employed to quantitatively evaluate the vascular (structural and physiological response to these inhibitors. GDC-0980, a dual PI3K/mTOR inhibitor, was found to reduce micro-CT angiography vascular density, while VSI MRI demonstrated a significant reduction in vessel density and an increase in mean vessel size, consistent with a loss of small functional vessels and a substantial antivascular response. DCE-MRI showed that GDC-0980 produces a strong functional response by decreasing the vascular permeability/perfusion-related parameter, Ktrans. Interestingly, comparable antivascular effects were observed for both GDC-980 and GNE-490 (a selective class I PI3K inhibitor. In addition, mTOR-selective inhibitors did not affect vascular density, suggesting that PI3K inhibition is sufficient to generate structural changes, characteristic of a robust antivascular response. This study supports the use of noninvasive microvascular imaging techniques (DCE-MRI, VSI MRI, DCE-U/S as pharmacodynamic assays to quantitatively measure the activity of PI3K and dual PI3K/mTOR inhibitors in vivo.

  12. Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury.

    Science.gov (United States)

    Kan, Wen-Hong; Hsu, Jun-Te; Schwacha, Martin G; Choudhry, Mashkoor A; Raju, Raghavan; Bland, Kirby I; Chaudry, Irshad H

    2008-10-01

    Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible nitric oxide (NO) synthase inhibitor, N-[3-(aminomethyl) benzyl]acetamidine (1400W), and a nonselective NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), we investigated whether inducible NO synthase plays any role in producing hepatic injury, inflammation, and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for approximately 90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg body wt ip), or L-NAME (30 mg/kg iv), 30 min before resuscitation and killed 2 h after resuscitation. Trauma-hemorrhage/resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma alpha-glutathione S-transferase, tissue myeloperoxidase activity, and nitrotyrosine formation). Hepatic expression of iNOS, hypoxia-inducible factor-1alpha, ICAM-1, IL-6, TNF-alpha, and neutrophil chemoattractant (cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2) protein levels were also markedly increased following trauma-hemorrhage/resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved mean blood pressure as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage under such conditions.

  13. Positive selection of mutants with cell envelope defects of a Salmonella typhimurium strain hypersensitive to the products of genes hisF and hisH

    International Nuclear Information System (INIS)

    Anton, D.N.

    1979-01-01

    Strain SB564 and its derivative DA78 are hypersensitive to the inhibitory action of the proteins coded for by genes hisF and hisH on cell division. Transduction of hisO1242, a regulatory mutation that elicits a very high level of expression of the histidine operon, into these strains resulted in the production of long filamentous cells carrying large balloons and in growth failure. Forty-one hisO1242 derivatives that escaped inhibition were isolated. These strains showed a large variety of alterations, many of which were related to the cell envelope. The more-frequent alterations included: changes in cell shape, increased sensitivity to one or more of several drugs (deoxycholate, cycloserine, penicillin, novobiocin, acridine orange), increased autolytic activity in alkaline buffer, anomalous fermentation of maltose on eosin--methylene blue plates, and temperature-conditional cell division. The alterations are produced, in some of the strains, by pleiotropic mutations in gene envB. Strains affected in divC, divD, and rodA loci have also been identified. Genetic analaysis has shown that several strains carry more than one envelope mutation. It is assumed that envelope mutations are positively selected because they somehow alleviate the particularly severe inhibition of cell division caused, in strains SB564 and DA78, by the excessive synthesis of hisF and hisH gene products

  14. Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

    Directory of Open Access Journals (Sweden)

    Dall’Olio Giovanni

    2012-06-01

    Full Text Available Abstract Background Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Results Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. Conclusions These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show

  15. Exposure to selected fragrance materials. A case study of fragrance-mix-positive eczema patients

    DEFF Research Database (Denmark)

    Johansen, J D; Rastogi, Suresh Chandra; Menné, T

    1996-01-01

    . In all cases, the use of these cosmetics completely or partly explained present or past episodes of eczema. Between 1 to 6 constituents of the fragrance mix were found in 22 out of 23 products. The cosmetics of all the patients sensitive to hydroxycitronellal, eugenol, cinnamic alcohol and alpha......The aim of the present study was to assess exposure to constituents of the fragrance mix from cosmetic products used by fragrance-mix-positive eczema patients. 23 products, which had either given a positive patch and/or use test in a total of 11 fragrance-mix-positive patients, were analyzed....... It is concluded that exposure to constituents of the fragrance mix is common in fragrance-allergic patients with cosmetic eczema, and that the fragrance mix is a good reflection of actual exposure....

  16. Response to Comment on "Positive Selection of Tyrosine Loss in Metazoan Evolution"

    DEFF Research Database (Denmark)

    Tan, Chris Soon Heng; Schoof, Erwin; Creixell, Pau

    2011-01-01

    Su et al. claim guanine-cytosine (GC) content variation can largely explain the observed tyrosine frequency variation, independent of adaptive evolution of cell-signaling complexity. We found that GC content variation, in the absence of selection for amino acid changes, can only maximally account...

  17. Detecting Positive Selection of Korean Native Goat Populations Using Next-Generation Sequencing

    Science.gov (United States)

    Lee, Wonseok; Ahn, Sojin; Taye, Mengistie; Sung, Samsun; Lee, Hyun-Jeong; Cho, Seoae; Kim, Heebal

    2016-01-01

    Goats (Capra hircus) are one of the oldest species of domesticated animals. Native Korean goats are a particularly interesting group, as they are indigenous to the area and were raised in the Korean peninsula almost 2,000 years ago. Although they have a small body size and produce low volumes of milk and meat, they are quite resistant to lumbar paralysis. Our study aimed to reveal the distinct genetic features and patterns of selection in native Korean goats by comparing the genomes of native Korean goat and crossbred goat populations. We sequenced the whole genome of 15 native Korean goats and 11 crossbred goats using next-generation sequencing (Illumina platform) to compare the genomes of the two populations. We found decreased nucleotide diversity in the native Korean goats compared to the crossbred goats. Genetic structural analysis demonstrated that the native Korean goat and crossbred goat populations shared a common ancestry, but were clearly distinct. Finally, to reveal the native Korean goat’s selective sweep region, selective sweep signals were identified in the native Korean goat genome using cross-population extended haplotype homozygosity (XP-EHH) and a cross-population composite likelihood ratio test (XP-CLR). As a result, we were able to identify candidate genes for recent selection, such as the CCR3 gene, which is related to lumbar paralysis resistance. Combined with future studies and recent goat genome information, this study will contribute to a thorough understanding of the native Korean goat genome. PMID:27989103

  18. Site suitability, selection and characterization: Branch technical position--Low-Level Waste Licensing Branch

    International Nuclear Information System (INIS)

    Siefken, D.; Pangburn, G.; Pennifill, R.; Starmer, R.J.

    1982-04-01

    The staff provides an expanded interpretation of the site suitability requirements in the proposed rule 10 CFR Part 61, a description of the anticipated site selection process, and a detailed discussion of the site characterization program needed to support a license application and environmental report. The paper provides early-on guidance to prospective applicants in these three subject areas

  19. Enrollees are positive about selective contracting, but not if it limits their freedom of choice.

    NARCIS (Netherlands)

    Bes, R.E.; Brabers, A.E.M.; Reitsma-van Rooijen, P.M.; Jong, J.D. de

    2013-01-01

    Background: In the last decades, health care systems in several European countries changed from a supply-oriented system to a demand-oriented system based on managed competition. In The Netherlands managed competition was introduced in 2006. Health insurers are allowed to selectively contract care

  20. Detecting Positive Selection of Korean Native Goat Populations Using Next-Generation Sequencing.

    Science.gov (United States)

    Lee, Wonseok; Ahn, Sojin; Taye, Mengistie; Sung, Samsun; Lee, Hyun-Jeong; Cho, Seoae; Kim, Heebal

    2016-12-01

    Goats ( Capra hircus ) are one of the oldest species of domesticated animals. Native Korean goats are a particularly interesting group, as they are indigenous to the area and were raised in the Korean peninsula almost 2,000 years ago. Although they have a small body size and produce low volumes of milk and meat, they are quite resistant to lumbar paralysis. Our study aimed to reveal the distinct genetic features and patterns of selection in native Korean goats by comparing the genomes of native Korean goat and crossbred goat populations. We sequenced the whole genome of 15 native Korean goats and 11 crossbred goats using next-generation sequencing (Illumina platform) to compare the genomes of the two populations. We found decreased nucleotide diversity in the native Korean goats compared to the crossbred goats. Genetic structural analysis demonstrated that the native Korean goat and crossbred goat populations shared a common ancestry, but were clearly distinct. Finally, to reveal the native Korean goat's selective sweep region, selective sweep signals were identified in the native Korean goat genome using cross-population extended haplotype homozygosity (XP-EHH) and a cross-population composite likelihood ratio test (XP-CLR). As a result, we were able to identify candidate genes for recent selection, such as the CCR3 gene, which is related to lumbar paralysis resistance. Combined with future studies and recent goat genome information, this study will contribute to a thorough understanding of the native Korean goat genome.

  1. Structure-Activity Relationships of 1,2-Disubstituted Benzimidazoles: Selective Inhibition of Heme Oxygenase-2 Activity.

    Science.gov (United States)

    Kong, Xianqi; Vukomanovic, Dragic; Nakatsu, Kanji; Szarek, Walter A

    2015-08-01

    Devising ways to up- or down-regulate heme oxygenase activity is attracting much interest as a strategy for the treatment of a variety of disorders. With a view of obtaining compounds that exhibit high potency and selectivity as inhibitors of the heme oxygenase-2 (HO-2) isozyme (constitutive) relative to the heme oxygenase-1 (HO-1) isozyme (inducible), several 1,2-disubstituted 1H-benzimidazoles were designed and synthesized. Specifically, analogues were synthesized in which the C2 substituent was the following: (1H-imidazol-1-yl)methyl, (N-morpholinyl)methyl, cyclopentylmethyl, cyclohexylmethyl, or (norborn-2-yl)methyl. Compounds with the cyclic system in the C2 substituent being a carbocyclic ring, especially cyclohexyl or norborn-2-yl, and the N1 substituent being a ring-substituted benzyl group, especially 4-chlorobenzyl or 4-bromobenzyl, best exhibited the target criteria of high potency and selectivity toward inhibition of HO-2. The new candidates should be useful pharmacological tools and may have therapeutic applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. FTO Inhibits Insulin Secretion and Promotes NF-κB Activation through Positively Regulating ROS Production in Pancreatic β cells.

    Directory of Open Access Journals (Sweden)

    Hong-Qi Fan

    Full Text Available FTO (Fat mass and obesity-associated is associated with increased risk of obesity and type 2 diabetes incurrence. Pancreas islet β cells dysfunction and insulin resistance are major causes of type 2 diabetes. However, whether FTO plays an important functional role in pancreatic β cells as well as the related molecular mechanism is still unclear. In the present study, the tissue expression profile of FTO was firstly determined using quantitative PCR and western blot. FTO is widely expressed in various tissues and presented with relative high expression in pancreas tissue, especially in endocrine pancreas. FTO overexpression in MIN6 cells achieved by lentivirus delivery significantly inhibits insulin secretion in the presence of glucose stimulus as well as KCl. FTO silence has no effect on insulin secretion of MIN6 cells. However, FTO overexpression doesn't affect the transcription of insulin gene. Furthermore, reactive oxygen species (ROS production and NF-κB activation are significantly promoted by FTO overexpression. Inhibition of intracellular ROS production by N-acetyl-L-cysteine (NAC can alleviate NF-κB activation and restore the insulin secretion mediated by FTO overexpression. A whole transcript-microarray is employed to analyze the differential gene expression mediated by FTO overexpression. The genes which are modulated by FTO are involved in many important biological pathways such as G-protein coupled receptor signaling and NF-κB signaling. Therefore, our study indicates that FTO may contribute to pancreas islet β cells dysfunction and the inhibition of FTO activity is a potential target for the treatment of diabetes.

  3. Ground Receiving Station Reference Pair Selection Technique for a Minimum Configuration 3D Emitter Position Estimation Multilateration System

    Directory of Open Access Journals (Sweden)

    Abdulmalik Shehu Yaro

    2017-01-01

    Full Text Available Multilateration estimates aircraft position using the Time Difference Of Arrival (TDOA with a lateration algorithm. The Position Estimation (PE accuracy of the lateration algorithm depends on several factors which are the TDOA estimation error, the lateration algorithm approach, the number of deployed GRSs and the selection of the GRS reference used for the PE process. Using the minimum number of GRSs for 3D emitter PE, a technique based on the condition number calculation is proposed to select the suitable GRS reference pair for improving the accuracy of the PE using the lateration algorithm. Validation of the proposed technique was performed with the GRSs in the square and triangular GRS configuration. For the selected emitter positions, the result shows that the proposed technique can be used to select the suitable GRS reference pair for the PE process. A unity condition number is achieved for GRS pair most suitable for the PE process. Monte Carlo simulation result, in comparison with the fixed GRS reference pair lateration algorithm, shows a reduction in PE error of at least 70% for both GRS in the square and triangular configuration.

  4. Sexual Orientation and Spatial Position Effects on Selective Forms of Object Location Memory

    Science.gov (United States)

    Rahman, Qazi; Newland, Cherie; Smyth, Beatrice Mary

    2011-01-01

    Prior research has demonstrated robust sex and sexual orientation-related differences in object location memory in humans. Here we show that this sexual variation may depend on the spatial position of target objects and the task-specific nature of the spatial array. We tested the recovery of object locations in three object arrays (object…

  5. Positive selection in the leucine-rich repeat domain of Gro1 genes in ...

    Indian Academy of Sciences (India)

    history during which the main structure of the domain has been conserved such that ... from the column using 100 μL of distilled water. The LRR fragments from the ... ture of the domain and to obtain the best PDB template for mapping positive ...

  6. A genome-wide signature of positive selection in ancient and recent invasive expansions of the honey bee Apis mellifera.

    Science.gov (United States)

    Zayed, Amro; Whitfield, Charles W

    2008-03-04

    Apis mellifera originated in Africa and extended its range into Eurasia in two or more ancient expansions. In 1956, honey bees of African origin were introduced into South America, their descendents admixing with previously introduced European bees, giving rise to the highly invasive and economically devastating "Africanized" honey bee. Here we ask whether the honey bee's out-of-Africa expansions, both ancient and recent (invasive), were associated with a genome-wide signature of positive selection, detected by contrasting genetic differentiation estimates (F(ST)) between coding and noncoding SNPs. In native populations, SNPs in protein-coding regions had significantly higher F(ST) estimates than those in noncoding regions, indicating adaptive evolution in the genome driven by positive selection. This signal of selection was associated with the expansion of honey bees from Africa into Western and Northern Europe, perhaps reflecting adaptation to temperate environments. We estimate that positive selection acted on a minimum of 852-1,371 genes or approximately 10% of the bee's coding genome. We also detected positive selection associated with the invasion of African-derived honey bees in the New World. We found that introgression of European-derived alleles into Africanized bees was significantly greater for coding than noncoding regions. Our findings demonstrate that Africanized bees exploited the genetic diversity present from preexisting introductions in an adaptive way. Finally, we found a significant negative correlation between F(ST) estimates and the local GC content surrounding coding SNPs, suggesting that AT-rich genes play an important role in adaptive evolution in the honey bee.

  7. Somatostatin-positive interneurons in the dentate gyrus of mice provide local- and long-range septal synaptic inhibition.

    Science.gov (United States)

    Yuan, Mei; Meyer, Thomas; Benkowitz, Christoph; Savanthrapadian, Shakuntala; Ansel-Bollepalli, Laura; Foggetti, Angelica; Wulff, Peer; Alcami, Pepe; Elgueta, Claudio; Bartos, Marlene

    2017-04-03

    Somatostatin-expressing-interneurons (SOMIs) in the dentate gyrus (DG) control formation of granule cell (GC) assemblies during memory acquisition. Hilar-perforant-path-associated interneurons (HIPP cells) have been considered to be synonymous for DG-SOMIs. Deviating from this assumption, we show two functionally contrasting DG-SOMI-types. The classical feedback-inhibitory HIPPs distribute axon fibers in the molecular layer. They are engaged by converging GC-inputs and provide dendritic inhibition to the DG circuitry. In contrast, SOMIs with axon in the hilus, termed hilar interneurons (HILs), provide perisomatic inhibition onto GABAergic cells in the DG and project to the medial septum. Repetitive activation of glutamatergic inputs onto HIPP cells induces long-lasting-depression (LTD) of synaptic transmission but long-term-potentiation (LTP) of synaptic signals in HIL cells. Thus, LTD in HIPPs may assist flow of spatial information from the entorhinal cortex to the DG, whereas LTP in HILs may facilitate the temporal coordination of GCs with activity patterns governed by the medial septum.

  8. The positive impact of women's employment on divorce: Context, selection, or anticipation?

    Directory of Open Access Journals (Sweden)

    Daniele Vignoli

    2018-03-01

    Full Text Available Background: Empirical findings regarding the impact of women's employment on divorce are mixed. One explanation is that the effects are moderated by the country context. Another is that previous studies have failed to account for unobserved factors that introduce bias into the estimated effects. Studies also rarely consider possible anticipatory employment behavior on the part of women who are thinking of divorce. Objective: The aim of this study is to deepen our understanding of the nexus between women's employment and divorce in a comparative perspective. Methods: We adopt an analytical strategy that allows us to account for selection and anticipation mechanisms. Namely, we estimate marital disruption and employment jointly, and monitor the timing of divorce after employment entry. This approach is implemented using micro-level data for Germany, Hungary, Italy, and Poland. Results: We find that women's employment facilitates marital disruption in Italy and Poland, but not in Germany and Hungary. We also show that selection effects play out differently in different contexts. Finally, we notice traces of anticipatory behavior in Italy. Contribution: We conclude that women's employment is less likely to be linked to divorce in countries with easier access to divorce and in countries with more generous financial support for families and single mothers, which in turn makes women less reliant on the market. With this study we hope to encourage future researchers to consider the potentially distorting effects of selection and anticipation strategies in (comparative divorce research.

  9. Soft sweeps III: the signature of positive selection from recurrent mutation.

    Directory of Open Access Journals (Sweden)

    Pleuni S Pennings

    2006-12-01

    Full Text Available Polymorphism data can be used to identify loci at which a beneficial allele has recently gone to fixation, given that an accurate description of the signature of selection is available. In the classical model that is used, a favored allele derives from a single mutational origin. This ignores the fact that beneficial alleles can enter a population recurrently by mutation during the selective phase. In this study, we present a combination of analytical and simulation results to demonstrate the effect of adaptation from recurrent mutation on summary statistics for polymorphism data from a linked neutral locus. We also analyze the power of standard neutrality tests based on the frequency spectrum or on linkage disequilibrium (LD under this scenario. For recurrent beneficial mutation at biologically realistic rates, we find substantial deviations from the classical pattern of a selective sweep from a single new mutation. Deviations from neutrality in the level of polymorphism and in the frequency spectrum are much less pronounced than in the classical sweep pattern. In contrast, for levels of LD, the signature is even stronger if recurrent beneficial mutation plays a role. We suggest a variant of existing LD tests that increases their power to detect this signature.

  10. Probing of RNA structures in a positive sense RNA virus reveals selection pressures for structural elements

    Science.gov (United States)

    Watters, Kyle E; Choudhary, Krishna; Aviran, Sharon; Perry, Keith L

    2018-01-01

    Abstract In single stranded (+)-sense RNA viruses, RNA structural elements (SEs) play essential roles in the infection process from replication to encapsidation. Using selective 2′-hydroxyl acylation analyzed by primer extension sequencing (SHAPE-Seq) and covariation analysis, we explore the structural features of the third genome segment of cucumber mosaic virus (CMV), RNA3 (2216 nt), both in vitro and in plant cell lysates. Comparing SHAPE-Seq and covariation analysis results revealed multiple SEs in the coat protein open reading frame and 3′ untranslated region. Four of these SEs were mutated and serially passaged in Nicotiana tabacum plants to identify biologically selected changes to the original mutated sequences. After passaging, loop mutants showed partial reversion to their wild-type sequence and SEs that were structurally disrupted by mutations were restored to wild-type-like structures via synonymous mutations in planta. These results support the existence and selection of virus open reading frame SEs in the host organism and provide a framework for further studies on the role of RNA structure in viral infection. Additionally, this work demonstrates the applicability of high-throughput chemical probing in plant cell lysates and presents a new method for calculating SHAPE reactivities from overlapping reverse transcriptase priming sites. PMID:29294088

  11. Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer.

    Science.gov (United States)

    Liu, Junjun; Chen, Xiaosong; Ward, Toby; Mao, Yan; Bockhorn, Jessica; Liu, Xiaofei; Wang, Gen; Pegram, Mark; Shen, Kunwei

    2016-02-01

    Acquired resistance to lapatinib, a human epidermal growth factor receptor 2 kinase inhibitor, remains a clinical problem for women with human epidermal growth factor receptor 2-positive advanced breast cancer, as metastasis is commonly observed in these patients. Niclosamide, an anti-helminthic agent, has recently been shown to exhibit cytotoxicity to tumor cells with stem-like characteristics. This study was designed to identify the mechanisms underlying lapatinib resistance and to determine whether niclosamide inhibits lapatinib resistance by reversing epithelial-mesenchymal transition. Here, two human epidermal growth factor receptor 2-positive breast cancer cell lines, SKBR3 and BT474, were exposed to increasing concentrations of lapatinib to establish lapatinib-resistant cultures. Lapatinib-resistant SKBR3 and BT474 cells exhibited up-regulation of the phenotypic epithelial-mesenchymal transition markers Snail, vimentin and α-smooth muscle actin, accompanied by activation of nuclear factor-кB and Src and a concomitant increase in stem cell marker expression (CD44(high)/CD24(low)), compared to naive lapatinib-sensitive SKBR3 and BT474 cells, respectively. Interestingly, niclosamide reversed epithelial-mesenchymal transition, induced apoptosis and inhibited cell growth by perturbing aberrant signaling pathway activation in lapatinib-resistant human epidermal growth factor receptor 2-positive cells. The ability of niclosamide to alleviate stem-like phenotype development and invasion was confirmed. Collectively, our results demonstrate that lapatinib resistance correlates with epithelial-mesenchymal transition and that niclosamide inhibits lapatinib-resistant cell viability and epithelial-mesenchymal transition. These findings suggest a role of niclosamide or derivatives optimized for more favorable bioavailability not only in reversing lapatinib resistance but also in reducing metastatic potential during the treatment of human epidermal growth factor receptor

  12. β-Elemene Selectively Inhibits the Proliferation of Glioma Stem-Like Cells Through the Downregulation of Notch1.

    Science.gov (United States)

    Feng, Hai-Bin; Wang, Jing; Jiang, Hao-Ran; Mei, Xin; Zhao, Yi-Ying; Chen, Fu-Rong; Qu, Yue; Sai, Ke; Guo, Cheng-Cheng; Yang, Qun-Ying; Zhang, Zong-Ping; Chen, Zhong-Ping

    2017-03-01

    Glioma is the most frequent primary central nervous system tumor. Although the current first-line medicine, temozolomide (TMZ), promotes patient survival, drug resistance develops easily. Thus, it is important to investigate novel therapeutic reagents to solidify the treatment effect. β-Elemene (bELE) is a compound from a Chinese herb whose anticancer effect has been shown in various types of cancer. However, its role in the inhibition of glioma stem-like cells (GSLCs) has not yet been reported. We studied both the in vitro and the in vivo inhibitory effect of bELE and TMZ in GSLCs and parental cells and their combined effects. The molecular mechanisms were also investigated. We also optimized the delivery methods of bELE. We found that bELE selectively inhibits the proliferation and sphere formation of GSLCs, other than parental glioma cells, and TMZ exerts its effects on parental cells instead of GSLCs. The in vivo data confirmed that the combination of bELE and TMZ worked better in the xenografts of GSLCs, mimicking the situation of tumorigenesis of human cancer. Notch1 was downregulated with bELE treatment. Our data also demonstrated that the continuous administration of bELE produces an ideal effect to control tumor progression. Our findings have demonstrated, for the first time, that bELE could compensate for TMZ to kill both GSLCs and nonstem-like cancer cells, probably improving the prognosis of glioma patients tremendously. Notch1 might be a downstream target of bELE. Therefore, our data shed light on improving the outcomes of glioma patients by combining bELE and TMZ. Stem Cells Translational Medicine 2017;6:830-839. © 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  13. β‐Elemene Selectively Inhibits the Proliferation of Glioma Stem‐Like Cells Through the Downregulation of Notch1

    Science.gov (United States)

    Feng, Hai‐bin; Wang, Jing; Jiang, Hao‐ran; Mei, Xin; Zhao, Yi‐ying; Chen, Fu‐rong; Qu, Yue; Sai, Ke; Guo, Cheng‐cheng; Yang, Qun‐ying; Zhang, Zong‐ping

    2016-01-01

    Abstract Glioma is the most frequent primary central nervous system tumor. Although the current first‐line medicine, temozolomide (TMZ), promotes patient survival, drug resistance develops easily. Thus, it is important to investigate novel therapeutic reagents to solidify the treatment effect. β‐Elemene (bELE) is a compound from a Chinese herb whose anticancer effect has been shown in various types of cancer. However, its role in the inhibition of glioma stem‐like cells (GSLCs) has not yet been reported. We studied both the in vitro and the in vivo inhibitory effect of bELE and TMZ in GSLCs and parental cells and their combined effects. The molecular mechanisms were also investigated. We also optimized the delivery methods of bELE. We found that bELE selectively inhibits the proliferation and sphere formation of GSLCs, other than parental glioma cells, and TMZ exerts its effects on parental cells instead of GSLCs. The in vivo data confirmed that the combination of bELE and TMZ worked better in the xenografts of GSLCs, mimicking the situation of tumorigenesis of human cancer. Notch1 was downregulated with bELE treatment. Our data also demonstrated that the continuous administration of bELE produces an ideal effect to control tumor progression. Our findings have demonstrated, for the first time, that bELE could compensate for TMZ to kill both GSLCs and nonstem‐like cancer cells, probably improving the prognosis of glioma patients tremendously. Notch1 might be a downstream target of bELE. Therefore, our data shed light on improving the outcomes of glioma patients by combining bELE and TMZ. Stem Cells Translational Medicine 2017;6:830–839 PMID:28297578

  14. [Selection of access and positioning for operative treatment of pelvic injuries. Decision-making strategies].

    Science.gov (United States)

    Ossendorf, C; Hofmann, A; Rommens, P M

    2013-03-01

    Surgical treatment of pelvic ring injuries requires in-depth knowledge of the topographic anatomy of the pelvic bones, joints and soft tissue structures. A wide range of stabilizing techniques is available including bridging plate osteosynthesis, iliosacral compression screw osteosynthesis and transpubic positioning screws. In this article the different treatment strategies with the respective surgical approaches and patient positioning for pelvic ring fractures and combined lesions of the pelvic ring and acetabulum are presented. Pelvic ring lesions with rotational instability are approached from the anterior and occasionally from both the anterior and posterior based on the amount and localization of the instability. In vertically unstable lesions the most unstable part must be addressed first by reduction and fixation of the dislocated part to the axial skeleton. In combined fractures of the pelvis and acetabulum dorsal stabilization is carried out first.

  15. Is self-selection the main driver of positive interpretations of general health checks?

    DEFF Research Database (Denmark)

    Bender, Anne Mette; Jørgensen, Torben; Pisinger, Charlotta

    2015-01-01

    OBJECTIVE: To investigate if the lower mortality among participants of a health check followed by lifestyle intervention of high risk persons is explained by self-selection. METHODS: All persons residing in the study area (Copenhagen; Denmark) were randomized to intervention (n=11,629) or control...... group (n=47,987). Persons in the intervention group were invited for a health check and individual lifestyle counselling. At baseline, 52.5% participated. Differences between participants and control group in 10-year all-cause and disease specific mortality was assessed. In survival analyses we...... was seen both for lifestyle related and non-lifestyle related diseases....

  16. Chondroitinase C Selectively Degrades Chondroitin Sulfate Glycosaminoglycans that Inhibit Axonal Growth within the Endoneurium of Peripheral Nerve.

    Directory of Open Access Journals (Sweden)

    James B Graham

    Full Text Available The success of peripheral nerve regeneration is highly dependent on the regrowth of axons within the endoneurial basal lamina tubes that promote target-oriented pathfinding and appropriate reinnervation. Restoration of nerve continuity at this structural level after nerve transection injury by direct repair and nerve grafting remains a major surgical challenge. Recently, biological approaches that alter the balance of growth inhibitors and promoters in nerve have shown promise to improve appropriate axonal regeneration and recovery of peripheral nerve function. Chondroitin sulfate proteoglycans (CSPGs are known inhibitors of axonal growth. This growth inhibition is mainly associated with a CSPG's glycosaminoglycan chains. Enzymatic degradation of these chains with chondroitinase eliminates this inhibitory activity and, when applied in vivo, can improve the outcome of nerve repair. To date, these encouraging findings were obtained with chondroitinase ABC (a pan-specific chondroitinase. The aim of this study was to examine the distribution of CSPG subtypes in rodent, rabbit, and human peripheral nerve and to test more selective biological enzymatic approaches to improve appropriate axonal growth within the endoneurium and minimize aberrant growth. Here we provide evidence that the endoneurium, but not the surrounding epineurium, is rich in CSPGs that have glycosaminoglycan chains readily degraded by chondroitinase C. Biochemical studies indicate that chondroitinase C has degradation specificity for 6-sulfated glycosaminoglycans found in peripheral nerve. We found that chondroitinase C degrades and inactivates inhibitory CSPGs within the endoneurium but not so much in the surrounding nerve compartments. Cryoculture bioassays (neurons grown on tissue sections show that chondroitinase C selectively and significantly enhanced neuritic growth associated with the endoneurial basal laminae without changing growth-inhibiting properties of the surrounding

  17. Chondroitinase C Selectively Degrades Chondroitin Sulfate Glycosaminoglycans that Inhibit Axonal Growth within the Endoneurium of Peripheral Nerve.

    Science.gov (United States)

    Graham, James B; Muir, David

    2016-01-01

    The success of peripheral nerve regeneration is highly dependent on the regrowth of axons within the endoneurial basal lamina tubes that promote target-oriented pathfinding and appropriate reinnervation. Restoration of nerve continuity at this structural level after nerve transection injury by direct repair and nerve grafting remains a major surgical challenge. Recently, biological approaches that alter the balance of growth inhibitors and promoters in nerve have shown promise to improve appropriate axonal regeneration and recovery of peripheral nerve function. Chondroitin sulfate proteoglycans (CSPGs) are known inhibitors of axonal growth. This growth inhibition is mainly associated with a CSPG's glycosaminoglycan chains. Enzymatic degradation of these chains with chondroitinase eliminates this inhibitory activity and, when applied in vivo, can improve the outcome of nerve repair. To date, these encouraging findings were obtained with chondroitinase ABC (a pan-specific chondroitinase). The aim of this study was to examine the distribution of CSPG subtypes in rodent, rabbit, and human peripheral nerve and to test more selective biological enzymatic approaches to improve appropriate axonal growth within the endoneurium and minimize aberrant growth. Here we provide evidence that the endoneurium, but not the surrounding epineurium, is rich in CSPGs that have glycosaminoglycan chains readily degraded by chondroitinase C. Biochemical studies indicate that chondroitinase C has degradation specificity for 6-sulfated glycosaminoglycans found in peripheral nerve. We found that chondroitinase C degrades and inactivates inhibitory CSPGs within the endoneurium but not so much in the surrounding nerve compartments. Cryoculture bioassays (neurons grown on tissue sections) show that chondroitinase C selectively and significantly enhanced neuritic growth associated with the endoneurial basal laminae without changing growth-inhibiting properties of the surrounding epineurium

  18. Evidence of positive selection at codon sites localized in extracellular domains of mammalian CC motif chemokine receptor proteins

    Directory of Open Access Journals (Sweden)

    Metzger Kelsey J

    2010-05-01

    Full Text Available Abstract Background CC chemokine receptor proteins (CCR1 through CCR10 are seven-transmembrane G-protein coupled receptors whose signaling pathways are known for their important roles coordinating immune system responses through targeted trafficking of white blood cells. In addition, some of these receptors have been identified as fusion proteins for viral pathogens: for example, HIV-1 strains utilize CCR5, CCR2 and CCR3 proteins to obtain cellular entry in humans. The extracellular domains of these receptor proteins are involved in ligand-binding specificity as well as pathogen recognition interactions. In mammals, the majority of chemokine receptor genes are clustered together; in humans, seven of the ten genes are clustered in the 3p21-24 chromosome region. Gene conversion events, or exchange of DNA sequence between genes, have been reported in chemokine receptor paralogs in various mammalian lineages, especially between the cytogenetically closely located pairs CCR2/5 and CCR1/3. Datasets of mammalian orthologs for each gene were analyzed separately to minimize the potential confounding impact of analyzing highly similar sequences resulting from gene conversion events. Molecular evolution approaches and the software package Phylogenetic Analyses by Maximum Likelihood (PAML were utilized to investigate the signature of selection that has acted on the mammalian CC chemokine receptor (CCR gene family. The results of neutral vs. adaptive evolution (positive selection hypothesis testing using Site Models are reported. In general, positive selection is defined by a ratio of nonsynonymous/synonymous nucleotide changes (dN/dS, or ω >1. Results Of the ten mammalian CC motif chemokine receptor sequence datasets analyzed, only CCR2 and CCR3 contain amino acid codon sites that exhibit evidence of positive selection using site based hypothesis testing in PAML. Nineteen of the twenty codon sites putatively indentified as likely to be under positive

  19. Selectivity of Inhibition of N-Succinyl-l,l-Diaminopimelic Acid Desuccinylase in Bacteria: The product of dapE-gene Is Not the Target of l-Captopril Antimicrobial Activity.

    Science.gov (United States)

    Uda, Narasimha Rao; Creus, Marc

    2011-01-01

    The emergence of bacterial strains that are resistant to virtually all currently available antibiotics underscores the importance of developing new antimicrobial compounds. N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) is a metallohydrolase involved in the meso-diaminopimelate (mDAP)/lysine biosynthetic pathway necessary for lysine biosynthesis and for building the peptidoglycan cell wall. Because DapE is essential for Gram-negative and some Gram-positive bacteria, DapE has been proposed as a good target for antibiotic development. Recently, l-captopril has been suggested as a lead compound for inhibition of DapE, although its selectivity for this enzyme target in bacteria remains unclear (Gillner et al. (2009)). Here, we tested the selectivity of l-captopril against DapE in bacteria. Since DapE knockout strains of gram-negative bacteria are viable upon chemical supplementation with mDAP, we reasoned that the antimicrobial activity of compounds targeting DapE should be abolished in mDAP-containing media. Although l-captopril had modest antimicrobial activity in Escherichia coli and in Salmonella enterica, to our surprise, inhibition of bacterial growth was independent both of mDAP supplementation and DapE over-expression. We conclude that DapE is not the main target of l-captopril inhibition in these bacteria. The methods implemented here will be useful for screening DapE-selective antimicrobial compounds directly in bacterial cultures.

  20. Positive selection results in frequent reversible amino acid replacements in the G protein gene of human respiratory syncytial virus.

    Science.gov (United States)

    Botosso, Viviane F; Zanotto, Paolo M de A; Ueda, Mirthes; Arruda, Eurico; Gilio, Alfredo E; Vieira, Sandra E; Stewien, Klaus E; Peret, Teresa C T; Jamal, Leda F; Pardini, Maria I de M C; Pinho, João R R; Massad, Eduardo; Sant'anna, Osvaldo A; Holmes, Eddie C; Durigon, Edison L

    2009-01-01

    Human respiratory syncytial virus (HRSV) is the major cause of lower respiratory tract infections in children under 5 years of age and the elderly, causing annual disease outbreaks during the fall and winter. Multiple lineages of the HRSVA and HRSVB serotypes co-circulate within a single outbreak and display a strongly temporal pattern of genetic variation, with a replacement of dominant genotypes occurring during consecutive years. In the present study we utilized phylogenetic methods to detect and map sites subject to adaptive evolution in the G protein of HRSVA and HRSVB. A total of 29 and 23 amino acid sites were found to be putatively positively selected in HRSVA and HRSVB, respectively. Several of these sites defined genotypes and lineages within genotypes in both groups, and correlated well with epitopes previously described in group A. Remarkably, 18 of these positively selected tended to revert in time to a previous codon state, producing a "flip-flop" phylogenetic pattern. Such frequent evolutionary reversals in HRSV are indicative of a combination of frequent positive selection, reflecting the changing immune status of the human population, and a limited repertoire of functionally viable amino acids at specific amino acid sites.

  1. Positive selection results in frequent reversible amino acid replacements in the G protein gene of human respiratory syncytial virus.

    Directory of Open Access Journals (Sweden)

    Viviane F Botosso

    2009-01-01

    Full Text Available Human respiratory syncytial virus (HRSV is the major cause of lower respiratory tract infections in children under 5 years of age and the elderly, causing annual disease outbreaks during the fall and winter. Multiple lineages of the HRSVA and HRSVB serotypes co-circulate within a single outbreak and display a strongly temporal pattern of genetic variation, with a replacement of dominant genotypes occurring during consecutive years. In the present study we utilized phylogenetic methods to detect and map sites subject to adaptive evolution in the G protein of HRSVA and HRSVB. A total of 29 and 23 amino acid sites were found to be putatively positively selected in HRSVA and HRSVB, respectively. Several of these sites defined genotypes and lineages within genotypes in both groups, and correlated well with epitopes previously described in group A. Remarkably, 18 of these positively selected tended to revert in time to a previous codon state, producing a "flip-flop" phylogenetic pattern. Such frequent evolutionary reversals in HRSV are indicative of a combination of frequent positive selection, reflecting the changing immune status of the human population, and a limited repertoire of functionally viable amino acids at specific amino acid sites.

  2. Plant operator selection system for evaluating employment candidates' potential for success in electric power plant operations positions

    International Nuclear Information System (INIS)

    Dunnette, M.D.

    1982-01-01

    The Plant Operator Selection System is a battery of tests and questionnaires that can be administered to job candidates in less than three hours. Various components of the battery measure what a job candidate has accomplished in previous educational and work situations, how well a candidate compares with others on a number of important aptitudes or abilities, and whether or not a candidate possesses the kind of personal stability required in power plant operations positions. A job candidate's answers to the tests and questionnaires of the Plant Operator Selection System are scored and converted to an OVERALL POTENTIAL INDEX. Values of the OVERALL POTENTIAL INDEX [OPI] range between 0 and 15. Candidates with high OPI values are much more likely to become effective and successful plant operators than candidates with low OPI values. It is possible to estimate the financial advantages to a company of using the Plant Operator Selection System in evaluating candidates for plant operations jobs

  3. Sexual orientation and spatial position effects on selective forms of object location memory.

    Science.gov (United States)

    Rahman, Qazi; Newland, Cherie; Smyth, Beatrice Mary

    2011-04-01

    Prior research has demonstrated robust sex and sexual orientation-related differences in object location memory in humans. Here we show that this sexual variation may depend on the spatial position of target objects and the task-specific nature of the spatial array. We tested the recovery of object locations in three object arrays (object exchanges, object shifts, and novel objects) relative to veridical center (left compared to right side of the arrays) in a sample of 35 heterosexual men, 35 heterosexual women, and 35 homosexual men. Relative to heterosexual men, heterosexual women showed better location recovery in the right side of the array during object exchanges and homosexual men performed better in the right side during novel objects. However, the difference between heterosexual and homosexual men disappeared after controlling for IQ. Heterosexual women and homosexual men did not differ significantly from each other in location change detection with respect to task or side of array. These data suggest that visual space biases in processing categorical spatial positions may enhance aspects of object location memory in heterosexual women. Copyright © 2010 Elsevier Inc. All rights reserved.

  4. Religiousness, well-being and ageing – selected explanations of positive relationships

    Directory of Open Access Journals (Sweden)

    Woźniak Barbara

    2015-12-01

    Full Text Available According to research that have been conducted in the field of gerontology, sociology and psychology of ageing, there is a relationship between the level of religious involvement and health status/ well-being/quality of life in older age. How does religiousness influence aging process and health status? The aim of the article is to review explanations of a positive relationship between religiousness and health that are discussed in the literature. Those explanations may be grouped in three broad categories reflecting three functions of religion that play a role for well-being in older age. Those functions are: (1 religiousness as a source of coherence and the role of religious coping and provision of meaning in dealing with stressful life events (including ageing losses (2 religiousness as a source of positive self-perception and a sense of personal control, (3 provision of social resources (i.e. social ties and social support within religious community and emphasis on interpersonal relations (with special focus on forgiveness as a norm in interpersonal relations. Those functions of religion are discussed in the context of their potential role in successful ageing, as determined by - among others - active engagement in life.

  5. Positive affect, meaning in life, and future time perspective: an application of socioemotional selectivity theory.

    Science.gov (United States)

    Hicks, Joshua A; Trent, Jason; Davis, William E; King, Laura A

    2012-03-01

    Four studies tested the prediction that positive affect (PA) would relate more strongly to meaning in life (MIL) as a function of perceived time limitations. In Study 1 (N = 360), adults completed measures of PA and MIL. As predicted, PA related more strongly to MIL for older, compared to younger, participants. In Studies 2 and 3, adults (N = 514) indicated their current position in their life span, and rated their MIL. PA, whether naturally occurring (Study 2) or induced (Study 3), was a stronger predictor of MIL for individuals who perceived themselves as having a limited amount of time left to live. Finally, in Study 4 (N = 98) students completed a measure of PA, MIL, and future time perspective (FTP). Results showed that PA was more strongly linked to MIL for those who believed they had fewer opportunities left to pursue their goals. Overall, these findings suggest that the experience of PA becomes increasingly associated with the experience of MIL as the perception of future time becomes limited. The contribution of age related processes to judgments of well-being are discussed.

  6. Position of the Mental Foramen in Panoramic Radiography and Its Relationship to Age in a Selected Iranian Population

    Directory of Open Access Journals (Sweden)

    Dehghani

    2016-02-01

    Full Text Available Background The position of the mental foramen is critical for surgery and local anesthesia. Objectives This study was conducted to assess the position of the mental foramen and its relationship to age in a selected Iranian population. Materials and Methods This was a cross-sectional descriptive study. Three hundred panoramic radiographs were assessed. Three variables were assessed for each radiograph: anterior-posterior position, superior-inferior position, and radiographic appearance. The position and appearance of the mental foramen were recorded according to gender and age. The results were analyzed using Chi-square and Fisher’s exact tests. Results Considering the anterior-posterior position, the mental foramina were located in the following positions: between premolars (41.5%, at the apex of the second premolars (31.7%, in the posterior area of the second premolars (19.2%, in the anterior area of the first premolars (4.3%, and at the apex of the first premolars (3.3%.The superior-inferior position of the mental foramina were below, above, and at the level of the apices of the premolars in 78.8%, 2.5%, and 18.7% of cases, respectively. The appearance of the mental foramen was continuous in relation to the mandibular canal in 55.9% of cases, while it was separated, diffuse, and unidentified in 29.5%, 9.7%, and 5% of cases, respectively. Age was found to affect the position and appearance of mental foramen. Conclusions The mental foramina were most commonly located between the first and second premolars and below the apex. A continuous appearance was the most common appearance for the mental foramen, which was similar in males and females.

  7. Likelihood analysis of the chalcone synthase genes suggests the role of positive selection in morning glories (Ipomoea).

    Science.gov (United States)

    Yang, Ji; Gu, Hongya; Yang, Ziheng

    2004-01-01

    Chalcone synthase (CHS) is a key enzyme in the biosynthesis of flavonoides, which are important for the pigmentation of flowers and act as attractants to pollinators. Genes encoding CHS constitute a multigene family in which the copy number varies among plant species and functional divergence appears to have occurred repeatedly. In morning glories (Ipomoea), five functional CHS genes (A-E) have been described. Phylogenetic analysis of the Ipomoea CHS gene family revealed that CHS A, B, and C experienced accelerated rates of amino acid substitution relative to CHS D and E. To examine whether the CHS genes of the morning glories underwent adaptive evolution, maximum-likelihood models of codon substitution were used to analyze the functional sequences in the Ipomoea CHS gene family. These models used the nonsynonymous/synonymous rate ratio (omega = d(N)/ d(S)) as an indicator of selective pressure and allowed the ratio to vary among lineages or sites. Likelihood ratio test suggested significant variation in selection pressure among amino acid sites, with a small proportion of them detected to be under positive selection along the branches ancestral to CHS A, B, and C. Positive Darwinian selection appears to have promoted the divergence of subfamily ABC and subfamily DE and is at least partially responsible for a rate increase following gene duplication.

  8. Does positive selection drive transcription factor binding site turnover? A test with Drosophila cis-regulatory modules.

    Directory of Open Access Journals (Sweden)

    Bin Z He

    2011-04-01

    Full Text Available Transcription factor binding site(s (TFBS gain and loss (i.e., turnover is a well-documented feature of cis-regulatory module (CRM evolution, yet little attention has been paid to the evolutionary force(s driving this turnover process. The predominant view, motivated by its widespread occurrence, emphasizes the importance of compensatory mutation and genetic drift. Positive selection, in contrast, although it has been invoked in specific instances of adaptive gene expression evolution, has not been considered as a general alternative to neutral compensatory evolution. In this study we evaluate the two hypotheses by analyzing patterns of single nucleotide polymorphism in the TFBS of well-characterized CRM in two closely related Drosophila species, Drosophila melanogaster and Drosophila simulans. An important feature of the analysis is classification of TFBS mutations according to the direction of their predicted effect on binding affinity, which allows gains and losses to be evaluated independently along the two phylogenetic lineages. The observed patterns of polymorphism and divergence are not compatible with neutral evolution for either class of mutations. Instead, multiple lines of evidence are consistent with contributions of positive selection to TFBS gain and loss as well as purifying selection in its maintenance. In discussion, we propose a model to reconcile the finding of selection driving TFBS turnover with constrained CRM function over long evolutionary time.

  9. Detecting loci under recent positive selection in dairy and beef cattle by combining different genome-wide scan methods.

    Directory of Open Access Journals (Sweden)

    Yuri Tani Utsunomiya

    Full Text Available As the methodologies available for the detection of positive selection from genomic data vary in terms of assumptions and execution, weak correlations are expected among them. However, if there is any given signal that is consistently supported across different methodologies, it is strong evidence that the locus has been under past selection. In this paper, a straightforward frequentist approach based on the Stouffer Method to combine P-values across different tests for evidence of recent positive selection in common variations, as well as strategies for extracting biological information from the detected signals, were described and applied to high density single nucleotide polymorphism (SNP data generated from dairy and beef cattle (taurine and indicine. The ancestral Bovinae allele state of over 440,000 SNP is also reported. Using this combination of methods, highly significant (P<3.17×10(-7 population-specific sweeps pointing out to candidate genes and pathways that may be involved in beef and dairy production were identified. The most significant signal was found in the Cornichon homolog 3 gene (CNIH3 in Brown Swiss (P = 3.82×10(-12, and may be involved in the regulation of pre-ovulatory luteinizing hormone surge. Other putative pathways under selection are the glucolysis/gluconeogenesis, transcription machinery and chemokine/cytokine activity in Angus; calpain-calpastatin system and ribosome biogenesis in Brown Swiss; and gangliosides deposition in milk fat globules in Gyr. The composite method, combined with the strategies applied to retrieve functional information, may be a useful tool for surveying genome-wide selective sweeps and providing insights in to the source of selection.

  10. Depression and selection of positive and negative social feedback: motivated preference or cognitive balance?

    Science.gov (United States)

    Alloy, L B; Lipman, A J

    1992-05-01

    In this commentary we examine Swann, Wenzlaff, Krull, and Pelham's (1992) findings with respect to each of 5 central propositions in self-verification theory. We conclude that although the data are consistent with self-verification theory, none of the 5 components of the theory have been demonstrated convincingly as yet. Specifically, we argue that depressed subjects' selection of social feedback appears to be balanced or evenhanded rather than biased toward negative feedback and that there is little evidence to indicate that depressives actively seek negative appraisals. Furthermore, we suggest that the studies are silent with respect to the motivational postulates of self-verification theory and that a variety of competing cognitive and motivational models can explain Swann et al.'s findings as well as self-verification theory.

  11. Inhibiting HER3-mediated tumor cell growth with affibody molecules engineered to low picomolar affinity by position-directed error-prone PCR-like diversification.

    Science.gov (United States)

    Malm, Magdalena; Kronqvist, Nina; Lindberg, Hanna; Gudmundsdotter, Lindvi; Bass, Tarek; Frejd, Fredrik Y; Höidén-Guthenberg, Ingmarie; Varasteh, Zohreh; Orlova, Anna; Tolmachev, Vladimir; Ståhl, Stefan; Löfblom, John

    2013-01-01

    The HER3 receptor is implicated in the progression of various cancers as well as in resistance to several currently used drugs, and is hence a potential target for development of new therapies. We have previously generated Affibody molecules that inhibit heregulin-induced signaling of the HER3 pathways. The aim of this study was to improve the affinity of the binders to hopefully increase receptor inhibition efficacy and enable a high receptor-mediated uptake in tumors. We explored a novel strategy for affinity maturation of Affibody molecules that is based on alanine scanning followed by design of library diversification to mimic the result from an error-prone PCR reaction, but with full control over mutated positions and thus less biases. Using bacterial surface display and flow-cytometric sorting of the maturation library, the affinity for HER3 was improved more than 30-fold down to 21 pM. The affinity is among the higher that has been reported for Affibody molecules and we believe that the maturation strategy should be generally applicable for improvement of affinity proteins. The new binders also demonstrated an improved thermal stability as well as complete refolding after denaturation. Moreover, inhibition of ligand-induced proliferation of HER3-positive breast cancer cells was improved more than two orders of magnitude compared to the previously best-performing clone. Radiolabeled Affibody molecules showed specific targeting of a number of HER3-positive cell lines in vitro as well as targeting of HER3 in in vivo mouse models and represent promising candidates for future development of targeted therapies and diagnostics.

  12. Impact of low-energy CT imaging on selection of positive oral contrast media concentration.

    Science.gov (United States)

    Patino, Manuel; Murcia, Diana J; Iamurri, Andrea Prochowski; Kambadakone, Avinash R; Hahn, Peter F; Sahani, Dushyant V

    2017-05-01

    To determine to what extent low-energy CT imaging affects attenuation of gastrointestinal tract (GIT) opacified with positive oral contrast media (OCM). Second, to establish optimal OCM concentrations for low-energy diagnostic CT exams. One hundred patients (38 men and 62 women; age 62 ± 11 years; BMI 26 ± 5) with positive OCM-enhanced 120-kVp single-energy CT (SECT), and follow-up 100-kVp acquisitions (group A; n = 50), or 40-70-keV reconstructions from rapid kV switching-single-source dual-energy CT (ssDECT) (group B; n = 50) were included. Luminal attenuation from different GIT segments was compared between exams. Standard dose of three OCM and diluted solutions (75%, 50%, and 25% concentrations) were introduced serially in a gastrointestinal phantom and scanned using SECT (120, 100, and 80 kVp) and DECT (80/140 kVp) acquisitions on a ssDECT scanner. Luminal attenuation was obtained on SECT and DECT images (40-70 keV), and compared to 120-kVp scans with standard OCM concentrations. Luminal attenuation was higher on 100-kVp (328 HU) and on 40-60-keV images (410-924 HU) in comparison to 120-kVp scans (298 HU) in groups A and B (p < 0.05). Phantom: There was an inverse correlation between luminal attenuation and X-ray energy, increasing up to 527 HU on low-kVp and 999 HU on low-keV images (p < 0.05). 25% and 50% diluted OCM solutions provided similar or higher attenuation than 120 kVp, at low kVp and keV, respectively. Low-energy CT imaging increases the attenuation of GIT opacified with positive OCM, permitting reduction of 25%-75% OCM concentration.

  13. Blocking the NOTCH pathway can inhibit the growth of CD133-positive A549 cells and sensitize to chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Juntao; Mao, Zhangfan; Huang, Jie; Xie, Songping; Liu, Tianshu; Mao, Zhifu, E-mail: 48151660@qq.com

    2014-02-21

    Highlights: • Notch signaling pathway members are expressed lower levels in CD133+ cells. • CD133+ cells are not as sensitive as CD133− cells to chemotherapy. • GSI could inhibit the growth of both CD133+ and CD133− cells. • Blockade of Notch signaling pathway enhanced the effect of chemotherapy with CDDP. • DAPT/CDDP co-therapy caused G2/M arrest and elimination in CD133+ cells. - Abstract: Cancer stem cells (CSCs) are believed to play an important role in tumor growth and recurrence. These cells exhibit self-renewal and proliferation properties. CSCs also exhibit significant drug resistance compared with normal tumor cells. Finding new treatments that target CSCs could significantly enhance the effect of chemotherapy and improve patient survival. Notch signaling is known to regulate the development of the lungs by controlling the cell-fate determination of normal stem cells. In this study, we isolated CSCs from the human lung adenocarcinoma cell line A549. CD133 was used as a stem cell marker for fluorescence-activated cell sorting (FACS). We compared the expression of Notch signaling in both CD133+ and CD133− cells and blocked Notch signaling using the γ-secretase inhibitor DAPT (GSI-IX). The effect of combining GSI and cisplatin (CDDP) was also examined in these two types of cells. We observed that both CD133+ and CD133− cells proliferated at similar rates, but the cells exhibited distinctive differences in cell cycle progression. Few CD133+ cells were observed in the G{sub 2}/M phase, and there were half as many cells in S phase compared with the CD133− cells. Furthermore, CD133+ cells exhibited significant resistance to chemotherapy when treated with CDDP. The expression of Notch signaling pathway members, such as Notch1, Notch2 and Hes1, was lower in CD133+ cells. GSI slightly inhibited the proliferation of both cell types and exhibited little effect on the cell cycle. The inhibitory effects of DPP on these two types of cells were

  14. Structure refinement and membrane positioning of selectively labeled OmpX in phospholipid nanodiscs

    Energy Technology Data Exchange (ETDEWEB)

    Hagn, Franz, E-mail: franz.hagn@tum.de; Wagner, Gerhard, E-mail: gerhard-wagner@hms.harvard.edu [Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology (United States)

    2015-04-15

    NMR structural studies on membrane proteins are often complicated by their large size, taking into account the contribution of the membrane mimetic. Therefore, classical resonance assignment approaches often fail. The large size of phospholipid nanodiscs, a detergent-free phospholipid bilayer mimetic, prevented their use in high-resolution solution-state NMR spectroscopy so far. We recently introduced smaller nanodiscs that are suitable for NMR structure determination. However, side-chain assignments of a membrane protein in nanodiscs still remain elusive. Here, we utilized a NOE-based approach to assign (stereo-) specifically labeled Ile, Leu, Val and Ala methyl labeled and uniformly {sup 15}N-Phe and {sup 15}N-Tyr labeled OmpX and calculated a refined high-resolution structure. In addition, we were able to obtain residual dipolar couplings (RDCs) of OmpX in nanodiscs using Pf1 phage medium for the induction of weak alignment. Back-calculated NOESY spectra of the obtained NMR structures were compared to experimental NOESYs in order to validate the quality of these structures. We further used NOE information between protonated lipid head groups and side-chain methyls to determine the position of OmpX in the phospholipid bilayer. These data were verified by paramagnetic relaxation enhancement (PRE) experiments obtained with Gd{sup 3+}-modified lipids. Taken together, this study emphasizes the need for the (stereo-) specific labeling of membrane proteins in a highly deuterated background for high-resolution structure determination, particularly in large membrane mimicking systems like phospholipid nanodiscs. Structure validation by NOESY back-calculation will be helpful for the structure determination and validation of membrane proteins where NOE assignment is often difficult. The use of protein to lipid NOEs will be beneficial for the positioning of a membrane protein in the lipid bilayer without the need for preparing multiple protein samples.

  15. Low concentrations of metformin selectively inhibit CD133⁺ cell proliferation in pancreatic cancer and have anticancer action.

    Directory of Open Access Journals (Sweden)

    Shanmiao Gou

    Full Text Available Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States. The prognosis remains dismal with little advance in treatment. Metformin is a drug widely used for the treatment of type II diabetes. Recent epidemiologic data revealed that oral administration of metformin is associated with a reduced risk of pancreatic cancer, suggesting its potential as a novel drug for this disease. Many studies have demonstrated the in vitro anticancer action of metformin, but the typically used concentrations were much higher than the in vivo plasma and tissue concentrations achieved with recommended therapeutic doses of metformin, and low concentrations of metformin had little effect on the proliferation of pancreatic cancer cells. We examined the effect of low concentrations of metformin on different subpopulations of pancreatic cancer cells and found that these selectively inhibited the proliferation of CD133⁺ but not CD24⁺CD44⁺ESA⁺ cells. We also examined the effect of low concentrations of metformin on cell invasion and in vivo tumor formation, demonstrating in vitro and in vivo anticancer action. Metformin was associated with a reduction of phospho-Erk and phospho-mTOR independent of Akt and AMPK phosphorylation. CD133⁺ pancreatic cancer cells are considered to be cancer stem cells that contribute to recurrence, metastasis and resistance to adjuvant therapies in pancreatic cancer. Our results provide a basis for combination of metformin with current therapies to improve the prognosis of this disease.

  16. Spermine selectively inhibits high-conductance, but not low-conductance calcium-induced permeability transition pore.

    Science.gov (United States)

    Elustondo, Pia A; Negoda, Alexander; Kane, Constance L; Kane, Daniel A; Pavlov, Evgeny V

    2015-02-01

    The permeability transition pore (PTP) is a large channel of the mitochondrial inner membrane, the opening of which is the central event in many types of stress-induced cell death. PTP opening is induced by elevated concentrations of mitochondrial calcium. It has been demonstrated that spermine and other polyamines can delay calcium-induced swelling of isolated mitochondria, suggesting their role as inhibitors of the mitochondrial PTP. Here we further investigated the mechanism by which spermine inhibits the calcium-induced, cyclosporine A (CSA) -sensitive PTP by using three indicators: 1) calcium release from the mitochondria detected with calcium green, 2) mitochondrial membrane depolarization using TMRM, and 3) mitochondrial swelling by measuring light absorbance. We found that despite calcium release and membrane depolarization, indicative of PTP activation, mitochondria underwent only partial swelling in the presence of spermine. This was in striking contrast to the high-amplitude swelling detected in control mitochondria and in mitochondria treated with the PTP inhibitor CSA. We conclude that spermine selectively prevents opening of the high-conductance state, while allowing activation of the lower conductance state of the PTP. We propose that the existence of lower conductance, stress-induced PTP might play an important physiological role, as it is expected to allow the release of toxic levels of calcium, while keeping important molecules (e.g., NAD) within the mitochondrial matrix. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Low Concentrations of Metformin Selectively Inhibit CD133+ Cell Proliferation in Pancreatic Cancer and Have Anticancer Action

    Science.gov (United States)

    Li, Xiangsheng; Shi, Pengfei; Liu, Tao; Wang, Chunyou

    2013-01-01

    Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States. The prognosis remains dismal with little advance in treatment. Metformin is a drug widely used for the treatment of type II diabetes. Recent epidemiologic data revealed that oral administration of metformin is associated with a reduced risk of pancreatic cancer, suggesting its potential as a novel drug for this disease. Many studies have demonstrated the in vitro anticancer action of metformin, but the typically used concentrations were much higher than the in vivo plasma and tissue concentrations achieved with recommended therapeutic doses of metformin, and low concentrations of metformin had little effect on the proliferation of pancreatic cancer cells. We examined the effect of low concentrations of metformin on different subpopulations of pancreatic cancer cells and found that these selectively inhibited the proliferation of CD133+ but not CD24+CD44+ESA+ cells. We also examined the effect of low concentrations of metformin on cell invasion and in vivo tumor formation, demonstrating in vitro and in vivo anticancer action. Metformin was associated with a reduction of phospho-Erk and phospho-mTOR independent of Akt and AMPK phosphorylation. CD133+ pancreatic cancer cells are considered to be cancer stem cells that contribute to recurrence, metastasis and resistance to adjuvant therapies in pancreatic cancer. Our results provide a basis for combination of metformin with current therapies to improve the prognosis of this disease. PMID:23667692

  18. James Cook University's rurally orientated medical school selection process: quality graduates and positive workforce outcomes.

    Science.gov (United States)

    Ray, Robin A; Woolley, Torres; Sen Gupta, Tarun

    2015-01-01

    The regionally based James Cook University (JCU) College of Medicine and Dentistry aims to meet its mission to address the health needs of the region by using a selection policy favouring rural origin applicants and providing students with early and repeated exposure to rural experiences during training. This study seeks to determine if the JCU medical school's policy of preferentially selecting rural and remote background students is associated with differing patterns of undergraduate performance or graduate practice location. Data at application to medical school and during the undergraduate years was retrieved from administrative databases held by the university and the medical school. Postgraduate location data were obtained either from personal contact via email, telephone or Facebook or electronically from the Australian Health Practitioner Regulation Authority website. Practice location was described across Australian Standard Geographical Classification Remoteness Area (ASGC-RA) categories, with 1 being a major city and 5 being a very remote location. The 856 Australian-based students accepted into the JCU medical program between 2000 and 2008 came from all geographical regions across Australia: 20% metropolitan (ASGC-RA 1), 20% inner regional (ASGC-RA 2), 56% outer regional (ASGC-RA 3), and 5% from remote or very remote locations (ASGC-RA 4 and 5). Having a rural or remote hometown at application (ASGC-RA 3-5) was significantly associated with a lower tertiary entrance score (pacademic achievement across years 1 to 3 (p=0.002, p=0.005 and p=0.025, respectively). Graduates having either a rural or a remote home town at application were more likely to practise in rural (RA 3-5) towns than graduates from metropolitan/inner regional centre across all postgraduate years. For example, the prevalence odds ratios (POR) for graduates practising in a rural town at postgraduate year 1 (PGY 1) having either a rural or remote hometown were 2.6 and 1.8, respectively

  19. Effect of repetitive yogic squats with specific hand position (Thoppukaranam) on selective attention and psychological states.

    Science.gov (United States)

    Chandrasekeran, Angelica; Rajesh, Sasidharan K; Srinivasan, Tm

    2014-01-01

    Research on the effect of Thoppukaranam is limited despite it being practiced as a form of worship to the elephant-headed deity Lord Ganapati and punishment in schools. The purpose of this study was to examine the effect of Thoppukaranam on selective attention and psychological states in a sample of young adults. A randomized self-as-control within subjects design was employed. Thirty undergraduate students (4 females and 26 males) from a residential Yoga University in Southern India were recruited for this study (group mean age ± standard deviation, 20.17 ± 2.92). The d2 test, State Anxiety Inventory-Short Form and State Mindful Attention Awareness Scale (SMAAS) were used to measure cognitive performance and psychological states. Assessments were made in three sessions: Baseline, control (squats), and experimental (Thoppukaranam) on 3 separate days. Data were analyzed using one-way repeated measures analyses of variance between three sessions, that is, baseline, squat, and Thoppukaranam. There was a significant improvement in all measures of the d2 test of attention (TN, E, TN-E, E%, and concentration performance) and state mindfulness after Thoppukaranam. Further state anxiety reduced significantly after the experimental session. These findings indicate Thoppukaranam results in enhancement of cognitive functioning and psychological states.

  20. Selective internalization of self-assembled artificial oil bodies by HER2/neu-positive cells

    International Nuclear Information System (INIS)

    Chiang, Chung-Jen; Lin, Che-Chin; Lin, Li-Jen; Chang, Chih-Hsiang; Chao, Yun-Peng

    2011-01-01

    A novel delivery carrier was developed using artificial oil bodies (AOBs). Plant seed oil bodies (OBs) consist of a triacylglycerol matrix surrounded by a monolayer of phospholipids embedded with the storage protein oleosin (Ole). Ole consists of a central hydrophobic domain with two amphiphatic arms that extrude from the surface of OBs. In this study, a bivalent anti-HER2/neu affibody domain (ZH2) was fused with Ole at the C terminus. After overproduction in Escherichia coli, the fusion protein (Ole-ZH2) was recovered to assemble AOBs. The size of self-assembled AOBs was tailored by varying the oil/Ole-ZH2 ratio and pH to reach a nanoscale. Upon co-incubation with tumor cells, the nanoscale AOBs encapsulated with a hydrophobic fluorescence dye were selectively internalized by HER2/neu-overexpressing cells and displayed biocompatibility with the cells. In addition, the ZH2-mediated endosomal entry of AOBs occurred in a time- and AOB dose-dependent manner. The internalization efficiency was as high as 90%. The internalized AOBs disintegrated at the non-permissive pH (e.g. in acidic endosomes) and the cargo dye was released. Results of in vitro study revealed a sustained and prolonged release profile. Taken together, our findings indicate the potential of AOBs as a delivery carrier.

  1. Multi-scale textural feature extraction and particle swarm optimization based model selection for false positive reduction in mammography.

    Science.gov (United States)

    Zyout, Imad; Czajkowska, Joanna; Grzegorzek, Marcin

    2015-12-01

    The high number of false positives and the resulting number of avoidable breast biopsies are the major problems faced by current mammography Computer Aided Detection (CAD) systems. False positive reduction is not only a requirement for mass but also for calcification CAD systems which are currently deployed for clinical use. This paper tackles two problems related to reducing the number of false positives in the detection of all lesions and masses, respectively. Firstly, textural patterns of breast tissue have been analyzed using several multi-scale textural descriptors based on wavelet and gray level co-occurrence matrix. The second problem addressed in this paper is the parameter selection and performance optimization. For this, we adopt a model selection procedure based on Particle Swarm Optimization (PSO) for selecting the most discriminative textural features and for strengthening the generalization capacity of the supervised learning stage based on a Support Vector Machine (SVM) classifier. For evaluating the proposed methods, two sets of suspicious mammogram regions have been used. The first one, obtained from Digital Database for Screening Mammography (DDSM), contains 1494 regions (1000 normal and 494 abnormal samples). The second set of suspicious regions was obtained from database of Mammographic Image Analysis Society (mini-MIAS) and contains 315 (207 normal and 108 abnormal) samples. Results from both datasets demonstrate the efficiency of using PSO based model selection for optimizing both classifier hyper-parameters and parameters, respectively. Furthermore, the obtained results indicate the promising performance of the proposed textural features and more specifically, those based on co-occurrence matrix of wavelet image representation technique. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Novel HER2 Aptamer Selectively Delivers Cytotoxic Drug to HER2-positive Breast Cancer Cells in Vitro

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    Liu Zhe

    2012-07-01

    Full Text Available Abstract Background Aptamer-based tumor targeted drug delivery system is a promising approach that may increase the efficacy of chemotherapy and reduce the related toxicity. HER2 protein is an attractive target for tumor-specific drug delivery because of its overexpression in multiple malignancies, including breast, gastric, ovarian, and lung cancers. Methods In this paper, we developed a new HER2 aptamer (HB5 by using systematic evolution of ligands by exponential enrichment technology (SELEX and exploited its role as a targeting ligand for delivering doxorubicin (Dox to breast cancer cells in vitro. Results The selected aptamer was an 86-nucleotide DNA molecule that bound to an epitope peptide of HER2 with a Kd of 18.9 nM. The aptamer also bound to the extracellular domain (ECD of HER2 protein with a Kdof 316 nM, and had minimal cross reactivity to albumin or trypsin. In addition, the aptamer was found to preferentially bind to HER2-positive but not HER2-negative breast cancer cells. An aptamer-doxorubicin complex (Apt-Dox was formulated by intercalating Dox into the DNA structure of HB5. The Apt-Dox complex could selectively deliver Dox to HER2-positive breast cancer cells while reducing the drug intake by HER2-negative cells in vitro. Moreover, Apt-Dox retained the cytotoxicity of Dox against HER2-positive breast cancer cells, but reduced the cytotoxicity to HER2-negative cells. Conclusions The results suggest that the selected HER2 aptamer may have application potentials in targeted therapy against HER2-positive breast cancer cells.

  3. Identifying selectively important amino acid positions associated with alternative habitat environments in fish mitochondrial genomes.

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    Xia, Jun Hong; Li, Hong Lian; Zhang, Yong; Meng, Zi Ning; Lin, Hao Ran

    2018-05-01

    Fish species inhabitating seawater (SW) or freshwater (FW) habitats have to develop genetic adaptations to alternative environment factors, especially salinity. Functional consequences of the protein variations associated with habitat environments in fish mitochondrial genomes have not yet received much attention. We analyzed 829 complete fish mitochondrial genomes and compared the amino acid differences of 13 mitochondrial protein families between FW and SW fish groups. We identified 47 specificity determining sites (SDS) that associated with FW or SW environments from 12 mitochondrial protein families. Thirty-two (68%) of the SDS sites are hydrophobic, 13 (28%) are neutral, and the remaining sites are acidic or basic. Seven of those SDS from ND1, ND2 and ND5 were scored as probably damaging to the protein structures. Furthermore, phylogenetic tree based Bayes Empirical Bayes analysis also detected 63 positive sites associated with alternative habitat environments across ten mtDNA proteins. These signatures could be important for studying mitochondrial genetic variation relevant to fish physiology and ecology.

  4. A design of a valid signal selecting and position decoding ASIC for PET using silicon photomultipliers

    International Nuclear Information System (INIS)

    Cho, M.; Lim, K.-T.; Kim, J.; Lee, C.; Cho, G.; Kim, H.; Yeom, J.-Y.; Choi, H.

    2017-01-01

    In most cases, a PET system has numerous electrical components and channel circuits and thus it would rather be a bulky product. Also, most existing systems receive analog signals from detectors which make them vulnerable to signal distortions. For these reasons, channel reduction techniques are important. In this work, an ASIC for PET module is being proposed. An ASIC chip for 16 PET detector channels, VSSPDC, has been designed and simulated. The main function of the chip is 16-to-1 channel reduction, i.e., finding the position of only the valid signals, signal timing, and magnitudes in all 16 channels at every recorded event. The ASIC comprises four of 4-channel modules and a 2 nd 4-to-1 router. A single channel module comprises a transimpedance amplifier for the silicon photomultipliers, dual comparators with high and low level references, and a logic circuitry. While the high level reference was used to test the validity of the signal, the low level reference was used for the timing. The 1-channel module of the ASIC produced an energy pulse by time-over-threshold method and it also produced a time pulse with a fixed delayed time. Since the ASIC chip outputs only a few digital pulses and does not require an external clock, it has an advantage over noise properties. The cadence simulation showed the good performance of the chip as designed.

  5. Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex.

    Science.gov (United States)

    Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; Frau, Roberto; Gessa, Gian L

    2015-10-01

    Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release. Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors. Fifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats. This research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The

  6. Selected Tea and Tea Pomace Extracts Inhibit Intestinal α-Glucosidase Activity in Vitro and Postprandial Hyperglycemia in Vivo

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    Jungbae Oh

    2015-04-01

    Full Text Available Type 2 diabetes mellitus (T2DM is a metabolic disorder characterized by postprandial hyperglycemia, which is an early defect of T2DM and thus a primary target for anti-diabetic drugs. A therapeutic approach is to inhibit intestinal α-glucosidase, the key enzyme for dietary carbohydrate digestion, resulting in delayed rate of glucose absorption. Although tea extracts have been reported to have anti-diabetic effects, the potential bioactivity of tea pomace, the main bio waste of tea beverage processing, is largely unknown. We evaluated the anti-diabetic effects of three selected tea water extracts (TWE and tea pomace extracts (TPE by determining the relative potency of extracts on rat intestinal α-glucosidase activity in vitro as well as hypoglycemic effects in vivo. Green, oolong, and black tea bags were extracted in hot water and the remaining tea pomace were dried and further extracted in 70% ethanol. The extracts were determined for intestinal rat α-glucosidases activity, radical scavenging activity, and total phenolic content. The postprandial glucose-lowering effects of TWE and TPE of green and black tea were assessed in male Sprague-Dawley (SD rats and compared to acarbose, a known pharmacological α-glucosidase inhibitor. The IC50 values of all three tea extracts against mammalian α-glucosidase were lower or similar in TPE groups than those of TWE groups. TWE and TPE of green tea exhibited the highest inhibitory effects against α-glucosidase activity with the IC50 of 2.04 ± 0.31 and 1.95 ± 0.37 mg/mL respectively. Among the specific enzymes tested, the IC50 values for TWE (0.16 ± 0.01 mg/mL and TPE (0.13 ± 0.01 mg/mL of green tea against sucrase activity were the lowest compared to those on maltase and glucoamylase activities. In the animal study, the blood glucose level at 30 min after oral intake (0.5 g/kg body wt of TPE and TWE of both green and black tea was significantly reduced compared to the control in sucrose-loaded SD

  7. Erroneous Magnet Positioning Leads to Failure of Inhibition of Inappropriate Shock during Fast Conducting Atrial Fibrillation Episodes.

    Science.gov (United States)

    Römers, Hans; VAN Dijk, Vincent; Balt, Jippe

    2017-06-01

    We present the case of a 75-year-old patient with a single-chamber St. Jude Medical internal cardioverter defibrillator (ICD; St. Jude Medical, St. Paul, MN, USA) for primary prevention, who was admitted with 39 inappropriate ICD shocks because of atrial fibrillation with rapid ventricular frequention, despite magnet placement. Review of the device manual and literature revealed that apart from different responses to magnet placement programmed for the various manufacturers, the type of magnet and the positioning can be of specific interest. In the case presented, the donut-shaped magnet should have been placed off-center instead of directly over the device. © 2017 Wiley Periodicals, Inc.

  8. Positive selection of a duplicated UV-sensitive visual pigment coincides with wing pigment evolution in Heliconius butterflies

    Science.gov (United States)

    Briscoe, Adriana D.; Bybee, Seth M.; Bernard, Gary D.; Yuan, Furong; Sison-Mangus, Marilou P.; Reed, Robert D.; Warren, Andrew D.; Llorente-Bousquets, Jorge; Chiao, Chuan-Chin

    2010-01-01

    The butterfly Heliconius erato can see from the UV to the red part of the light spectrum with color vision proven from 440 to 640 nm. Its eye is known to contain three visual pigments, rhodopsins, produced by an 11-cis-3-hydroxyretinal chromophore together with long wavelength (LWRh), blue (BRh) and UV (UVRh1) opsins. We now find that H. erato has a second UV opsin mRNA (UVRh2)—a previously undescribed duplication of this gene among Lepidoptera. To investigate its evolutionary origin, we screened eye cDNAs from 14 butterfly species in the subfamily Heliconiinae and found both copies only among Heliconius. Phylogeny-based tests of selection indicate positive selection of UVRh2 following duplication, and some of the positively selected sites correspond to vertebrate visual pigment spectral tuning residues. Epi-microspectrophotometry reveals two UV-absorbing rhodopsins in the H. erato eye with λmax = 355 nm and 398 nm. Along with the additional UV opsin, Heliconius have also evolved 3-hydroxy-DL-kynurenine (3-OHK)-based yellow wing pigments not found in close relatives. Visual models of how butterflies perceive wing color variation indicate this has resulted in an expansion of the number of distinguishable yellow colors on Heliconius wings. Functional diversification of the UV-sensitive visual pigments may help explain why the yellow wing pigments of Heliconius are so colorful in the UV range compared to the yellow pigments of close relatives lacking the UV opsin duplicate. PMID:20133601

  9. Micronutrient Availability in Relation to Selected Soil Properties and landscape Position in Calcareous Soils of Golpayegan

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    Mojtaba Fathi

    2017-02-01

    Full Text Available Introduction: Variety of soil reactions govern the distribution of metal micronutrients that includes complexation with organic and inorganic ligands, ion exchange, adsorption and desorption processes, precipitation and dissolution of solids and acid-based equilibria. The relative importance of these reactions depends on many factors such as soil physical, chemical, and mineralogical properties and the nature of metal ions. Environmental factors such as climate, physiographic position, and soil development may affect variability of some soil properties and thereby nutrient availability. The present research was conducted to find relationships between Iron, manganese, zinc, and copper availability and some major soil properties, physiographic condition and soil development. Materials and Methods: Golpayegan region is located in northwest of Isfahan province in central Iran. The mean elevation of the studied area is 1790 above sea level. Annual precipitation was about 244mm and mean monthly temperature ranges from -6 in January to 34°C in August. The soils were developed on different physiographic conditions including piedmont plains, alluvial-fan, plateaus, and flood plains belonging to Entisols and Aridisols. Soil samples (0–60 cm were collected from 98 grid points with 2000m distance in the agricultural area of Golpayegan. Particle size distribution, calcium carbonate, organic carbon, available potassium and phosphorus of the soils were measured by SWRI standard methods. Available Zn, Cu, Mn, and Fe were determined by addition of 10 g soil to 20mL 0.005M diethylentriaminepentacetic‏. The solutions were shaken for 2 h at 25°C, centrifuged, filtered, and Fe, Mn, Zn, and Cu concentrations were measured by an atomic absorption spectrophotometer. Results Discussion: Studied soils were developed on calcareous material and about 60% of samples have more than 20% of calcium carbonate. Available Fe ranged from 1.4 to 6.5 mg kg-1 (mean 15.8 mg kg-1

  10. Segregating Top-Down Selective Attention from Response Inhibition in a Spatial Cueing Go/NoGo Task: An ERP and Source Localization Study.

    Science.gov (United States)

    Hong, Xiangfei; Wang, Yao; Sun, Junfeng; Li, Chunbo; Tong, Shanbao

    2017-08-29

    Successfully inhibiting a prepotent response tendency requires the attentional detection of signals which cue response cancellation. Although neuroimaging studies have identified important roles of stimulus-driven processing in the attentional detection, the effects of top-down control were scarcely investigated. In this study, scalp EEG was recorded from thirty-two participants during a modified Go/NoGo task, in which a spatial-cueing approach was implemented to manipulate top-down selective attention. We observed classical event-related potential components, including N2 and P3, in the attended condition of response inhibition. While in the ignored condition of response inhibition, a smaller P3 was observed and N2 was absent. The correlation between P3 and CNV during the foreperiod suggested an inhibitory role of P3 in both conditions. Furthermore, source analysis suggested that P3 generation was mainly localized to the midcingulate cortex, and the attended condition showed increased activation relative to the ignored condition in several regions, including inferior frontal gyrus, middle frontal gyrus, precentral gyrus, insula and uncus, suggesting that these regions were involved in top-down attentional control rather than inhibitory processing. Taken together, by segregating electrophysiological correlates of top-down selective attention from those of response inhibition, our findings provide new insights in understanding the neural mechanisms of response inhibition.

  11. Positive Darwinian selection in the piston that powers proton pumps in complex I of the mitochondria of Pacific salmon.

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    Michael R Garvin

    Full Text Available The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm.

  12. Positive Darwinian selection in the piston that powers proton pumps in complex I of the mitochondria of Pacific salmon.

    Science.gov (United States)

    Garvin, Michael R; Bielawski, Joseph P; Gharrett, Anthony J

    2011-01-01

    The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm.

  13. Positive Darwinian Selection in the Piston That Powers Proton Pumps in Complex I of the Mitochondria of Pacific Salmon

    Science.gov (United States)

    Garvin, Michael R.; Bielawski, Joseph P.; Gharrett, Anthony J.

    2011-01-01

    The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm. PMID:21969854

  14. Blocking S1P interaction with S1P1 receptor by a novel competitive S1P1-selective antagonist inhibits angiogenesis

    International Nuclear Information System (INIS)

    Fujii, Yasuyuki; Ueda, Yasuji; Ohtake, Hidenori; Ono, Naoya; Takayama, Tetsuo; Nakazawa, Kiyoshi; Igarashi, Yasuyuki; Goitsuka, Ryo

    2012-01-01

    Highlights: ► The effect of a newly developed S1P 1 -selective antagonist on angiogenic responses. ► S1P 1 is a critical component of VEGF-related angiogenic responses. ► S1P 1 -selective antagonist showed in vitro activity to inhibit angiogenesis. ► S1P 1 -selective antagonist showed in vivo activity to inhibit angiogenesis. ► The efficacy of S1P 1 -selective antagonist for anti-cancer therapies. -- Abstract: Sphingosine 1-phosphate receptor type 1 (S1P 1 ) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P 1 and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P 1 -selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P 1 antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P 1 is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

  15. Positive Selection Drives the Evolution of rhino, a Member of the Heterochromatin Protein 1 Family in Drosophila.

    Directory of Open Access Journals (Sweden)

    2005-07-01

    Full Text Available Heterochromatin comprises a significant component of many eukaryotic genomes. In comparison to euchromatin, heterochromatin is gene poor, transposon rich, and late replicating. It serves many important biological roles, from gene silencing to accurate chromosome segregation, yet little is known about the evolutionary constraints that shape heterochromatin. A complementary approach to the traditional one of directly studying heterochromatic DNA sequence is to study the evolution of proteins that bind and define heterochromatin. One of the best markers for heterochromatin is the heterochromatin protein 1 (HP1, which is an essential, nonhistone chromosomal protein. Here we investigate the molecular evolution of five HP1 paralogs present in Drosophila melanogaster. Three of these paralogs have ubiquitous expression patterns in adult Drosophila tissues, whereas HP1D/rhino and HP1E are expressed predominantly in ovaries and testes respectively. The HP1 paralogs also have distinct localization preferences in Drosophila cells. Thus, Rhino localizes to the heterochromatic compartment in Drosophila tissue culture cells, but in a pattern distinct from HP1A and lysine-9 dimethylated H3. Using molecular evolution and population genetic analyses, we find that rhino has been subject to positive selection in all three domains of the protein: the N-terminal chromo domain, the C-terminal chromo-shadow domain, and the hinge region that connects these two modules. Maximum likelihood analysis of rhino sequences from 20 species of Drosophila reveals that a small number of residues of the chromo and shadow domains have been subject to repeated positive selection. The rapid and positive selection of rhino is highly unusual for a gene encoding a chromosomal protein and suggests that rhino is involved in a genetic conflict that affects the germline, belying the notion that heterochromatin is simply a passive recipient of "junk DNA" in eukaryotic genomes.

  16. Positive selection drives the evolution of rhino, a member of the heterochromatin protein 1 family in Drosophila.

    Directory of Open Access Journals (Sweden)

    Danielle Vermaak

    2005-07-01

    Full Text Available Heterochromatin comprises a significant component of many eukaryotic genomes. In comparison to euchromatin, heterochromatin is gene poor, transposon rich, and late replicating. It serves many important biological roles, from gene silencing to accurate chromosome segregation, yet little is known about the evolutionary constraints that shape heterochromatin. A complementary approach to the traditional one of directly studying heterochromatic DNA sequence is to study the evolution of proteins that bind and define heterochromatin. One of the best markers for heterochromatin is the heterochromatin protein 1 (HP1, which is an essential, nonhistone chromosomal protein. Here we investigate the molecular evolution of five HP1 paralogs present in Drosophila melanogaster. Three of these paralogs have ubiquitous expression patterns in adult Drosophila tissues, whereas HP1D/rhino and HP1E are expressed predominantly in ovaries and testes respectively. The HP1 paralogs also have distinct localization preferences in Drosophila cells. Thus, Rhino localizes to the heterochromatic compartment in Drosophila tissue culture cells, but in a pattern distinct from HP1A and lysine-9 dimethylated H3. Using molecular evolution and population genetic analyses, we find that rhino has been subject to positive selection in all three domains of the protein: the N-terminal chromo domain, the C-terminal chromo-shadow domain, and the hinge region that connects these two modules. Maximum likelihood analysis of rhino sequences from 20 species of Drosophila reveals that a small number of residues of the chromo and shadow domains have been subject to repeated positive selection. The rapid and positive selection of rhino is highly unusual for a gene encoding a chromosomal protein and suggests that rhino is involved in a genetic conflict that affects the germline, belying the notion that heterochromatin is simply a passive recipient of "junk DNA" in eukaryotic genomes.

  17. Breast conservation therapy based on liberal selection criteria and less extensive surgery. Analysis of cases with positive margins

    International Nuclear Information System (INIS)

    Amemiya, Atsushi; Kondo, Makoto

    1999-01-01

    The relationship between the margin status and the risk of in-breast recurrence (IBR) is an important consideration in patients treated with breast conservation therapy but has not been defined adequately. To address this issue, 1533 clinical stage I and II patients who completed irradiation therapy between 1983 and 1998 were evaluated. Only selection criterion was whether she could be satisfied with cosmesis after lumpectomy. Size and location of the tumor, nodal status, histology and age were not primary consideration. The tumor was excised in such a way to obtain macroscopically clear margins. The breast was treated with 50 Gy of external irradiation but without boost. Margins were evaluated by serially sectioning of the specimen and the margin was judged positive only when cancer cells were present on the inked surface. Margins were also evaluated by scratch cytology. Seventy two IBR were experienced within 5 years. Only age and margin status were found to be independent risk factors. Five-year IBR rate with negative and positive margins was 3.7% and 10.0%, respectively. In patients with positive margins, number of positive site and positive cytology were independent risk factor for IBR. IBR rate among patients with focally involved margins by non-comedo, comedo and invasive ca, was 0.0%, 3.5%, and 8.7%, respectively. IBR rate in more than focal involvement by non-comedo, comedo, and invasive ca, was 4.0%, 33.0% and 30.0%, respectively. If histologically positive margin was also positive cytologically, IBR was 14.8%, whereas only 3.6% if negative cytologically. Even with liberal patient selection and less extensive local treatment, adequate local control can be obtained, provided that margins are histologically and/or cytologically negative. Focal margin involvement by DCIS or more than focal involvement by non-comedo type DCIS does not jeopardize local control. More than focal involvement by comedo DCIS or involvement by invasive ca results in high IBR rate

  18. Population genetic evidence for positive and purifying selection acting at the human IFN-γ locus in Africa.

    Science.gov (United States)

    Campbell, Michael C; Smith, Lunden T; Harvey, Jayla

    2018-03-29

    Despite its critical role in the defense against microbial infection and tumor development, little is known about the range of nucleotide and haplotype variation at IFN-γ, or the evolutionary forces that have shaped patterns of diversity at this locus. To address this gap in knowledge, we examined sequence data from the IFN-γ gene in 1461 individuals from 15 worldwide populations. Our analyses uncovered novel patterns of variation in distinct African populations, including an excess of high frequency-derived alleles, unusually long haplotype structure surrounding the IFN-γ gene, and a "star-like" genealogy of African-specific haplotypes carrying variants previously associated with infectious disease. We also inferred a deep time to coalescence of variation at IFN-γ (~ 0.8 million years ago) and ancient ages for common polymorphisms predating the evolution of modern humans. Taken together, these results are congruent with a model of positive selection on standing variation in African populations. Furthermore, we inferred that common variants in intron 3 of IFN-γ are the likely targets of selection. In addition, we observed a paucity of non-synonymous substitutions relative to synonymous changes in the exons of IFN-γ in African and non-African populations, suggestive of strong purifying selection. Therefore, we contend that positive and purifying selection have influenced levels of diversity in different regions of IFN-γ, implying that these distinct genic regions are, or have been, functionally important. Overall, this study provides additional insights into the evolutionary events that have contributed to the frequency and distribution of alleles having a role in human health and disease.

  19. Device to position selectively a tool carried by a vehicle moving on the perforated plate of a tube bundle

    International Nuclear Information System (INIS)

    Bernardin, M.

    1985-01-01

    The aim of the invention is an examination device for a tube bundle of an apparatus such as, but not restrictively, a steam generator, situated in a dangerous zone, e.g. radioactive and designed to be introduced into the water box of the said and placed against the perforated plate of the tube bundle by an operator working outside of the said apparatus and able to operate whatever the vertical or horizontal position of the tube plate. The device has a selectively positionable tool - carrying vehicle comprising pistons positioning fingers extendable into the tubes and mounted on extendable supports perpendicular to the pistons and to each other, and an articulated telescopic arm fixed at one end to a rotary mounting on the vehicle and at the other end to an access opening in the vessel containing the tube plate, to hold the vehicle against the plate [fr

  20. Selective inhibition by harmane of the apurinic apyrimidinic endonuclease activity of phage T4-induced UV endonuclease.

    Science.gov (United States)

    Warner, H R; Persson, M L; Bensen, R J; Mosbaugh, D W; Linn, S

    1981-11-25

    1-Methyl-9H-pyrido-[3,4-b]indole (harmane) inhibits the apurinic/apyrimidinic (AP) endonuclease activity of the UV endonuclease induced by phage T4, whereas it stimulates the pyrimidine dimer-DNA glycosylase activity of that enzyme. E. coli endonuclease IV, E. coli endonuclease VI (the AP endonuclease activity associated with E. coli exonuclease III), and E. coli uracil-DNA glycosylase were not inhibited by harmane. Human fibroblast AP endonucleases I and II also were only slightly inhibited. Therefore, harmane is neither a general inhibitor of AP endonucleases, nor a general inhibitor of Class I AP endonucleases which incise DNA on the 3'-side of AP sites. However, E. coli endonuclease III and its associated dihydroxythymine-DNA glycosylase activity were both inhibited by harmane. This observation suggests that harmane may inhibit only AP endonucleases which have associated glycosylase activities.

  1. HIV-positive patients’ perceptions of care received at a selected antiretroviral therapy clinic in Vhembe district, South Africa

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    Tshifhiwa V. Ndou

    2016-04-01

    Full Text Available Background: Patients’ experiences are a reflection of what has happened during the care process and, therefore, provide information about the performance of health care professional workers. They refer to the process of care provision at the antiretroviral therapy (ART sites. Aim and setting: This article explored the perceptions of HIV-positive patients of care received at the Gateway Clinic of the regional hospital that provides antiretroviral treatment in the Vhembe district. Methods: A qualitative, explorative and descriptive design was used. A non-probability, convenient sampling method was used to select 20 HIV-positive patients who were above 18 years of age. In-depth individual interviews were used to collect data. Data were analysed through Tech’s open coding method. Results: One theme and two sub-themes emerged, namely positive experiences related to the environment and attitudes of health professionals, and negative experiences concerning the practices by health care providers. Conclusion: Patients’ perceptions of quality of, and satisfaction with, health care may affect health outcomes. Recommendations are made to consider, practice and strengthen the protocols, the standard operating procedures and the principles of infection control in the health facilities. Keywords: Human Immunodeficiecy Virus, Antiretroviral Treatment, HIV positive, Limpopo

  2. PHA665752, a small-molecule inhibitor of c-Met, inhibits hepatocyte growth factor-stimulated migration and proliferation of c-Met-positive neuroblastoma cells

    International Nuclear Information System (INIS)

    Crosswell, Hal E; Dasgupta, Anindya; Alvarado, Carlos S; Watt, Tanya; Christensen, James G; De, Pradip; Durden, Donald L; Findley, Harry W

    2009-01-01

    c-Met is a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF), and both c-Met and its ligand are expressed in a variety of tissues. C-Met/HGF/SF signaling is essential for normal embryogenesis, organogenesis, and tissue regeneration. Abnormal c-Met/HGF/SF signaling has been demonstrated in different tumors and linked to aggressive and metastatic tumor phenotypes. In vitro and in vivo studies have demonstrated inhibition of c-Met/HGF/SF signaling by the small-molecule inhibitor PHA665752. This study investigated c-Met and HGF expression in two neuroblastoma (NBL) cell lines and tumor tissue from patients with NBL, as well as the effects of PHA665752 on growth and motility of NBL cell lines. The effect of the tumor suppressor protein PTEN on migration and proliferation of tumor cells treated with PHA665752 was also evaluated. Expression of c-Met and HGF in NBL cell lines SH-EP and SH-SY5Y and primary tumor tissue was assessed by immunohistochemistry and quantitative RT-PCR. The effect of PHA665752 on c-Met/HGF signaling involved in NBL cell proliferation and migration was evaluated in c-Met-positive cells and c-Met-transfected cells. The transwell chemotaxis assay and the MTT assay were used to measure migration and proliferation/cell-survival of tumor cells, respectively. The PPAR-γ agonist rosiglitazone was used to assess the effect of PTEN on PHA665752-induced inhibition of NBL cell proliferation/cell-survival and migration High c-Met expression was detected in SH-EP cells and primary tumors from patients with advanced-stage disease. C-Met/HGF signaling induced both migration and proliferation of SH-EP cells. Migration and proliferation/cell-survival were inhibited by PHA665752 in a dose-dependent manner. We also found that induced overexpression of PTEN following treatment with rosiglitazone significantly enhanced the inhibitory effect of PHA665752 on NBL-cell migration and proliferation. c-Met is highly expressed in most tumors from

  3. Silver-doped manganese dioxide and trioxide nanoparticles inhibit both gram positive and gram negative pathogenic bacteria.

    Science.gov (United States)

    Kunkalekar, R K; Prabhu, M S; Naik, M M; Salker, A V

    2014-01-01

    Palladium, ruthenium and silver-doped MnO2 and silver doped Mn2O3 nanoparticles were synthesized by simple co-precipitation technique. SEM-TEM analysis revealed the nano-size of these synthesized samples. XPS data illustrates that Mn is present in 4+ and 3+ oxidation states in MnO2 and Mn2O3 respectively. Thermal analysis gave significant evidence for the phase changes with increasing temperature. Antibacterial activity of these synthesized nanoparticles on three Gram positive bacterial cultures (Staphylococcus aureus ATCC 6538, Streptococcus epidermis ATCC 12228, Bacillus subtilis ATCC 6633) and three Gram negative cultures (Escherichia coli ATCC 8739, Salmonella abony NCTC 6017 and Klebsiella pneumoniae ATCC 1003) was investigated using a disc diffusion method and live/dead assay. Only Ag-doped MnO2 and Ag-doped Mn2O3 nanoparticles showed antibacterial property against all six-test bacteria but Ag-doped MnO2 was found to be more effective than Ag-doped Mn2O3. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Inhibition of telomerase activity preferentially targets aldehyde dehydrogenase-positive cancer stem-like cells in lung cancer

    Directory of Open Access Journals (Sweden)

    Iniesta Pilar

    2011-08-01

    Full Text Available Abstract Background Mortality rates for advanced lung cancer have not declined for decades, even with the implementation of novel chemotherapeutic regimens or the use of tyrosine kinase inhibitors. Cancer Stem Cells (CSCs are thought to be responsible for resistance to chemo/radiotherapy. Therefore, targeting CSCs with novel compounds may be an effective approach to reduce lung tumor growth and metastasis. We have isolated and characterized CSCs from non-small cell lung cancer (NSCLC cell lines and measured their telomerase activity, telomere length, and sensitivity to the novel telomerase inhibitor MST312. Results The aldehyde dehydrogenase (ALDH positive lung cancer cell fraction is enriched in markers of stemness and endowed with stem cell properties. ALDH+ CSCs display longer telomeres than the non-CSC population. Interestingly, MST312 has a strong antiproliferative effect on lung CSCs and induces p21, p27 and apoptosis in the whole tumor population. MST312 acts through activation of the ATM/pH2AX DNA damage pathway (short-term effect and through decrease in telomere length (long-term effect. Administration of this telomerase inhibitor (40 mg/kg in the H460 xenograft model results in significant tumor shrinkage (70% reduction, compared to controls. Combination therapy consisting of irradiation (10Gy plus administration of MST312 did not improve the therapeutic efficacy of the telomerase inhibitor alone. Treatment with MST312 reduces significantly the number of ALDH+ CSCs and their telomeric length in vivo. Conclusions We conclude that antitelomeric therapy using MST312 mainly targets lung CSCs and may represent a novel approach for effective treatment of lung cancer.

  5. A genomic survey of positive selection in Burkholderia pseudomallei provides insights into the evolution of accidental virulence.

    Directory of Open Access Journals (Sweden)

    Tannistha Nandi

    2010-04-01

    Full Text Available Certain environmental microorganisms can cause severe human infections, even in the absence of an obvious requirement for transition through an animal host for replication ("accidental virulence". To understand this process, we compared eleven isolate genomes of Burkholderia pseudomallei (Bp, a tropical soil microbe and causative agent of the human and animal disease melioidosis. We found evidence for the existence of several new genes in the Bp reference genome, identifying 282 novel genes supported by at least two independent lines of supporting evidence (mRNA transcripts, database homologs, and presence of ribosomal binding sites and 81 novel genes supported by all three lines. Within the Bp core genome, 211 genes exhibited significant levels of positive selection (4.5%, distributed across many cellular pathways including carbohydrate and secondary metabolism. Functional experiments revealed that certain positively selected genes might enhance mammalian virulence by interacting with host cellular pathways or utilizing host nutrients. Evolutionary modifications improving Bp environmental fitness may thus have indirectly facilitated the ability of Bp to colonize and survive in mammalian hosts. These findings improve our understanding of the pathogenesis of melioidosis, and establish Bp as a model system for studying the genetics of accidental virulence.

  6. Natural resistance to experimental feline infectious peritonitis virus infection is decreased rather than increased by positive genetic selection.

    Science.gov (United States)

    Pedersen, Niels C; Liu, Hongwei; Durden, Monica; Lyons, Leslie A

    2016-03-01

    A previous study demonstrated the existence of a natural resistance to feline infectious peritonitis virus (FIPV) among 36% of randomly bred laboratory cats. A genome wide association study (GWAS) on this population suggested that resistance was polygenic but failed to identify any strong specific associations. In order to enhance the power of GWAS or whole genome sequencing to identify strong genetic associations, a decision was made to positively select for resistance over three generations. The inbreeding experiment began with a genetically related parental (P) population consisting of three toms and four queens identified from among the survivors of the earlier study and belonging to a closely related subgroup (B). The subsequent effects of inbreeding were measured using 42 genome-wide STR markers. P generation cats produced 57 first filial (F1) kittens, only five of which (9.0%) demonstrated a natural resistance to FIPV infection. One of these five F1 survivors was then used to produce six F1/P-backcrosses kittens, only one of which proved resistant to FIP. Six of eight of the F1 and F1/P survivors succumbed to a secondary exposure 4-12 months later. Therefore, survival after both primary and secondary infection was decreased rather than increased by positive selection for resistance. The common genetic factor associated with this diminished resistance was a loss of heterozygosity. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  7. A Novel Variant with Positive Natural Selection Influenced Hb A2 Levels in Chinese Individuals with β-Thalassemia.

    Science.gov (United States)

    Yu, Shanjuan; Chen, Yang; Lai, Ketong; Dewan, Roma Kajal; He, Yunyan

    2017-05-01

    β-Thalassemia (β-thal) is the most common inherited hemolytic anemia worldwide. Elevated Hb A 2 is a mark of β-thal carriers. The aim of this study was to identify the pathogenic variants associated with the Hb A 2 levels. One thousand and thirty β-thal carriers were recruited for this study. Using positive natural expression quantitative trait loci (eQTL) analysis, a significant variant was selected. Genotyping for the rs231841 polymorphism was performed by the Sequenom MassARRAY IPLEX platform. All genetic association analyses were performed with the PLINK program. The linear regression analysis showed that rs231841 in the intron region of the potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene on chromosome 11p15 was significantly associated with Hb A 2 levels. The presence of the C allele was associated with elevated Hb A 2 levels. Our results suggest that rs231841 on the KCNQ1 gene with positive natural selection is related to Hb A 2 levels in Chinese β-thal carriers, and KCNQ1 is probably associated with the expression of the β-like globin gene cluster.

  8. Arctigenin inhibits the activation of the mTOR pathway, resulting in autophagic cell death and decreased ER expression in ER-positive human breast cancer cells.

    Science.gov (United States)

    Maxwell, Thressi; Lee, Kyu Shik; Kim, Soyoung; Nam, Kyung-Soo

    2018-04-01

    Arctigenin, a member of the Asteraceae family, is a biologically active lignan that is consumed worldwide due to its several health benefits. However, its use may pose a problem for patients with estrogen receptor (ER)α-positive breast cancer, since studies have shown that arctigenin is a phytoestrogen that exerts a proliferative effect by binding to the ER. Thus, in this study, we examined the effect of arctigenin on ERα-positive MCF-7 human breast cancer cells to determine whether the consumption of arctigenin is safe for patients with breast cancer. First, we found that arctigenin inhibited the viability of the MCF-7 cells, and colony formation assay confirmed that this effect was cytotoxic rather than cytostatic. The cytotoxic effects were not mediated by cell cycle arrest, apoptosis, or necroptosis, despite DNA damage, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and phosphorylated H2A.X. An increase in lipidated LC3, a marker of autophagosome formation, was observed, indicating that autophagy was induced by arctigenin, which was found to be triggered by the inhibition of the mechanistic target of rapamycin (mTOR) pathway. We then examined the effects of arctigenin on ERα expression and determined whether it affects the sensitivity of the cells to tamoxifen, as tamoxifen is commonly used against hormone-responsive cancers and is known to act via the ERα. We found that treatment with arctigenin effectively downregulated ERα expression, which was found to be a consequence of the inhibition of the mTOR pathway. However, treatment with arctigenin in combination with tamoxifen did not affect the sensitivity of the cells to tamoxifen, but instead, exerted a synergistic effect. On the whole, our data indicate that the phytoestrogen, arctigenin, mainly targeted the mTOR pathway in ERα-positive MCF-7 human breast cancer cells, leading to autophagy-induced cell death and the downregulation of ERα expression. Furthermore, the synergistic effects

  9. Selection criteria for patients with chronic ankle instability in controlled research: a position statement of the International Ankle Consortium.

    Science.gov (United States)

    Gribble, Phillip A; Delahunt, Eamonn; Bleakley, Chris; Caulfield, Brian; Docherty, Carrie; Fourchet, François; Fong, Daniel Tik-Pui; Hertel, Jay; Hiller, Claire; Kaminski, Thomas; McKeon, Patrick; Refshauge, Kathryn; van der Wees, Philip; Vincenzino, Bill; Wikstrom, Erik

    2014-07-01

    While research on chronic ankle instability (CAI) and awareness of its impact on society and health care systems has grown substantially in the last 2 decades, the inconsistency in participant/patient selection criteria across studies presents a potential obstacle to addressing the problem properly. This major gap within the literature limits the ability to generalise this evidence to the target patient population. Therefore, there is a need to provide standards for patient/participant selection criteria in research focused on CAI with justifications using the best available evidence. The International Ankle Consortium provides this position paper to present and discuss an endorsed set of selection criteria for patients with CAI based on the best available evidence to be used in future research and study designs. These recommendations will enhance the validity of research conducted in this clinical population with the end goal of bringing the research evidence to the clinician and patient. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  10. Hippocampal volume is positively associated with behavioural inhibition (BIS) in a large community-based sample of mid-life adults: the PATH through life study.

    Science.gov (United States)

    Cherbuin, Nicolas; Windsor, Tim D; Anstey, Kaarin J; Maller, Jerome J; Meslin, Chantal; Sachdev, Perminder S

    2008-09-01

    The fields of personality research and neuropsychology have developed with very little overlap. Gray and McNaughton were among the first to recognize that personality traits must have neurobiological correlates and developed models relating personality factors to brain structures. Of particular note was their description of associations between conditioning, inhibition and activation of behaviours, and specific neural structures such as the hippocampus, amygdala and the prefrontal cortex. The aim of this study was to determine whether personality constructs representing the behavioural inhibition and activation systems (BIS/BAS) were associated with volumetric measures of the hippocampus and amygdala in humans. Amygdalar and hippocampal volumes were measured in 430 brain scans of cognitively intact community-based volunteers. Linear associations between brain volumes and the BIS/BAS measures were assessed using multiple regression, controlling for age, sex, education, intra-cranial and total brain volume. Results showed that hippocampal volumes were positively associated with BIS sensitivity and to a lesser extent with BAS sensitivity. No association was found between amygdalar volume and either the BIS or BAS. These findings add support to the model of Gray and McNaughton, which proposes a role of the hippocampus in the regulation of defensive/approach behaviours and trait anxiety but suggest an absence of associations between amygdala volume and BIS/BAS measures.

  11. Meta-analysis of age and skill effects on recalling chess positions and selecting the best move.

    Science.gov (United States)

    Moxley, Jerad H; Charness, Neil

    2013-10-01

    A meta-analysis was conducted of studies that measured the effects of both age and skill in chess on the tasks of selecting the best move for chess positions (the best move task) as well as recalling chess game positions (the recall task). Despite a small sample of studies, we demonstrated that there are age and skill effects on both tasks: age being negatively associated with performance on both tasks and skill being positively associated with performance on both tasks. On the best move task, we found that skill was the dominant effect, while on the recall task, skill and age were approximately equally strong effects. We also found that skill was best measured by the best move task. In the case of the best move task, this result is consistent with the argument that it accurately replicates expert performance (Ericsson & Smith, 1991). Results for the recall task argue that this task captures effects related to skill, but also effects likely due to a general aging process. Implications for our understanding of aging in skilled domains are also discussed.

  12. Optimization of Cognitive Radio Secondary Information Gathering Station Positioning and Operating Channel Selection for IoT Sensor Networks

    Directory of Open Access Journals (Sweden)

    Jinyi Wen

    2018-01-01

    Full Text Available The Internet of Things (IoT is the interconnection of different objects through the internet using different communication technologies. The objects are equipped with sensors and communications modules. The cognitive radio network is a key technique for the IoT and can effectively address spectrum-related issues for IoT applications. In our paper, a novel method for IoT sensor networks is proposed to obtain the optimal positions of secondary information gathering stations (SIGSs and to select the optimal operating channel. Our objective is to maximize secondary system capacity while protecting the primary system. In addition, we propose an appearance probability matrix for secondary IoT devices (SIDs to maximize the supportable number of SIDs that can be installed in a car, in wearable devices, or for other monitoring devices, based on optimal deployment and probability. We derive fitness functions based on the above objectives and also consider signal to interference-plus-noise ratio (SINR and position constraints. The particle swarm optimization (PSO technique is used to find the best position and operating channel for the SIGSs. In a simulation study, the performance of the proposed method is evaluated and compared with a random resources allocation algorithm (parts of this paper were presented at the ICTC2017 conference (Wen et al., 2017.

  13. Effect of process parameters and injector position on the efficiency of NOx reduction by selective non catalytic reduction technique

    International Nuclear Information System (INIS)

    Hamid, A.; Mehmood, M.A.; Irfan, N.; Javed, M.T.; Waheed, K.

    2009-01-01

    An experimental investigation has been performed to study the effect of atomizer pressure dilution of the reducing reagent and the injector position on the efficiency or the NOx reduction by a selective non-catalytic reduction technique using urea as a reducing agent. Experiments were performed with a flow reactor in which flue gas was generated by the combustion of methane in air at stoichiometric amount of oxygen and the desired levels of initial NOx (400-450 ppm) were achieved by doping the flame with ammonia. The work was directed to investigate the effect of atomizer pressure, dilution of urea reagent and the injector position. The atomizer pressure was varied from 1 to 3bar and 20-25% increase in efficiency was observed by decreasing the pressure. Effect of dilution of urea solution was investigated by varying the strength of the solution from the 8 to 32% and 40-45% increase in the efficiency was observed. Effects of injector position was investigated by injecting the urea solution both in co current and counter current direction of the flue gases and 20-25% increase in the efficiency was observed in counter current direction. (author)

  14. Compound 13, an α1-selective small molecule activator of AMPK, inhibits Helicobacter pylori-induced oxidative stresses and gastric epithelial cell apoptosis

    International Nuclear Information System (INIS)

    Zhao, Hangyong; Zhu, Huanghuang; Lin, Zhou; Lin, Gang; Lv, Guoqiang

    2015-01-01

    Half of the world's population experiences Helicobacter pylori (H. pylori) infection, which is a main cause of gastritis, duodenal and gastric ulcer, and gastric cancers. In the current study, we investigated the potential role of compound 13 (C13), a novel α1-selective small molecule activator of AMP-activated protein kinase (AMPK), against H. pylori-induced cytotoxicity in cultured gastric epithelial cells (GECs). We found that C13 induced significant AMPK activation, evidenced by phosphorylation of AMPKα1 and ACC (acetyl-CoA carboxylase), in both primary and transformed GECs. Treatment of C13 inhibited H. pylori-induced GEC apoptosis. AMPK activation was required for C13-mediated GEC protection. Inhibition of AMPK kinase activity by the AMPK inhibitor Compound C, or silencing AMPKα1 expression by targeted-shRNAs, alleviated C13-induced GEC protective activities against H. pylori. Significantly, C13 inhibited H. pylori-induced reactive oxygen species (ROS) production in GECs. C13 induced AMPK-dependent expression of anti-oxidant gene heme oxygenase (HO-1) in GECs. Zinc protoporphyrin (ZnPP) and tin protoporphyrin (SnPP), two HO-1 inhibitors, not only suppressed C13-mediated ROS scavenging activity, but also alleviated its activity in GECs against H. pylori. Together, these results indicate that C13 inhibits H. pylori-induced ROS production and GEC apoptosis through activating AMPK–HO–1 signaling. - Highlights: • We synthesized compound 13 (C13), a α1-selective small molecule AMPK activator. • C13-induced AMPK activation requires α1 subunit in gastric epithelial cells (GECs). • C13 enhances Helicobacter pylori-induced pro-survival AMPK activation to inhibit GEC apoptosis. • C13 inhibits H. pylori-induced reactive oxygen species (ROS) production in GECs. • AMPK-heme oxygenase (HO-1) activation is required for C13-mediated anti-oxidant activity

  15. Compound 13, an α1-selective small molecule activator of AMPK, inhibits Helicobacter pylori-induced oxidative stresses and gastric epithelial cell apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Hangyong; Zhu, Huanghuang; Lin, Zhou; Lin, Gang; Lv, Guoqiang, E-mail: lvguoqiangwuxivip@163.com

    2015-08-07

    Half of the world's population experiences Helicobacter pylori (H. pylori) infection, which is a main cause of gastritis, duodenal and gastric ulcer, and gastric cancers. In the current study, we investigated the potential role of compound 13 (C13), a novel α1-selective small molecule activator of AMP-activated protein kinase (AMPK), against H. pylori-induced cytotoxicity in cultured gastric epithelial cells (GECs). We found that C13 induced significant AMPK activation, evidenced by phosphorylation of AMPKα1 and ACC (acetyl-CoA carboxylase), in both primary and transformed GECs. Treatment of C13 inhibited H. pylori-induced GEC apoptosis. AMPK activation was required for C13-mediated GEC protection. Inhibition of AMPK kinase activity by the AMPK inhibitor Compound C, or silencing AMPKα1 expression by targeted-shRNAs, alleviated C13-induced GEC protective activities against H. pylori. Significantly, C13 inhibited H. pylori-induced reactive oxygen species (ROS) production in GECs. C13 induced AMPK-dependent expression of anti-oxidant gene heme oxygenase (HO-1) in GECs. Zinc protoporphyrin (ZnPP) and tin protoporphyrin (SnPP), two HO-1 inhibitors, not only suppressed C13-mediated ROS scavenging activity, but also alleviated its activity in GECs against H. pylori. Together, these results indicate that C13 inhibits H. pylori-induced ROS production and GEC apoptosis through activating AMPK–HO–1 signaling. - Highlights: • We synthesized compound 13 (C13), a α1-selective small molecule AMPK activator. • C13-induced AMPK activation requires α1 subunit in gastric epithelial cells (GECs). • C13 enhances Helicobacter pylori-induced pro-survival AMPK activation to inhibit GEC apoptosis. • C13 inhibits H. pylori-induced reactive oxygen species (ROS) production in GECs. • AMPK-heme oxygenase (HO-1) activation is required for C13-mediated anti-oxidant activity.

  16. Determination of the irradiation dose for the inhibition (D-10 radiation doses) of some gram negative and gram positive bacteria in peptone saline water

    International Nuclear Information System (INIS)

    Ayhan, H.; Tutluer, H.

    1994-01-01

    Determination of the irradiation dose for the inhibition of some pathogenic bacteria which cause food poisoning and spoilage were aimed. For this purpose, Salmonella typhi, Salmonella typhimurium,Salmonella enteridits,Klebsiella pneumonia, Pseudomonas fluorescence,Proteus vulgaris, Aeromonas hydrophila ,(gram-negative bacteria) and Bacillus cereus, Staphylococcus aureus strain 24,Staphylococcus aureus ATCC 6538 P,Staphylococcus epidermidis strain 115 and Clostridium perfringens A4TTK,(gram-positive bacteria) were used.Sensitivity of above mentioned bacteria to gamma rays (source Cs-137) was examined in saline with 0.1% peptone at different temperatures.Survivor plots (log.10 number of survivors versus dose) were determined by regression analysis of the data.Decimal reduction doses (D values in kGy) were calculated as the slope obtained from the regression analysis

  17. A group-specific inhibitor of lysosomal cysteine proteinases selectively inhibits both proteolytic degradation and presentation of the antigen dinitrophenyl-poly-L-lysine by guinea pig accessory cells to T cells

    DEFF Research Database (Denmark)

    Buus, S; Werdelin, O

    1986-01-01

    of antigens by guinea pig accessory cells. The proteinase inhibitor benzyloxycarbonyl-phenylalanylalanine-diazomethyl-ketone, which selectively inhibits cysteine proteinases, was used to block this set of enzymes in cultured cells. We demonstrate that the selective inhibition of the cysteine proteinases...

  18. Analysis of seasonal position variation for selected GNSS sites in Poland using loading modelling and GRACE data

    Directory of Open Access Journals (Sweden)

    Marcin Rajner

    2017-07-01

    Full Text Available In this study we compared weekly GNSS position time series with modelled values of crustal deformations on the basis of Gravity Recovery and Climate Experiment (GRACE data. The Global Navigation Satellite Systems (GNSS time series were taken from homogeneously reprocessed global network solutions within the International GNSS Service (IGS Reprocessing 1 project and from regional solutions performed by Warsaw University of Technology (WUT European Permanent Network (EPN Local Analysis Center (LAC within the EPN reprocessing project. Eight GNSS sites from the territory of Poland with observation timespans between 2.5 and 13 years were selected for this study. The Total Water Equivalent (TWE estimation from GRACE data was used to compute deformations using the Green's function formalism. High frequency components were removed from GRACE data to avoid aliasing problems. Since GRACE observes mainly the mass transport in continental storage of water, we also compared GRACE deformations and the GNSS position time series, with the deformations computed on the basis of a hydrosphere model. We used the output of Water GAP Hydrology Model (WGHM to compute deformations in the same manner as for the GRACE data. The WGHM gave slightly larger amplitudes than GNSS and GRACE. The atmospheric non-tidal loading effect was removed from GNSS position time series before comparing them with modelled deformations. The results confirmed that the major part of observed seasonal variations for GNSS vertical components can be attributed to the hydrosphere loading. The results for these components agree very well both in the amplitude and phase. The decrease in standard deviation of the residual GNSS position time series for vertical components corrected for the hydrosphere loading reached maximally 36% and occurred for all but one stations for both global and regional solutions. For horizontal components the amplitudes are about three times smaller than for vertical

  19. FAM134B, the Selective Autophagy Receptor for Endoplasmic Reticulum Turnover, Inhibits Replication of Ebola Virus Strains Makona and Mayinga.

    Science.gov (United States)

    Chiramel, Abhilash I; Dougherty, Jonathan D; Nair, Vinod; Robertson, Shelly J; Best, Sonja M

    2016-10-15

    Selective autophagy of the endoplasmic reticulum (termed ER-phagy) is controlled by members of the FAM134 reticulon protein family. Here we used mouse embryonic fibroblasts from mice deficient in FAM134B to examine the role of the ER in replication of historic (Mayinga) or contemporary (Makona GCO7) strains of Ebola virus (EBOV). Loss of FAM134B resulted in 1-2 log 10 higher production of infectious EBOV, which was associated with increased production of viral proteins GP and VP40 and greater accumulation of nucleocaspid lattices. In addition, only 10% of wild-type cells contained detectable nucleoprotein, whereas knockout of FAM134B resulted in 80% of cells positive for nucleoprotein. Together, these data suggest that FAM134B-dependent ER-phagy is an important limiting event in EBOV replication in mouse cells and may have implications for further development of antiviral therapeutics and murine models of infection. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  20. Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode.

    Science.gov (United States)

    Sawatzky, Edgar; Wehle, Sarah; Kling, Beata; Wendrich, Jan; Bringmann, Gerhard; Sotriffer, Christoph A; Heilmann, Jörg; Decker, Michael

    2016-03-10

    Butyrylcholinesterase (BChE) is a promising target for the treatment of later stage cognitive decline in Alzheimer's disease. A set of pseudo-irreversible BChE inhibitors with high selectivity over hAChE was synthesized based on carbamates attached to tetrahydroquinazoline scaffolds with the 2-thiophenyl compound 2p as the most potent inhibitor of eqBChE (KC = 14.3 nM) and also of hBChE (KC = 19.7 nM). The inhibitors transfer the carbamate moiety onto the active site under release of the phenolic tetrahydroquinazoline scaffolds that themselves act as neuroprotectants. By combination of kinetic data with molecular docking studies, a plausible binding model was probed describing how the tetrahydroquinazoline scaffold guides the carbamate into a close position to the active site. The model explains the influence of the carrier scaffold onto the affinity of an inhibitor just before carbamate transfer. This strategy can be used to utilize the binding mode of other carbamate-based inhibitors.

  1. Phylodynamic analysis of clinical and environmental Vibrio cholerae isolates from Haiti reveals diversification driven by positive selection.

    Science.gov (United States)

    Azarian, Taj; Ali, Afsar; Johnson, Judith A; Mohr, David; Prosperi, Mattia; Veras, Nazle M; Jubair, Mohammed; Strickland, Samantha L; Rashid, Mohammad H; Alam, Meer T; Weppelmann, Thomas A; Katz, Lee S; Tarr, Cheryl L; Colwell, Rita R; Morris, J Glenn; Salemi, Marco

    2014-12-23

    Phylodynamic analysis of genome-wide single-nucleotide polymorphism (SNP) data is a powerful tool to investigate underlying evolutionary processes of bacterial epidemics. The method was applied to investigate a collection of 65 clinical and environmental isolates of Vibrio cholerae from Haiti collected between 2010 and 2012. Characterization of isolates recovered from environmental samples identified a total of four toxigenic V. cholerae O1 isolates, four non-O1/O139 isolates, and a novel nontoxigenic V. cholerae O1 isolate with the classical tcpA gene. Phylogenies of strains were inferred from genome-wide SNPs using coalescent-based demographic models within a Bayesian framework. A close phylogenetic relationship between clinical and environmental toxigenic V. cholerae O1 strains was observed. As cholera spread throughout Haiti between October 2010 and August 2012, the population size initially increased and then fluctuated over time. Selection analysis along internal branches of the phylogeny showed a steady accumulation of synonymous substitutions and a progressive increase of nonsynonymous substitutions over time, suggesting diversification likely was driven by positive selection. Short-term accumulation of nonsynonymous substitutions driven by selection may have significant implications for virulence, transmission dynamics, and even vaccine efficacy. Cholera, a dehydrating diarrheal disease caused by toxigenic strains of the bacterium Vibrio cholerae, emerged in 2010 in Haiti, a country where there were no available records on cholera over the past 100 years. While devastating in terms of morbidity and mortality, the outbreak provided a unique opportunity to study the evolutionary dynamics of V. cholerae and its environmental presence. The present study expands on previous work and provides an in-depth phylodynamic analysis inferred from genome-wide single nucleotide polymorphisms of clinical and environmental strains from dispersed geographic settings in

  2. The oncogenic fusion protein RUNX1-CBFA2T1 supports proliferation and inhibits senescence in t(8;21)-positive leukaemic cells

    International Nuclear Information System (INIS)

    Martinez, Natalia; Heidenreich, Olaf; Drescher, Bettina; Riehle, Heidemarie; Cullmann, Claire; Vornlocher, Hans-Peter; Ganser, Arnold; Heil, Gerhard; Nordheim, Alfred; Krauter, Jürgen

    2004-01-01

    The fusion protein RUNX1-CBFA2T1 associated with t(8;21)-positive acute myeloid leukaemia is a potent inhibitor of haematopoetic differentiation. The role of RUNX1-CBFA2T1 in leukaemic cell proliferation is less clear. We examined the consequences of siRNA-mediated RUNX1-CBFA2T1 depletion regarding proliferation and clonogenicity of t(8;21)-positive cell lines. The t(8;21)-positive cell line Kasumi-1 was electroporated with RUNX1-CBFA2T1 or control siRNAs followed by analysis of proliferation, colony formation, cell cycle distribution, apoptosis and senescence. Electroporation of Kasumi-1 cells with RUNX1-CBFA2T1 siRNAs, but not with control siRNAs, resulted in RUNX1-CBFA2T1 suppression which lasted for at least 5 days. A single electroporation with RUNX1-CBFA2T1 siRNA severely diminished the clonogenicity of Kasumi-1 cells. Prolonged RUNX1-CBFA2T1 depletion inhibited proliferation in suspension culture and G1-S transition during the cell cycle, diminished the number of apoptotic cells, but induced cellular senescence. The addition of haematopoetic growth factors could not rescue RUNX1-CBFA2T1-depleted cells from senescence, and could only partially restore their clonogenicity. RUNX1-CBFA2T1 supports the proliferation and expansion of t(8;21)-positive leukaemic cells by preventing cellular senescence. These findings suggest a central role of RUNX1-CBFA2T1 in the maintenance of the leukaemia. Therefore, RUNX1-CBFA2T1 is a promising and leukaemia-specific target for molecularly defined therapeutic approaches

  3. Shared and unique components of human population structure and genome-wide signals of positive selection in South Asia.

    Science.gov (United States)

    Metspalu, Mait; Romero, Irene Gallego; Yunusbayev, Bayazit; Chaubey, Gyaneshwer; Mallick, Chandana Basu; Hudjashov, Georgi; Nelis, Mari; Mägi, Reedik; Metspalu, Ene; Remm, Maido; Pitchappan, Ramasamy; Singh, Lalji; Thangaraj, Kumarasamy; Villems, Richard; Kivisild, Toomas

    2011-12-09

    South Asia harbors one of the highest levels genetic diversity in Eurasia, which could be interpreted as a result of its long-term large effective population size and of admixture during its complex demographic history. In contrast to Pakistani populations, populations of Indian origin have been underrepresented in previous genomic scans of positive selection and population structure. Here we report data for more than 600,000 SNP markers genotyped in 142 samples from 30 ethnic groups in India. Combining our results with other available genome-wide data, we show that Indian populations are characterized by two major ancestry components, one of which is spread at comparable frequency and haplotype diversity in populations of South and West Asia and the Caucasus. The second component is more restricted to South Asia and accounts for more than 50% of the ancestry in Indian populations. Haplotype diversity associated with these South Asian ancestry components is significantly higher than that of the components dominating the West Eurasian ancestry palette. Modeling of the observed haplotype diversities suggests that both Indian ancestry components are older than the purported Indo-Aryan invasion 3,500 YBP. Consistent with the results of pairwise genetic distances among world regions, Indians share more ancestry signals with West than with East Eurasians. However, compared to Pakistani populations, a higher proportion of their genes show regionally specific signals of high haplotype homozygosity. Among such candidates of positive selection in India are MSTN and DOK5, both of which have potential implications in lipid metabolism and the etiology of type 2 diabetes. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  4. Absence of positive selection on CenH3 in Luzula suggests that holokinetic chromosomes may suppress centromere drive.

    Science.gov (United States)

    Zedek, František; Bureš, Petr

    2016-12-01

    The centromere drive theory explains diversity of eukaryotic centromeres as a consequence of the recurrent conflict between centromeric repeats and centromeric histone H3 (CenH3), in which selfish centromeres exploit meiotic asymmetry and CenH3 evolves adaptively to counterbalance deleterious consequences of driving centromeres. Accordingly, adaptively evolving CenH3 has so far been observed only in eukaryotes with asymmetric meiosis. However, if such evolution is a consequence of centromere drive, it should depend not only on meiotic asymmetry but also on monocentric or holokinetic chromosomal structure. Selective pressures acting on CenH3 have never been investigated in organisms with holokinetic meiosis despite the fact that holokinetic chromosomes have been hypothesized to suppress centromere drive. Therefore, the present study evaluates selective pressures acting on the CenH3 gene in holokinetic organisms for the first time, specifically in the representatives of the plant genus Luzula (Juncaceae), in which the kinetochore formation is not co-localized with any type of centromeric repeat. PCR, cloning and sequencing, and database searches were used to obtain coding CenH3 sequences from Luzula species. Codon substitution models were employed to infer selective regimes acting on CenH3 in Luzula KEY RESULTS: In addition to the two previously published CenH3 sequences from L. nivea, 16 new CenH3 sequences have been isolated from 12 Luzula species. Two CenH3 isoforms in Luzula that originated by a duplication event prior to the divergence of analysed species were found. No signs of positive selection acting on CenH3 in Luzula were detected. Instead, evidence was found that selection on CenH3 of Luzula might have been relaxed. The results indicate that holokinetism itself may suppress centromere drive and, therefore, holokinetic chromosomes might have evolved as a defence against centromere drive. © The Author 2016. Published by Oxford University Press on behalf of

  5. Positive dielectrophoresis used for selective trapping of nanoparticles from flue gas in a gradient field electrodes device

    Energy Technology Data Exchange (ETDEWEB)

    Lungu, Mihail, E-mail: lmihai@physics.uvt.ro; Neculae, Adrian; Lungu, Antoanetta [West University of Timisoara, Faculty of Physics (Romania)

    2015-12-15

    This paper investigates the possibility to use positive dielectrophoresis (pDEP) for selective trapping of nanoparticle dispersed in flue gas in a vertical pDEP-based microfluidic system. The experimental gradient field electrodes device contains as main part a vertical deposition plate with parallel planar electrodes in single connection on an insulating substrate, parallel to the reference electrode—a dielectric plate with a metalized side. The performances of the device were described and analyzed by numerical simulations and experimental tests in terms of two new specific parameters, called Retention rate and Filtration, related to the trapping of nanoparticles in suspension inside the device and the consequent purification of flue gas. It is outlined, both numerically and experimentally, that the concentration of particles trapped inside the device decreases as they are moving away from the inlet zone. The experimental results also highlight the nanoparticle size distribution of the particles collected from the deposition plate, using a nanoparticle tracking analysis method, and their selective capture on the deposition plate, depending on the amplitude and shape of the applied voltage, in a good agreement with the numerical simulations results.

  6. A high efficiency gene disruption strategy using a positive-negative split selection marker and electroporation for Fusarium oxysporum.

    Science.gov (United States)

    Liang, Liqin; Li, Jianqiang; Cheng, Lin; Ling, Jian; Luo, Zhongqin; Bai, Miao; Xie, Bingyan

    2014-11-01

    The Fusarium oxysporum species complex consists of fungal pathogens that cause serial vascular wilt disease on more than 100 cultivated species throughout the world. Gene function analysis is rapidly becoming more and more important as the whole-genome sequences of various F. oxysporum strains are being completed. Gene-disruption techniques are a common molecular tool for studying gene function, yet are often a limiting step in gene function identification. In this study we have developed a F. oxysporum high-efficiency gene-disruption strategy based on split-marker homologous recombination cassettes with dual selection and electroporation transformation. The method was efficiently used to delete three RNA-dependent RNA polymerase (RdRP) genes. The gene-disruption cassettes of three genes can be constructed simultaneously within a short time using this technique. The optimal condition for electroporation is 10μF capacitance, 300Ω resistance, 4kV/cm field strength, with 1μg of DNA (gene-disruption cassettes). Under these optimal conditions, we were able to obtain 95 transformants per μg DNA. And after positive-negative selection, the transformants were efficiently screened by PCR, screening efficiency averaged 85%: 90% (RdRP1), 85% (RdRP2) and 77% (RdRP3). This gene-disruption strategy should pave the way for high throughout genetic analysis in F. oxysporum. Copyright © 2014 Elsevier GmbH. All rights reserved.

  7. Disruption of HPV16-E7 by CRISPR/Cas System Induces Apoptosis and Growth Inhibition in HPV16 Positive Human Cervical Cancer Cells

    Directory of Open Access Journals (Sweden)

    Zheng Hu

    2014-01-01

    Full Text Available High-risk human papillomavirus (HR-HPV has been recognized as a major causative agent for cervical cancer. Upon HPV infection, early genes E6 and E7 play important roles in maintaining malignant phenotype of cervical cancer cells. By using clustered regularly interspaced short palindromic repeats- (CRISPR- associated protein system (CRISPR/Cas system, a widely used genome editing tool in many organisms, to target HPV16-E7 DNA in HPV positive cell lines, we showed for the first time that the HPV16-E7 single-guide RNA (sgRNA guided CRISPR/Cas system could disrupt HPV16-E7 DNA at specific sites, inducing apoptosis and growth inhibition in HPV positive SiHa and Caski cells, but not in HPV negative C33A and HEK293 cells. Moreover, disruption of E7 DNA directly leads to downregulation of E7 protein and upregulation of tumor suppressor protein pRb. Therefore, our results suggest that HPV16-E7 gRNA guided CRISPR/Cas system might be used as a therapeutic strategy for the treatment of cervical cancer.

  8. Exploring evidence of positive selection reveals genetic basis of meat quality traits in Berkshire pigs through whole genome sequencing.

    Science.gov (United States)

    Jeong, Hyeonsoo; Song, Ki-Duk; Seo, Minseok; Caetano-Anollés, Kelsey; Kim, Jaemin; Kwak, Woori; Oh, Jae-Don; Kim, EuiSoo; Jeong, Dong Kee; Cho, Seoae; Kim, Heebal; Lee, Hak-Kyo

    2015-08-20

    Natural and artificial selection following domestication has led to the existence of more than a hundred pig breeds, as well as incredible variation in phenotypic traits. Berkshire pigs are regarded as having superior meat quality compared to other breeds. As the meat production industry seeks selective breeding approaches to improve profitable traits such as meat quality, information about genetic determinants of these traits is in high demand. However, most of the studies have been performed using trained sensory panel analysis without investigating the underlying genetic factors. Here we investigate the relationship between genomic composition and this phenotypic trait by scanning for signatures of positive selection in whole-genome sequencing data. We generated genomes of 10 Berkshire pigs at a total of 100.6 coverage depth, using the Illumina Hiseq2000 platform. Along with the genomes of 11 Landrace and 13 Yorkshire pigs, we identified genomic variants of 18.9 million SNVs and 3.4 million Indels in the mapped regions. We identified several associated genes related to lipid metabolism, intramuscular fatty acid deposition, and muscle fiber type which attribute to pork quality (TG, FABP1, AKIRIN2, GLP2R, TGFBR3, JPH3, ICAM2, and ERN1) by applying between population statistical tests (XP-EHH and XP-CLR). A statistical enrichment test was also conducted to detect breed specific genetic variation. In addition, de novo short sequence read assembly strategy identified several candidate genes (SLC25A14, IGF1, PI4KA, CACNA1A) as also contributing to lipid metabolism. Results revealed several candidate genes involved in Berkshire meat quality; most of these genes are involved in lipid metabolism and intramuscular fat deposition. These results can provide a basis for future research on the genomic characteristics of Berkshire pigs.

  9. Extensive evolutionary changes in regulatory element activity during human origins are associated with altered gene expression and positive selection.

    Directory of Open Access Journals (Sweden)

    Yoichiro Shibata

    2012-06-01

    Full Text Available Understanding the molecular basis for phenotypic differences between humans and other primates remains an outstanding challenge. Mutations in non-coding regulatory DNA that alter gene expression have been hypothesized as a key driver of these phenotypic differences. This has been supported by differential gene expression analyses in general, but not by the identification of specific regulatory elements responsible for changes in transcription and phenotype. To identify the genetic source of regulatory differences, we mapped DNaseI hypersensitive (DHS sites, which mark all types of active gene regulatory elements, genome-wide in the same cell type isolated from human, chimpanzee, and macaque. Most DHS sites were conserved among all three species, as expected based on their central role in regulating transcription. However, we found evidence that several hundred DHS sites were gained or lost on the lineages leading to modern human and chimpanzee. Species-specific DHS site gains are enriched near differentially expressed genes, are positively correlated with increased transcription, show evidence of branch-specific positive selection, and overlap with active chromatin marks. Species-specific sequence differences in transcription factor motifs found within these DHS sites are linked with species-specific changes in chromatin accessibility. Together, these indicate that the regulatory elements identified here are genetic contributors to transcriptional and phenotypic differences among primate species.

  10. Blocking S1P interaction with S1P{sub 1} receptor by a novel competitive S1P{sub 1}-selective antagonist inhibits angiogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Fujii, Yasuyuki, E-mail: y.fujii@po.rd.taisho.co.jp [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Ueda, Yasuji; Ohtake, Hidenori; Ono, Naoya; Takayama, Tetsuo; Nakazawa, Kiyoshi [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Igarashi, Yasuyuki [Laboratory of Biomembrane and Biofunctional Chemistry, Hokkaido University, Sapporo, Hokkaido 060-0812 (Japan); Goitsuka, Ryo [Division of Development and Aging, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022 (Japan)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer The effect of a newly developed S1P{sub 1}-selective antagonist on angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1} is a critical component of VEGF-related angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vitro activity to inhibit angiogenesis. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vivo activity to inhibit angiogenesis. Black-Right-Pointing-Pointer The efficacy of S1P{sub 1}-selective antagonist for anti-cancer therapies. -- Abstract: Sphingosine 1-phosphate receptor type 1 (S1P{sub 1}) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P{sub 1} and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P{sub 1}-selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P{sub 1} antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P{sub 1} is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

  11. Thymic commitment of regulatory T cells is a pathway of TCR-dependent selection that isolates repertoires undergoing positive or negative selection.

    Science.gov (United States)

    Coutinho, A; Caramalho, I; Seixas, E; Demengeot, J

    2005-01-01

    The seminal work of Le Douarin and colleagues (Ohki et al. 1987; Ohki et al. 1988; Salaun et al. 1990; Coutinho et al. 1993) first demonstrated that peripheral tissue-specific tolerance is centrally established in the thymus, by epithelial stromal cells (TEC). Subsequent experiments have shown that TEC-tolerance is dominant and mediated by CD4 regulatory T cells (Treg) that are generated intrathymically by recognition of antigens expressed on TECs (Modigliani et al. 1995; Modigliani et al. 1996a). From these and other observations, in 1996 Modigliani and colleagues derived a general model for the establishment and maintenance of natural tolerance (MM96) (Modigliani et al. 1996b), with two central propositions: (1) T cell receptor (TCR)-dependent sorting of emergent repertoires generates TEC-specific Treg displaying the highest TCR self-affinities below deletion thresholds, thus isolating repertoires undergoing positive and negative selection; (2) Treg are intrathymically committed (and activated) for a unique differentiative pathway with regulatory effector functions. The model explained the embryonic/perinatal time window of natural tolerance acquisition, by developmental programs determining (1) TCR multireactivity, (2) the cellular composition in the thymic stroma (relative abundance of epithelial vs hemopoietic cells), and (3) the dynamics of peripheral lymphocyte pools, built by accumulation of recent thymic emigrants (RTE) that remain recruitable to regulatory functions. We discuss here the MM96 in the light of recent results demonstrating the promiscuous expression of tissue-specific antigens by medullary TECs (Derbinski et al. 2001; Anderson et al. 2002; Gotter et al. 2004) and indicating that Treg represent a unique differentiative pathway (Fontenot et al. 2003; Hori et al. 2003; Khattri et al. 2003), which is adopted by CD4 T cells with high avidity for TEC-antigens (Bensinger et al. 2001; Jordan et al. 2001; Apostolou et al. 2002). In the likelihood that

  12. Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer

    Directory of Open Access Journals (Sweden)

    Ling Li

    2015-04-01

    Full Text Available Inhibition of glycolysis using 2-deoxy-d-glucose (2DG, 20 mM, 24–48 h combined with inhibition of the pentose cycle using dehydroepiandrosterone (DHEA, 300 µM, 24–48 h increased clonogenic cell killing in both human prostate (PC-3 and DU145 and human breast (MDA-MB231 cancer cells via a mechanism involving thiol-mediated oxidative stress. Surprisingly, when 2DG+DHEA treatment was combined with an inhibitor of glutathione (GSH synthesis (l-buthionine sulfoximine; BSO, 1 mM that depleted GSH>90% of control, no further increase in cell killing was observed during 48 h exposures. In contrast, when an inhibitor of thioredoxin reductase (TrxR activity (Auranofin; Au, 1 µM, was combined with 2DG+DHEA or DHEA-alone for 24 h, clonogenic cell killing was significantly increased in all three human cancer cell lines. Furthermore, enhanced clonogenic cell killing seen with the combination of DHEA+Au was nearly completely inhibited using the thiol antioxidant, N-acetylcysteine (NAC, 20 mM. Redox Western blot analysis of PC-3 cells also supported the conclusion that thioredoxin-1 (Trx-1 oxidation was enhanced by treatment DHEA+Au and inhibited by NAC. Importantly, normal human mammary epithelial cells (HMEC were not as sensitive to 2DG, DHEA, and Au combinations as their cancer cell counterparts (MDA-MB-231. Overall, these results support the hypothesis that inhibition of glycolysis and pentose cycle activity, combined with inhibition of Trx metabolism, may provide a promising strategy for selectively sensitizing human cancer cells to oxidative stress-induced cell killing.

  13. Selective and rapid monitoring of dual platelet inhibition by aspirin and P2Y12 antagonists by using multiple electrode aggregometry

    Directory of Open Access Journals (Sweden)

    Lorenz Reinhard

    2010-05-01

    Full Text Available Abstract Background Poor platelet inhibition by aspirin or clopidogrel has been associated with adverse outcomes in patients with cardiovascular diseases. A reliable and facile assay to measure platelet inhibition after treatment with aspirin and a P2Y12 antagonist is lacking. Multiple electrode aggregometry (MEA, which is being increasingly used in clinical studies, is sensitive to platelet inhibition by aspirin and clopidogrel, but a critical evaluation of MEA monitoring of dual anti-platelet therapy with aspirin and P2Y12 antagonists is missing. Design and Methods By performing in vitro and ex vivo experiments, we evaluated in healthy subjects the feasibility of using MEA to monitor platelet inhibition of P2Y12 antagonists (clopidogrel in vivo, cangrelor in vitro and aspirin (100 mg per day in vivo, and 1 mM or 5.4 mM in vitro alone, and in combination. Statistical analyses were performed by the Mann-Whitney rank sum test, student' t-test, analysis of variance followed by the Holm-Sidak test, where appropriate. Results ADP-induced platelet aggregation in hirudin-anticoagulated blood was inhibited by 99.3 ± 1.4% by in vitro addition of cangrelor (100 nM; p 95% and 100 ± 3.2%, respectively (p in vitro or ex vivo. Oral intake of clopidogrel did not significantly reduce AA-induced aggregation, but P2Y12 blockade by cangrelor (100 nM in vitro diminished AA-stimulated aggregation by 53 ± 26% (p Conclusions Selective platelet inhibition by aspirin and P2Y12 antagonists alone and in combination can be rapidly measured by MEA. We suggest that dual anti-platelet therapy with these two types of anti-platelet drugs can be optimized individually by measuring platelet responsiveness to ADP and AA with MEA before and after drug intake.

  14. Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle–coupled loss of IRF4

    Science.gov (United States)

    Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Bretz, Jamieson; Shaffer, Arthur L.; Louie, Tracey; Chen, Isan; Randolph, Sophia; Hahn, William C.; Staudt, Louis M.; Niesvizky, Ruben; Moore, Malcolm A. S.

    2012-01-01

    Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G1 block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy. PMID:22718837

  15. Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4.

    Science.gov (United States)

    Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Bretz, Jamieson; Shaffer, Arthur L; Louie, Tracey; Chen, Isan; Randolph, Sophia; Hahn, William C; Staudt, Louis M; Niesvizky, Ruben; Moore, Malcolm A S; Chen-Kiang, Selina

    2012-08-02

    Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.

  16. UCLA1 aptamer inhibition of human immunodeficiency virus type 1 subtype C primary isolates in macrophages and selection of resistance

    CSIR Research Space (South Africa)

    Mufhandu, Hazel T

    2016-09-01

    Full Text Available isolates in monocyte-derived macrophages (MDMs). Of 4 macrophage-tropic isolates tested, 3 were inhibited by UCLA1 in the low nanomolar range (IC80 <29 nM). One isolate that showed reduced susceptibility (<50 nM) to UCLA1 contained mutations in the a5 helix...

  17. Understanding Selective Downregulation of c-Myc Expression through Inhibition of General Transcription Regulators in Multiple Myeloma

    Science.gov (United States)

    2015-06-01

    We next tested whether BET bromodomain inhibition mitigated the acti- vation of proadhesion pathways in aortic endothelium, which oc- curs during the...tinuum of activity as Myc flickers on and off of weakly bound, weakly expressed promoters, but stays longer or more frequently at high output promoters

  18. Improved methods in Agrobacterium-mediated transformation of almond using positive (mannose/pmi) or negative (kanamycin resistance) selection-based protocols.

    Science.gov (United States)

    Ramesh, Sunita A; Kaiser, Brent N; Franks, Tricia; Collins, Graham; Sedgley, Margaret

    2006-08-01

    A protocol for Agrobacterium-mediated transformation with either kanamycin or mannose selection was developed for leaf explants of the cultivar Prunus dulcis cv. Ne Plus Ultra. Regenerating shoots were selected on medium containing 15 muM kanamycin (negative selection), while in the positive selection strategy, shoots were selected on 2.5 g/l mannose supplemented with 15 g/l sucrose. Transformation efficiencies based on PCR analysis of individual putative transformed shoots from independent lines relative to the initial numbers of leaf explants tested were 5.6% for kanamycin/nptII and 6.8% for mannose/pmi selection, respectively. Southern blot analysis on six randomly chosen PCR-positive shoots confirmed the presence of the nptII transgene in each, and five randomly chosen lines identified to contain the pmi transgene by PCR showed positive hybridisation to a pmi DNA probe. The positive (mannose/pmi) and the negative (kanamycin) selection protocols used in this study have greatly improved transformation efficiency in almond, which were confirmed with PCR and Southern blot. This study also demonstrates that in almond the mannose/pmi selection protocol is appropriate and can result in higher transformation efficiencies over that of kanamycin/nptII selection protocols.

  19. Outstanding Anti-inflammatory Potential of Selected Asteraceae Species through the Potent Dual Inhibition of Cyclooxygenase-1 and 5-Lipoxygenase.

    Science.gov (United States)

    Chagas-Paula, Daniela Aparecida; Oliveira, Tiago Branquinho; Faleiro, Danniela Príscylla Vasconcelos; Oliveira, Rejane Barbosa; Costa, Fernando Batista Da

    2015-09-01

    Cyclooxygenase and 5-lipoxygenase are enzymes that catalyze important inflammatory pathways, suggesting that dual cyclooxygenase/lipoxygenase inhibitors should be more efficacious as anti-inflammatory medicines with lower side effects than the currently available nonsteroidal anti-inflammatory drugs. Many plants from the family Asteraceae have anti-inflammatory activities, which could be exerted by inhibiting the cyclooxygenase-1 and 5-lipoxygenase enzymes. Nevertheless, only a small number of compounds from this family have been directly evaluated for their ability to inhibit the enzymes in cell-free assays. Therefore, this study systematically evaluated 57 Asteraceae extracts in vitro in enzyme activity experiments to determine whether any of these extracts exhibit dual inhibition of cyclooxygenase-1 and 5-lipoxygenase. The chemical profiles of the extracts were obtained by the high-performance liquid chromatography-ultraviolet-diode array detector method, and their major constituents were dereplicated. Of the 57 tested extracts, 13 (26.6 %, IC50 range from 0.03-36.2 µg/mL) of them displayed dual inhibition. Extracts from known anti-inflammatory herbs, food plants, and previously uninvestigated species are among the most active. Additionally, the extract action was found to be specific with IC50 values close to or below those of the standard inhibitors. Thus, the active extracts and active substances of these species are potent inhibitors acting through the mechanism of dual inhibition of cyclooxygenase-1 and 5-lipoxygenase. The extracts were prepared for this study using nontoxic extraction solvents (EtOH-H2O), requiring only a small amount of plant material to carry out the bioassays and the phytochemical analyses. In summary, this study demonstrated the potential of the investigated species as dual inhibitors, revealing their potential as pharmaceuticals or nutraceuticals. Georg Thieme Verlag KG Stuttgart · New York.

  20. Children of Few Words: Relations Among Selective Mutism, Behavioral Inhibition, and (Social) Anxiety Symptoms in 3- to 6-Year-Olds.

    Science.gov (United States)

    Muris, Peter; Hendriks, Eline; Bot, Suili

    2016-02-01

    Children with selective mutism (SM) fail to speak in specific public situations (e.g., school), despite speaking normally in other situations (e.g., at home). The current study explored the phenomenon of SM in a sample of 57 non-clinical children aged 3-6 years. Children performed two speech tasks to assess their absolute amount of spoken words, while their parents completed questionnaires for measuring children's levels of SM, social anxiety and non-social anxiety symptoms as well as the temperament characteristic of behavioral inhibition. The results indicated that high levels of parent-reported SM were primarily associated with high levels of social anxiety symptoms. The number of spoken words was negatively related to behavioral inhibition: children with a more inhibited temperament used fewer words during the speech tasks. Future research is necessary to test whether the temperament characteristic of behavioral inhibition prompts children to speak less in novel social situations, and whether it is mainly social anxiety that turns this taciturnity into the psychopathology of SM.

  1. Sulindac, a nonsteroidal anti-inflammatory drug, selectively inhibits interferon-γ-induced expression of the chemokine CXCL9 gene in mouse macrophages

    International Nuclear Information System (INIS)

    Sakaeda, Yoshiichi; Hiroi, Miki; Shimojima, Takahiro; Iguchi, Mayumi; Kanegae, Haruhide; Ohmori, Yoshihiro

    2006-01-01

    Sulindac, a non-steroidal anti-inflammatory drug, has been shown to exert an anti-tumor effect on several types of cancer. To determine the effect of sulindac on intracellular signaling pathways in host immune cells such as macrophages, we investigated the effect of the drug on interferon gamma (IFNγ)-induced expression of signal transducer and activator of transcription 1 (STAT1) and other genes in mouse macrophage-like cell line RAW264.7 cells. Sulindac, but not aspirin or sodium salicylate, inhibited IFNγ-induced expression of the CXC ligand 9 (CXCL9) mRNA, a chemokine for activated T cells, whereas the interferon-induced expression of CXCL10 or IFN regulatory factor-1 was not affected by sulindac. Luciferase reporter assay demonstrated that sulindac inhibited IFNγ-induced promoter activity of the CXCL9 gene. Surprisingly, sulindac had no inhibitory effect on IFNγ-induced STAT1 activation; however, constitutive nuclear factor κB activity was suppressed by the drug. These results indicate that sulindac selectively inhibited IFNγ-inducible gene expression without inhibiting STAT1 activation

  2. Selective loss of Purkinje cells in a patient with anti-gliadin-antibody-positive autoimmune cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Hasegawa Akira

    2011-02-01

    Full Text Available Abstract The patient was an 84-year-old woman who had the onset of truncal ataxia at age 77 and a history of Basedow's disease. Her ataxic gait gradually deteriorated. She could not walk without support at age 81 and she was admitted to our hospital at age 83. Gaze-evoked nystagmus and dysarthria were observed. Mild ataxia was observed in all limbs. Her deep tendon reflex and sense of position were normal. IgA anti-gliadin antibody, IgG anti-gliadin antibody, anti-SS-A/Ro antibody, anti-SS-B/La antibody and anti-TPO antibody were positive. A conventional brain MRI did not show obvious cerebellar atrophy. However, MRI voxel based morphometry (VBM and SPECT-eZIS revealed cortical cerebellar atrophy and reduced cerebellar blood flow. IVIg treatment was performed and was moderately effective. After her death at age 85, the patient was autopsied. Neuropathological findings were as follows: selective loss of Purkinje cells; no apparent degenerative change in the efferent pathways, such as the dentate nuclei or vestibular nuclei; no prominent inflammatory reaction. From these findings, we diagnosed this case as autoimmune cerebellar atrophy associated with gluten ataxia. All 3 autopsies previously reported on gluten ataxia have noted infiltration of inflammatory cells in the cerebellum. In this case, we postulated that the infiltration of inflammatory cells was not found because the patient's condition was based on humoral immunity. The clinical conditions of gluten ataxia have not yet been properly elucidated, but are expected to be revealed as the number of autopsied cases increases.

  3. IFN-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria.

    Directory of Open Access Journals (Sweden)

    Shyamala Thirunavukkarasu

    Full Text Available According to most models of mycobacterial infection, inhibition of the pro-inflammatory macrophage immune responses contributes to the persistence of bacteria. Mycobacterium avium subsp. paratuberculosis (MAP is a highly successful pathogen in cattle and sheep and is also implicated as the causative agent of Crohn's disease in humans. Pathogenic mycobacteria such as MAP have developed multiple strategies to evade host defence mechanisms including interfering with the macrophages' capacity to respond to IFN-γ, a feature which might be lacking in non-pathogenic mycobacteria such as M. smegmatis. We hypothesized that pre-sensitisation of macrophages with the pro-inflammatory cytokine IFN-γ would help in overcoming the inhibitory effect of MAP or its antigens on macrophage inflammatory responses. Herein we have compared a series of macrophage activation parameters in response to MAP and M. smegmatis as well as mycobacterial antigens. While IFN-γ did overcome the inhibition in immune suppressive mechanisms in response to MAP antigen as well as M. smegmatis, we could not find a clear role for IFN-γ in overcoming the inhibition of macrophage inflammatory responses to the pathogenic mycobacterium, MAP. We demonstrate that suppression of macrophage defence mechanisms by pathogenic mycobacteria is unlikely to be overcome by prior sensitization with IFN-γ alone. This indicates that IFN-γ signaling pathway-independent mechanisms may exist for overcoming inhibition of macrophage effector functions in response to pathogenic mycobacteria. These findings have important implications in understanding the survival mechanisms of pathogenic mycobacteria directed towards finding better therapeutics and vaccination strategies.

  4. Selective inhibition of Erwinia amylovora by the herbicidally active germination-arrest factor (GAF) produced by Pseudomonas bacteria.

    Science.gov (United States)

    Halgren, A; Azevedo, M; Mills, D; Armstrong, D; Thimmaiah, M; McPhail, K; Banowetz, G

    2011-10-01

     The germination-arrest factor (GAF) produced by Pseudomonas fluorescens WH6, and identified as 4-formylaminooxyvinylglycine, specifically inhibits the germination of a wide range of grassy weeds. This study was undertaken to determine whether GAF has antimicrobial activity in addition to its inhibitory effects on grass seed germination. Culture filtrate from Ps. fluorescens WH6 had little or no effect on 17 species of bacteria grown in Petri dish lawns, but the in vitro growth of Erwinia amylovora, the causal agent of the disease of orchard crops known as fire blight, was strongly inhibited by the filtrate. The anti-Erwinia activity of WH6 culture filtrate was shown to be due to its GAF content, and a commercially available oxyvinylglycine, 4-aminoethoxyvinylglycine (AVG), exhibited anti-Erwinia activity similar to that of GAF. The effects of GAF on Erwinia were reversed by particular amino acids. The biological properties of GAF include a rather specific antimicrobial activity against Erw. amylovora. This may be a general property of oxyvinylglycines as AVG exhibited similar activity. The ability of particular amino acids to reverse GAF inhibition is consistent with a potential effect of this compound on the activity of aminotransferases. The results presented here demonstrate a novel antimicrobial activity of oxyvinylglycines and suggest that GAF and/or GAF-producing bacteria may have potential for the control of fire blight. Journal of Applied Microbiology © 2011 The Society for Applied Microbiology. No claim to US Government works.

  5. Inhibition of Klebsiella pneumoniae growth by selected Australian plants: natural approaches for the prevention and management of ankylosing spondylitis.

    Science.gov (United States)

    Winnett, V; Sirdaarta, J; White, A; Clarke, F M; Cock, I E

    2017-04-01

    A wide variety of herbal remedies are used in traditional Australian medicine to treat inflammatory disorders, including autoimmune inflammatory diseases. One hundred and six extracts from 40 native Australian plant species traditionally used for the treatment of inflammation and/or to inhibit bacterial growth were investigated for their ability to inhibit the growth of a microbial trigger for ankylosing spondylitis (K. pneumoniae). Eighty-six of the extracts (81.1%) inhibited the growth of K. pneumoniae. The D. leichardtii, Eucalyptus spp., K. flavescens, Leptospermum spp., M. quinquenervia, Petalostigma spp., P. angustifolium, S. spinescens, S. australe, S. forte and Tasmannia spp. extracts were effective K. pneumoniae growth inhibitors, with MIC values generally <1000 µg/mL. The T. lanceolata peppercorn extracts were the most potent growth inhibitors, with MIC values as low as 16 µg/mL. These extracts were examined by non-biased GC-MS headspace analysis and comparison with a compound database. A notable feature was the high relative abundance of the sesquiterpenoids polygodial, guaiol and caryophyllene oxide, and the monoterpenoids linalool, cineole and α-terpineol in the T. lanceolata peppercorn methanolic and aqueous extracts. The extracts with the most potent K. pneumoniae inhibitory activity (including the T. lanceolata peppercorn extracts) were nontoxic in the Artemia nauplii bioassay. The lack of toxicity and the growth inhibitory activity of these extracts against K. pneumoniae indicate their potential for both preventing the onset of ankylosing spondylitis and minimising its symptoms once the disease is established.

  6. Glucocorticoids selectively inhibit the transcription of the interleukin 1β gene and decrease the stability of interleukin 1β mRNA

    International Nuclear Information System (INIS)

    Lee, S.W.; Tsou, A.P.; Chan, H.; Thomas, J.; Petrie, K.; Eugui, E.M.; Allison, A.C.

    1988-01-01

    Transcription of the interleukin 1β (IL-1β) gene was studied by mRNA hybridization with a cDNA probe in the human promonocytic cell line U-937. Phorbol ester and lipopolysaccharide increased the steady-state level of Il-1β mRNA. Glucocorticoids markedly decreased IL-1β mRNA levels by two mechanisms. Transcription of the IL-1 gene was inhibited, as shown by in vitro transcription assays with nuclei isolated from glucocorticoid-treated cells. Moreover, kinetic analyses and pulse-labeling of mRNAs showed that glucocorticoids selectively decrease the stability of IL-1β mRNA, without affecting the stability of β-actin and FOS mRNAs. Inhibition of the formation and effects IL-1 is a mechanism by which glucocorticoids can exert antiinflammatory and immunosuppressive effects

  7. Bare eye detection of Hg(II) ions based on enzyme inhibition and using mercaptoethanol as a reagent to improve selectivity.

    Science.gov (United States)

    He, Liuying; Lu, Yuexiang; Wang, Feiyang; Gao, Xinxin; Chen, Ying; Liu, Yueying

    2018-02-13

    The authors describe a colorimetric method for the determination of Hg 2+ ions based on the inhibition of the activity of the enzyme urease. The pH value of solution increases when urease hydrolyzes urea, which can be visualized by adding a pH indicator such as Phenol Red (PhR). Mercaptoethanol as a typical thiol is added to the system to improve selectivity because it binds metal ions and then - unlike the Hg 2+ mercaptoethanol complex - does not inhibit urease. Hence, the color of the pH indicator PhR turns from yellow to pink as the solution becomes alkaline. The Hg 2+ mercaptoethanol complex, in contrast, strongly inhibits urease and the color of the solution remains yellow. The findings were used to design a photometric assay based on the measurement of the ratio of absorptions of PhR at 558 nm and 430 nm. It has a linear response over the 25 to 40 nM Hg 2+ concentration range and a 5 nM detection limit. This is well below the guideline values of Hg 2+ specified by the US Environmental Protection Agency and the World Health Organization for drinking water (10 nM and 30 nM, respectively). The method was employed to the determination of Hg 2+ in water samples spiked with 10 nM levels of Hg 2+ where color changes still can be observed visually. Graphical Abstract Schematic presentation of a colorimetric method for the ultrasensitive detection of Hg 2+ based on the inhibition of urease activity. Mercaptoethanol is used to improve the selectivity. Even at Hg 2+ concentrations as low as 5 nM, the color change still can be easily observed by bare eyes.

  8. Extracellular matrix metalloproteinase inducer (EMMPRIN) remodels the extracellular matrix through enhancing matrix metalloproteinases (MMPs) and inhibiting tissue inhibitors of MMPs expression in HPV-positive cervical cancer cells.

    Science.gov (United States)

    Xu, Q; Cao, X; Pan, J; Ye, Y; Xie, Y; Ohara, N; Ji, H

    2015-01-01

    PUPOSE OF INVESTIGATION: To study the expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), and tissue inhibitors of MMP (TIMPs) in uterine cervical cancer cell lines in vitro. EMMPRIN, MMPs, and TIMPs expression were assessed by Western blot and real-time RT-PCR from cervical carcinoma SiHa, HeLa, and C33-A cells. EMMPRIN recombinant significantly increased MMP-2, MMP-9 protein and mRNA expression in SiHa and Hela cells, but not in C33-A cells by Western blot analysis and real-time RT-PCR. EMMPRIN recombinant significantly inhibited TIMP-1 protein and mRNA levels in SiHa and Hela cells, but not in C33-A cells. There was no difference on the TIMP-2 expression in those cells with the treatment of EMMPRIN recombinant. EMMPRIN RNAi decreased MMP-2 and MMP-9 and increased TIMP-1 expression in SiHa and HeLa cells, but not in C33-A cells. There was no change on the expression of TIMP-2 mRNA levels in SiHa, HeLa and C33-A cells transfected with siEMMPRIN. EMMPRIN may induce MMP-2 and MMP-9, and downregulate TIMP-1 in HPV-positive cervical cancer cells in vitro.

  9. Selective inhibition of sheep kidney 11 beta-hydroxysteroid dehydrogenase isoform 2 activity by 5 alpha-reduced (but not 5 beta) derivatives of adrenocorticosteroids.

    Science.gov (United States)

    Latif, S A; Sheff, M F; Ribeiro, C E; Morris, D J

    1997-02-01

    We have previously reported that 5 alpha and 5 beta pathways of steroid metabolism are controlled in vivo by dietary Na+ and glycyrrhetinic acid, see Gorsline et al. 1988; Latif et al. 1990. The present investigations provide evidence supporting the suggestion that endogenous substances may regulate the glucocorticoid inactivating isoenzymes, 11 beta-HSD (hydroxysteroid dehydrogenase) 1 (liver) and 11 beta-HSD2 (kidney). The activity of 11 beta-HSD is impaired in essential hypertension, following licorice ingestion, and in patients with apparent mineralocorticoid excess where 11 beta-HSD2 is particularly affected. In all three conditions, excretion of the less common 5 alpha metabolites is elevated in urine. We now report on the differential abilities of a series of Ring A reduced (5 alpha and 5 beta) adrenocorticosteroid and progesterone metabolites to inhibit these isoenzymes. Using liver microsomes with NADP+ as co-factor (11 beta-HSD1), and sheep kidney microsomes with NAD+ as co-factor (11 beta-HSD2), we have systematically investigated the abilities of a number of adrenocorticosteroids and their derivatives to inhibit the individual isoforms of 11 beta-HSD. A striking feature is the differential sensitivity of the two isoenzymes to inhibition by 5 alpha and 5 beta derivatives. 11 beta-HSD1 is inhibited by both 5 alpha and certain 5 beta derivatives. 11 beta-HSD-2 was selectively inhibited only by 5 alpha derivatives: 5 beta derivatives were without inhibitory activity toward this isoform of 11 beta-HSD. These results indicate the importance of the structural conformation of the A and B Rings in conferring specific inhibitory properties on these compounds. In addition, we discuss the effects of additions or substitutions of other functional groups on the inhibitory potency of these steroid molecules against 11 beta-HSD1 and 11 beta-HSD2.

  10. The EG95 Antigen of Echinococcus spp. Contains Positively Selected Amino Acids, which May Influence Host Specificity and Vaccine Efficacy

    Science.gov (United States)

    Haag, Karen Luisa; Gottstein, Bruno; Ayala, Francisco Jose

    2009-01-01

    Echinococcosis is a worldwide zoonotic parasitic disease of humans and various herbivorous domestic animals (intermediate hosts) transmitted by the contact with wild and domestic carnivores (definitive hosts), mainly foxes and dogs. Recently, a vaccine was developed showing high levels of protection against one parasite haplotype (G1) of Echinococcus granulosus, and its potential efficacy against distinct parasite variants or species is still unclear. Interestingly, the EG95 vaccine antigen is a secreted glycosylphosphatydilinositol (GPI)-anchored protein containing a fibronectin type III domain, which is ubiquitous in modular proteins involved in cell adhesion. EG95 is highly expressed in oncospheres, the parasite life cycle stage which actively invades the intermediate hosts. After amplifying and sequencing the complete CDS of 57 Echinococcus isolates belonging to 7 distinct species, we uncovered a large amount of genetic variability, which may influence protein folding. Two positively selected sites are outside the vaccine epitopes, but are predicted to alter protein conformation. Moreover, phylogenetic analyses indicate that EG95 isoform evolution is convergent with regard to the number of beta-sheets and alpha-helices. We conclude that having a variety of EG95 isoforms is adaptive for Echinococcus parasites, in terms of their ability to invade different hosts, and we propose that a mixture of isoforms could possibly maximize vaccine efficacy. PMID:19401778

  11. Whole-gene positive selection, elevated synonymous substitution rates, duplication, and indel evolution of the chloroplast clpP1 gene.

    Directory of Open Access Journals (Sweden)

    Per Erixon

    Full Text Available BACKGROUND: Synonymous DNA substitution rates in the plant chloroplast genome are generally relatively slow and lineage dependent. Non-synonymous rates are usually even slower due to purifying selection acting on the genes. Positive selection is expected to speed up non-synonymous substitution rates, whereas synonymous rates are expected to be unaffected. Until recently, positive selection has seldom been observed in chloroplast genes, and large-scale structural rearrangements leading to gene duplications are hitherto supposed to be rare. METHODOLOGY/PRINCIPLE FINDINGS: We found high substitution rates in the exons of the plastid clpP1 gene in Oenothera (the Evening Primrose family and three separate lineages in the tribe Sileneae (Caryophyllaceae, the Carnation family. Introns have been lost in some of the lineages, but where present, the intron sequences have substitution rates similar to those found in other introns of their genomes. The elevated substitution rates of clpP1 are associated with statistically significant whole-gene positive selection in three branches of the phylogeny. In two of the lineages we found multiple copies of the gene. Neighboring genes present in the duplicated fragments do not show signs of elevated substitution rates or positive selection. Although non-synonymous substitutions account for most of the increase in substitution rates, synonymous rates are also markedly elevated in some lineages. Whereas plant clpP1 genes experiencing negative (purifying selection are characterized by having very conserved lengths, genes under positive selection often have large insertions of more or less repetitive amino acid sequence motifs. CONCLUSIONS/SIGNIFICANCE: We found positive selection of the clpP1 gene in various plant lineages to correlated with repeated duplication of the clpP1 gene and surrounding regions, repetitive amino acid sequences, and increase in synonymous substitution rates. The present study sheds light on the

  12. The proteolytically stable peptidomimetic Pam-(Lys-βNSpe)6-NH2 selectively inhibits human neutrophil activation via formyl peptide receptor 2.

    Science.gov (United States)

    Skovbakke, Sarah Line; Heegaard, Peter M H; Larsen, Camilla J; Franzyk, Henrik; Forsman, Huamei; Dahlgren, Claes

    2015-01-15

    Immunomodulatory host defense peptides (HDPs) are considered to be lead compounds for novel anti-sepsis and anti-inflammatory agents. However, development of drugs based on HDPs has been hampered by problems with toxicity and low bioavailability due to in vivo proteolysis. Here, a subclass of proteolytically stable HDP mimics consisting of lipidated α-peptide/β-peptoid oligomers was investigated for their effect on neutrophil function. The most promising compound, Pam-(Lys-βNSpe)6-NH2, was shown to inhibit formyl peptide receptor 2 (FPR2) agonist-induced neutrophil granule mobilization and release of reactive oxygen species. The potency of Pam-(Lys-βNSpe)6-NH2 was comparable to that of PBP10, the most potent FPR2-selective inhibitor known. The immunomodulatory effects of structural analogs of Pam-(Lys-βNSpe)6-NH2 emphasized the importance of both the lipid and peptidomimetic parts. By using imaging flow cytometry in primary neutrophils and FPR-transfected cell lines, we found that a fluorescently labeled analog of Pam-(Lys-βNSpe)6-NH2 interacted selectively with FPR2. Furthermore, the interaction between Pam-(Lys-βNSpe)6-NH2 and FPR2 was found to prevent binding of the FPR2-specific activating peptide agonist Cy5-WKYMWM, while the binding of an FPR1-selective agonist was not inhibited. To our knowledge, Pam-(Lys-βNSpe)6-NH2 is the first HDP mimic found to inhibit activation of human neutrophils via direct interaction with FPR2. Hence, we consider Pam-(Lys-βNSpe)6-NH2 to be a convenient tool in the further dissection of the role of FPR2 in inflammation and homeostasis as well as for investigation of the importance of neutrophil stimulation in anti-infective therapy involving HDPs. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Epoxy fatty acids and inhibition of the soluble epoxide hydrolase selectively modulate GABA mediated neurotransmission to delay onset of seizures.

    Directory of Open Access Journals (Sweden)

    Bora Inceoglu

    Full Text Available In the brain, seizures lead to release of large amounts of polyunsaturated fatty acids including arachidonic acid (ARA. ARA is a substrate for three major enzymatic routes of metabolism by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes. These enzymes convert ARA to potent lipid mediators including prostanoids, leukotrienes and epoxyeicosatrienoic acids (EETs. The prostanoids and leukotrienes are largely pro-inflammatory molecules that sensitize neurons whereas EETs are anti-inflammatory and reduce the excitability of neurons. Recent evidence suggests a GABA-related mode of action potentially mediated by neurosteroids. Here we tested this hypothesis using models of chemically induced seizures. The level of EETs in the brain was modulated by inhibiting the soluble epoxide hydrolase (sEH, the major enzyme that metabolizes EETs to inactive molecules, by genetic deletion of sEH and by direct administration of EETs into the brain. All three approaches delayed onset of seizures instigated by GABA antagonists but not seizures through other mechanisms. Inhibition of neurosteroid synthesis by finasteride partially blocked the anticonvulsant effects of sEH inhibitors while the efficacy of an inactive dose of neurosteroid allopregnanolone was enhanced by sEH inhibition. Consistent with earlier findings, levels of prostanoids in the brain were elevated. In contrast, levels of bioactive EpFAs were decreased following seizures. Overall these results demonstrate that EETs are natural molecules which suppress the tonic component of seizure related excitability through modulating the GABA activity and that exploration of the EET mediated signaling in the brain could yield alternative approaches to treat convulsive disorders.

  14. Inhibiting mitochondrial β-oxidation selectively reduces levels of nonenzymatic oxidative polyunsaturated fatty acid metabolites in the brain.

    Science.gov (United States)

    Chen, Chuck T; Trépanier, Marc-Olivier; Hopperton, Kathryn E; Domenichiello, Anthony F; Masoodi, Mojgan; Bazinet, Richard P

    2014-03-01

    Schönfeld and Reiser recently hypothesized that fatty acid β-oxidation is a source of oxidative stress in the brain. To test this hypothesis, we inhibited brain mitochondrial β-oxidation with methyl palmoxirate (MEP) and measured oxidative polyunsaturated fatty acid (PUFA) metabolites in the rat brain. Upon MEP treatment, levels of several nonenzymatic auto-oxidative PUFA metabolites were reduced with few effects on enzymatically derived metabolites. Our finding confirms the hypothesis that reduced fatty acid β-oxidation decreases oxidative stress in the brain and β-oxidation inhibitors may be a novel therapeutic approach for brain disorders associated with oxidative stress.

  15. Biochanin A, a Phytoestrogenic Isoflavone with Selective Inhibition of Phosphodiesterase 4, Suppresses Ovalbumin-Induced Airway Hyperresponsiveness

    Directory of Open Access Journals (Sweden)

    Wun-Chang Ko

    2011-01-01

    the serum and BALF, and enhanced the total IgG2a level in the serum of these mice. The PDE4H/PDE4L value of biochanin A was calculated as >35. Biochanin A did not influence xylazine/ketamine-induced anesthesia. Biochanin A (10~30 μM significantly reduced cumulative OVA (10~100 μg/mL-induced contractions in the isolated guinea pig trachealis, suggesting that it inhibits degranulation of mast cells. In conclusion, red clover containing biochanin A has the potential for treating allergic asthma and COPD.

  16. Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

    International Nuclear Information System (INIS)

    Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng

    2015-01-01

    Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice.

  17. Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng, E-mail: zhouqs@suda.edu.cn

    2015-10-15

    Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice.

  18. Corrosion inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, A O

    1965-12-29

    An acid corrosion-inhibiting composition consists essentially of a sugar, and an alkali metal salt selected from the group consisting of iodides and bromides. The weight ratio of the sugar to the alkali metal salt is between 2:1 and about 20,000:1. Also, a corrosion- inhibited phosphoric acid composition comprising at least about 20 wt% of phosphoric acid and between about 0.1 wt% and about 10 wt% of molasses, and between about 0.0005 wt% and about 1 wt% of potassium iodide. The weight ratio of molasses to iodide is greater than about 2:1. (11 claims)

  19. A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection.

    Directory of Open Access Journals (Sweden)

    George Nicholson

    2011-09-01

    Full Text Available We have performed a metabolite quantitative trait locus (mQTL study of the (1H nuclear magnetic resonance spectroscopy ((1H NMR metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs. Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%-64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from

  20. A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity.

    Directory of Open Access Journals (Sweden)

    Xiang Ling

    Full Text Available Drug/radiation resistance to treatment and tumor relapse are major obstacles in identifying a cure for cancer. Development of novel agents that address these challenges would therefore be of the upmost importance in the fight against cancer. In this regard, studies show that the antiapoptotic protein survivin is a central molecule involved in both hurdles. Using cancer cell-based survivin-reporter systems (US 7,569,221 B2 via high throughput screening (HTS of compound libraries, followed by in vitro and in vivo analyses of HTS-derived hit-lead compounds, we identified a novel anticancer compound (designated FL118. FL118 shows structural similarity to irinotecan. However, while the inhibition of DNA topoisomerase 1 activity by FL118 was no better than the active form of irinotecan, SN-38 at 1 µM, FL118 effectively inhibited cancer cell growth at less than nM levels in a p53 status-independent manner. Moreover, FL118 selectively inhibited survivin promoter activity and gene expression also in a p53 status-independent manner. Although the survivin promoter-reporter system was used for the identification of FL118, our studies revealed that FL118 not only inhibits survivin expression but also selectively and independently inhibits three additional cancer-associated survival genes (Mcl-1, XIAP and cIAP2 in a p53 status-independent manner, while showing no inhibitory effects on control genes. Genetic silencing or overexpression of FL118 targets demonstrated a role for these targets in FL118's effects. Follow-up in vivo studies revealed that FL118 exhibits superior antitumor efficacy in human tumor xenograft models in comparison with irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin, and a majority of mice treated with FL118 showed tumor regression with a weekly × 4 schedule. FL118 induced favorable body-weight-loss profiles (temporary and reversible and was able to eliminate large tumors. Together

  1. Examination of 12-lipoxygenase (12-LOX) as a therapeutic target in non-small cell lung cancer (NSCLC): Mechanisms controlling survival and induction of apoptosis following selective inhibition

    LENUS (Irish Health Repository)

    Cathcart, Mary Clare

    2011-06-01

    Background: Platelet-type 12-LOX is an arachidonic acid metabolising enzyme resulting in the formation of 12(S)-HETE, which stimulates tumour cell adhesion, invasion and metastasis. This study aimed to examine the expression profile and role of this enzyme in NSCLC, and determine if it is a potential target for intervention. Methods: A panel of retrospective resected lung tumours was stained for 12-LOX expression by IHC. Levels of the 12-LOX metabolite, 12(S)-HETE, were examined in 50 NSCLC serum samples, and correlated with serum VEGF. A panel of NSCLC cell lines were treated with baicalein (10 uM), a selective inhibitor of 12-LOX, or 12(S)-HETE (100 ng\\/ml) and cell survival\\/proliferation examined by BrdU. Apoptosis following 12-LOX inhibition was examined by HCS and validated by FACS and DNA laddering. The effect of 12-LOX inhibition on NSCLC tumour growth and survival was examined in-vivo using an athymic nude mouse model. Gene alterations following 12-LOX inhibition in NSCLC cell lines were assessed by qPCR arrays and validated by RT-PCR. Transient transfection methods were used to examine the effects of 12-LOX overexpression in NSCLC cells. Results: 12-LOX expression was observed to a varying degree in human lung cancers of varying histological subtypes. 12(S)-HETE levels were correlated (p<0.05) with those of VEGF. Baicalein inhibited proliferation\\/survival in all cell lines, while 12(S)-HETE increased proliferation. 12-LOX inhibition increased apoptosis, indicated by a reduction in f-actin content and mitochondrial mass potential. Treatment with baicalein significantly reduced the growth of NSCLC tumours and increased overall survival in athymic nude mice. qPCR array data implicated a number of apoptosis\\/angiogenesis genes regulating these effects, including bcl-2, VEGF, integrin A2 and A4. 12-LOX overexpression resulted in an increase in VEGF secretion, confirming qPCR observations. Conclusions: 12-LOX is a survival factor\\/potential target in

  2. Enzyme-like specificity in zeolites: a unique site position in mordenite for selective carbonylation of methanol and dimethyl ether with CO.

    Science.gov (United States)

    Boronat, Mercedes; Martínez-Sánchez, Cristina; Law, David; Corma, Avelino

    2008-12-03

    The mechanism of methanol carbonylation at different positions of zeolite MOR is investigated by quantum-chemical methods in order to discover which are the active sites that can selectively catalyze the desired reaction. It is shown that when methanol carbonylation competes with hydrocarbon formation, the first reaction occurs preferentially within 8MR channels. However, the unique selectivity for the carbonylation of methanol and dimethyl ether in mordenite is not only due to the size of the 8MR channel: neither process occurs equally at the two T3-O31 and T3-O33 positions. We show that only the T3-O33 positions are selective and that this selectivity is due to the unusual orientation of the methoxy group in relation to the 8MR channel (parallel to the cylinder axis). Only in this situation does the transition state for the attack of CO fit perfectly in the 8MR channel, while the reaction with methanol or DME is sterically impeded. This result explains why T3-O31, while also located in the 8MR channel of mordenite, is not as selective as the T3-O33 position and why ferrierite, although it contains 8MR channels, is less selective than mordenite. The competing effect of water is explained at the molecular level, and the molecular microkinetic reaction model has been established.

  3. Ibrutinib (ImbruvicaTM) potently inhibits ErbB receptor phosphorylation and cell viability of ErbB2-positive breast cancer cells.

    Science.gov (United States)

    Grabinski, Nicole; Ewald, Florian

    2014-12-01

    Ibrutinib (formerly PCI-32765) is a specific, irreversible, and potent inhibitor of Burton's tyrosine kinase (BTK) developed for the treatment of several forms of blood cancer. It is now an FDA-approved drug marketed under the name Imbruvica(TM) (Pharmacyclics, Inc.) and successfully used as an orally administered second-line drug in the treatment of mantle cell lymphoma. Since BTK is predominantly expressed in hematopoietic cells, the sensitivity of solid tumor cells to Ibrutinib has not been analyzed. In this study, we determined the effect of Ibrutinib on breast cancer cells. We demonstrate that Ibrutinib efficiently reduces the phosphorylation of the receptor tyrosine kinases ErbB1, ErbB2 and ErbB3, thereby suppressing AKT and MAPK signaling in ErbB2-positive (ErbB2+) breast cancer cell lines. Treatment with Ibrutinib significantly reduced the viability of ErbB2+ cell lines with IC50 values at nanomolar concentrations, suggesting therapeutic potential of Ibrutinib in breast cancer. Combined treatment with Ibrutinib and the dual PI3K/mTOR inhibitor BEZ235 synergistically reduces cell viability of ErbB2+ breast cancer cells. Combination indices below 0.25 at 50% inhibition of cell viability were determined by the Chou-Talalay method. Therefore, the combination of Ibrutinib and canonical PI3K pathway inhibitors could be a new and effective approach in the treatment of breast cancer with activated ErbB receptors. Ibrutinib could thus become a valuable component of targeted therapy in aggressive ErbB2+ breast cancer.

  4. Inhibition of miR-146b expression increases radioiodine-sensitivity in poorly differential thyroid carcinoma via positively regulating NIS expression

    Energy Technology Data Exchange (ETDEWEB)

    Li, Luchuan; Lv, Bin; Chen, Bo [Department of General Surgery, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China); Guan, Ming [Department of General Surgery, Qihe People' s Hospital, Qihe, Shandong 251100 (China); Sun, Yongfeng [Department of General Surgery, Licheng District People' s Hospital, Jinan, Shandong 250115 (China); Li, Haipeng [Department of General Surgery, Caoxian People' s Hospital, Caoxian, Shandong 274400 (China); Zhang, Binbin; Ding, Changyuan; He, Shan [Department of General Surgery, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China); Zeng, Qingdong, E-mail: qingdz0201@163.com [Department of General Surgery, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China)

    2015-07-10

    Dedifferentiated thyroid carcinoma (DTC) with the loss of radioiodine uptake (RAIU) is often observed in clinical practice under radioiodine therapy, indicating the challenge for poor prognosis. MicroRNA (miRNA) has emerged as a promising therapeutic target in many diseases; yet, the role of miRNAs in RAIU has not been generally investigated. Based on recent studies about miRNA expression in papillary or follicular thyroid carcinomas, the expression profiles of several thyroid relative miRNAs were investigated in one DTC cell line, derived from normal DTC cells by radioiodine treatment. The top candidate miR-146b, with the most significant overexpression profiles in dedifferentiated cells, was picked up. Further research found that miR-146b could be negatively regulated by histone deacetylase 3 (HDAC3) in normal cells, indicating the correlation between miR-146b and Na{sup +}/I{sup −} symporter (NIS)-mediated RAIU. Fortunately, it was confirmed that miR-146b could regulate NIS expression/activity; what is more important, miR-146b interference would contribute to the recovery of radioiodine-sensitivity in dedifferentiated cells via positively regulating NIS. In the present study, it was concluded that NIS-mediated RAIU could be modulated by miR-146b; accordingly, miR-146b might serve as one of targets to enhance efficacy of radioactive therapy against poorly differential thyroid carcinoma (PDTC). - Highlights: • Significant upregulated miR-146b was picked up from thyroid relative miRNAs in DTC. • MiR-146b was negatively regulated by HDAC3 in normal thyroid carcinoma cells. • NIS activity and expression could be regulated by miR-146b in thyroid carcinoma. • MiR-146b inhibition could recover the decreased radioiodine-sensitivity of DTC cells.

  5. The Bibenzyl Canniprene Inhibits the Production of Pro-Inflammatory Eicosanoids and Selectively Accumulates in Some Cannabis sativa Strains.

    Science.gov (United States)

    Allegrone, Gianna; Pollastro, Federica; Magagnini, Gianmaria; Taglialatela-Scafati, Orazio; Seegers, Julia; Koeberle, Andreas; Werz, Oliver; Appendino, Giovanni

    2017-03-24

    Canniprene (1), an isoprenylated bibenzyl unique to Cannabis sativa, can be vaporized and therefore potentially inhaled from marijuana. Canniprene (1) potently inhibited the production of inflammatory eicosanoids via the 5-lipoxygenase pathway (IC 50 0.4 μM) and also affected the generation of prostaglandins via the cyclooxygenase/microsomal prostaglandin E 2 synthase pathway (IC 50 10 μM), while the related spiranoid bibenzyls cannabispiranol (2) and cannabispirenone (3) were almost inactive in these bioassays. The concentration of canniprene (1) was investigated in the leaves of 160 strains of C. sativa, showing wide variations, from traces to >0.2%, but no correlation was found between its accumulation and a specific phytocannabinoid profile.

  6. Peroxisome Proliferator-Activated Receptor-γ Inhibits Transformed Growth of Non-Small Cell Lung Cancer Cells through Selective Suppression of Snail

    Directory of Open Access Journals (Sweden)

    Rashmi Choudhary

    2010-03-01

    Full Text Available Work from our laboratory and others has demonstrated that activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ inhibits transformed growth of non-small cell lung cancer (NSCLC cell lines in vitro and in vivo. We have demonstrated that activation of PPARγ promotes epithelial differentiation of NSCLC by increasing expression of E-cadherin, as well as inhibiting expression of COX-2 and nuclear factor-κB. The Snail family of transcription factors, which includes Snail (Snail1, Slug (Snail2, and ZEB1, is an important regulator of epithelial-mesenchymal transition, as well as cell survival. The goal of this study was to determine whether the biological responses to rosiglitazone, a member of the thiazolidinedione family of PPARγ activators, are mediated through the regulation of Snail family members. Our results indicate that, in two independent NSCLC cell lines, rosiglitazone specifically decreased expression of Snail, with no significant effect on either Slug or ZEB1. Suppression of Snail using short hairpin RNA silencing mimicked the effects of PPARγ activation, in inhibiting anchorage-independent growth, promoting acinar formation in three-dimensional culture, and inhibiting invasiveness. This was associated with the increased expression of E-cadherin and decreased expression of COX-2 and matrix metaloproteinases. Conversely, overexpression of Snail blocked the biological responses to rosiglitazone, increasing anchorage-independent growth, invasiveness, and promoting epithelial-mesenchymal transition. The suppression of Snail expression by rosiglitazone seemed to be independent of GSK-3 signaling but was rather mediated through suppression of extracellular signal-regulated kinase activity. These findings suggest that selective regulation of Snail may be critical in mediating the antitumorigenic effects of PPARγ activators.

  7. The selective vitamin D receptor agonist, elocalcitol, reduces endometriosis development in a mouse model by inhibiting peritoneal inflammation.

    Science.gov (United States)

    Mariani, Margherita; Viganò, Paola; Gentilini, Davide; Camisa, Barbara; Caporizzo, Elvira; Di Lucia, Pietro; Monno, Antonella; Candiani, Massimo; Somigliana, Edgardo; Panina-Bordignon, Paola

    2012-07-01

    Endometriosis, which is characterized by the growth of endometrial tissue at ectopic locations as well as vascular development and inflammation, is still an unmet clinical need since an optimal drug that allows for both pain and infertility management does not exist. Since both the eutopic and the ectopic endometrium express the vitamin D receptor (VDR), and VDR agonists are endowed with anti-proliferative and anti-inflammatory properties, we evaluated the effect of elocalcitol, a VDR agonist with low calcaemic liability, in a mouse model of experimentally induced endometriosis. Endometriosis was induced by injection of syngeneic endometrial tissue fragments into adult Balb/c female mice. After having confirmed by immunohistochemistry that endometriotic lesions developing in mice expressed VDR, the mice were administered with elocalcitol (100 μg/kg) or vehicle orally, once a day, for various durations of time. In this model, elocalcitol was able to reduce total lesion weight up to 70% upon treatment for 1 week before and 2 weeks after disease induction. Interestingly, a therapeutic effect was also observed on already established lesions. Elocalcitol was shown to reduce the capacity of mouse endometrial cells to adhere to collagen. In addition in treated mice, a decreased state of peritoneal inflammation was demonstrated by the inhibition of macrophage recruitment and inflammatory cytokine secretion. The VDR agonist elocalcitol inhibits lesion development in a validated mouse model of endometriosis, and exerts a protective effect on both the implantation and organization of transferred endometrial tissue. These preliminary data in mice provide a sound rationale for further testing in primate models and eventually in humans.

  8. Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

    Directory of Open Access Journals (Sweden)

    Katrin Hack

    Full Text Available We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787 retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

  9. Selective COX-2 inhibition by a Pterocarpus marsupium extract characterized by pterostilbene, and its activity in healthy human volunteers.

    NARCIS (Netherlands)

    Hougee, S.; Faber, J.; Sanders, A.; Jong, R.B. de; Berg, W.B. van den; Garssen, J.; Hoijer, M.A.; Smit, H.F.

    2005-01-01

    In this study, an extract of Pterocarpus marsupium Roxb. containing pterostilbene has been evaluated for its PGE2-inhibitory activity in LPS-stimulated PBMC. In addition, the COX-1/2 selective inhibitory activity of P. marsupium (PM) extract was investigated. Biological activity, as well as safety

  10. Phylogenetic selection of target species in Amaryllidaceae tribe Haemantheae for acetylcholinesterase inhibition and affinity to the serotonin reuptake transport protein

    Science.gov (United States)

    We present phylogenetic analyses of 37 taxa of Amaryllidaceae, tribe Haemantheae and Amaryllis belladonna L. as an outgroup, in order to provide a phylogenetic framework for the selection of candidate plants for lead discoveries in relation to Alzheimer´s disease and depression. DNA sequences from t...

  11. Effect of selective inhibition of renal inducible nitric oxide synthase on renal blood flow and function in experimental hyperdynamic sepsis.

    Science.gov (United States)

    Ishikawa, Ken; Calzavacca, Paolo; Bellomo, Rinaldo; Bailey, Michael; May, Clive N

    2012-08-01

    Nitric oxide plays an important role in the control of renal blood flow and renal function. In sepsis, increased levels of inducible nitric oxide synthase produce excessive nitric oxide, which may contribute to the development of acute kidney injury. We, therefore, examined the effects of intrarenal infusion of selective inducible nitric oxide synthase inhibitors in a large animal model of hyperdynamic sepsis in which acute kidney injury occurs in the presence of increased renal blood flow. Prospective crossover randomized controlled interventional studies. University-affiliated research institute. Twelve unilaterally nephrectomized Merino ewes. Infusion of a selective (1400W) and a partially selective inducible nitric oxide synthase inhibitor (aminoguanidine) into the renal artery for 2 hrs after the induction of sepsis, and comparison with a nonselective inhibitor (Nω-nitro-L-arginine methyl ester). In sheep with nonhypotensive hyperdynamic sepsis, creatinine clearance halved (32 to 16 mL/min, ratio [95% confidence interval] 0.51 [0.28-0.92]) despite increased renal blood flow (241 to 343 mL/min, difference [95% confidence interval] 102 [78-126]). Infusion of 1400W did not change renal blood flow, urine output, or creatinine clearance, whereas infusion of Nω-nitro-L-arginine methyl ester and a high dose of aminoguanidine normalized renal blood flow, but did not alter creatinine clearance. In hyperdynamic sepsis, intrarenal infusion of a highly selective inducible nitric oxide synthase inhibitor did not reduce the elevated renal blood flow or improve renal function. In contrast, renal blood flow was reduced by infusion of a nonselective NOS inhibitor or a high dose of a partially selective inducible nitric oxide synthase inhibitor. The renal vasodilatation in septic acute kidney injury may be due to nitric oxide derived from the endothelial and neural isoforms of nitric oxide synthase, but their blockade did not restore renal function.

  12. Insights into structural features of HDAC1 and its selectivity inhibition elucidated by Molecular dynamic simulation and Molecular Docking.

    Science.gov (United States)

    Sixto-López, Yudibeth; Bello, Martiniano; Correa-Basurto, José

    2018-03-06

    Histone deacetylases (HDACs) are a family of proteins whose main function is the removal of acetyl groups from lysine residues located on histone and non-histone substrates, which regulates gene transcription and other activities in cells. HDAC1 dysfunction has been implicated in cancer development and progression; thus, its inhibition has emerged as a new therapeutic strategy. Two additional metal binding sites (Site 1 and Site 2) in HDACs have been described that are primarily occupied by potassium ions, suggesting a possible structural role that affects HDAC activity. In this work, we explored the structural role of potassium ions in Site 1 and Site 2 and how they affect the interactions of compounds with high affinities for HDAC1 (AC1OCG0B, Chlamydocin, Dacinostat and Quisinostat) and SAHA (a pan-inhibitor) using molecular docking and molecular dynamics (MD) simulations in concert with a Molecular-Mechanics-Generalized-Born-Surface-Area (MMGBSA) approach. Four models were generated: one with a potassium ion (K + ) in both sites (HDAC1 k ), a second with K + only at site 1 (HDAC1 ks1 ), a third with K + only at site 2 (HDAC1 ks2 ) and a fourth with no K + (HDAC1 wk ). We found that the presence or absence of K + not only impacted the structural flexibility of HDAC1, but also its molecular recognition, consistent with experimental findings. These results could therefore be useful for further structure-based drug design studies addressing new HDAC1 inhibitors.

  13. Inhibition of Pain and Pain-Related Brain Activity by Heterotopic Noxious Counter-Stimulation and Selective Attention in Chronic Non-Specific Low Back Pain.

    Science.gov (United States)

    Ladouceur, Alexandra; Rustamov, Nabi; Dubois, Jean-Daniel; Tessier, Jessica; Lehmann, Alexandre; Descarreaux, Martin; Rainville, Pierre; Piché, Mathieu

    2017-10-10

    The aim of the present study was to assess inhibition of pain and somatosensory-evoked potentials (SEPs) by heterotopic noxious counter-stimulation (HNCS) and by selective attention in patients with chronic non-specific LBP. Seventeen patients and age/sex-matched controls were recruited (10 men, 7 women; mean age ± SD: 43.3 ± 10.4 and 42.7 ± 11.1, respectively). On average, patients with LBP reported pain duration of 7.6 ± 6.5 years, light to moderate disability (19.3 ± 5.7/100) and low clinical pain intensity (21.8 ± 1.5/100), while pain catastrophizing, state and trait anxiety and depressive symptoms were not significantly different between groups (all p's >0.05). HNCS and selective attention had differential inhibitory effects on pain and SEP, but no difference was observed between groups. Across both groups, HNCS decreased pain (p = 0.06) as well as the N100 and the N150 components of SEP (p's selective attention only decreased pain (p attention was directed toward the HNCS stimulus (pselective attention. Importantly, this experiment was carefully designed to control for non-specific effects associated with the repetition of the test stimulus and the effect of an innocuous counter-stimulation. It remains to be determined if these results hold for patients with severe LBP and psychological symptoms or whether symptom severity may be associated with pain inhibition deficits. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. Inhibition of Pseudomonas aeruginosa virulence: characterization of the AprA-AprI interface and species selectivity.

    Science.gov (United States)

    Bardoel, Bart W; van Kessel, Kok P M; van Strijp, Jos A G; Milder, Fin J

    2012-01-20

    Pseudomonas aeruginosa secretes the virulence factor alkaline protease (AprA) to enhance its survival. AprA cleaves one of the key microbial recognition molecules, monomeric flagellin, and thereby diminishes Toll-like receptor 5 activation. In addition, AprA degrades host proteins such as complement proteins and cytokines. P. aeruginosa encodes a highly potent inhibitor of alkaline protease (AprI) that is solely located in the periplasm where it is presumed to protect periplasmic proteins against secreted AprA. We set out to study the enzyme-inhibitor interactions in more detail in order to provide a basis for future drug development. Structural and mutational studies reveal that the conserved N-terminal residues of AprI occupy the protease active site and are essential for inhibitory activity. We constructed peptides mimicking the N-terminus of AprI; however, these were incapable of inhibiting AprA-mediated flagellin cleavage. Furthermore, we expressed and purified AprI of P. aeruginosa and the homologous (37% sequence identity) AprI of Pseudomonas syringae, which remarkably show species specificity for their cognate protease. Exchange of the first five N-terminal residues between AprI of P. syringae and P. aeruginosa did not affect the observed specificity, whereas exchange of only six residues located at the AprI surface that contacts the protease did abolish specificity. These findings are elementary steps toward the design of molecules derived from the natural inhibitor of the virulence factor AprA and their use in therapeutic applications in Pseudomonas and other Gram-negative infections. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. Selective Enhancement of Synaptic Inhibition by Hypocretin (Orexin) in Rat Vagal Motor Neurons: Implications for Autonomic Regulation

    Science.gov (United States)

    Davis, Scott F.; Williams, Kevin W.; Xu, Weiye; Glatzer, Nicholas R.; Smith, Bret N.

    2012-01-01

    The hypocretins (orexins) are hypothalamic neuropeptides implicated in feeding, arousal, and autonomic regulation. These studies were designed to determine the actions of hypocretin peptides on synaptic transmission in the dorsal motor nucleus of the vagus nerve (DMV). Whole-cell patch-clamp recordings were made from DMV neurons in transverse slices of rat brainstem. Some of the neurons were identified as gastric-related by retrograde labeling after inoculation of the stomach wall with pseudorabies virus 152, a viral label that reports enhanced green fluorescent protein. Consistent with previous findings, hypocretins caused an inward current (6–68 pA) in most neurons at holding potentials near rest. In addition, the frequency of spontaneous IPSCs was increased in a concentration-related manner (up to 477%), with little change in EPSCs. This effect was preserved in the presence of tetrodotoxin, suggesting a presynaptic site of action. Hypocretins increased the amplitude of IPSCs evoked by electrical stimulation of the nucleus tractus solitarius (NTS) but not evoked EPSCs. Hypocretin-induced increases in the frequency of IPSCs evoked by photoactivation of caged glutamate within the NTS were also observed. Identical effects of the peptides were observed in identified gastric-related and unlabeled DMV neurons. In contrast to some previous studies, which have reported primarily excitatory actions of the hypocretins in many regions of the CNS, these data support a role for hypocretin in preferentially enhancing synaptic inhibition, including inhibitory inputs arising from neurons in the NTS. These findings indicate that the hypocretins can modulate and coordinate visceral autonomic output by acting directly on central vagal circuits. PMID:12736355

  16. Mechanism of selective VEGF-A binding by neuropilin-1 reveals a basis for specific ligand inhibition.

    Directory of Open Access Journals (Sweden)

    Matthew W Parker

    Full Text Available Neuropilin (Nrp receptors function as essential cell surface receptors for the Vascular Endothelial Growth Factor (VEGF family of proangiogenic cytokines and the semaphorin 3 (Sema3 family of axon guidance molecules. There are two Nrp homologues, Nrp1 and Nrp2, which bind to both overlapping and distinct members of the VEGF and Sema3 family of molecules. Nrp1 specifically binds the VEGF-A(164/5 isoform, which is essential for developmental angiogenesis. We demonstrate that VEGF-A specific binding is governed by Nrp1 residues in the b1 coagulation factor domain surrounding the invariant Nrp C-terminal arginine binding pocket. Further, we show that Sema3F does not display the Nrp-specific binding to the b1 domain seen with VEGF-A. Engineered soluble Nrp receptor fragments that selectively sequester ligands from the active signaling complex are an attractive modality for selectively blocking the angiogenic and chemorepulsive functions of Nrp ligands. Utilizing the information on Nrp ligand binding specificity, we demonstrate Nrp constructs that specifically sequester Sema3 in the presence of VEGF-A. This establishes that unique mechanisms are used by Nrp receptors to mediate specific ligand binding and that these differences can be exploited to engineer soluble Nrp receptors with specificity for Sema3.

  17. Alpha-conotoxin analogs with additional positive charge show increased selectivity towards Torpedo californica and some neuronal subtypes of nicotinic acetylcholine receptors

    NARCIS (Netherlands)

    Kasheverov, I.E.; Zhmak, M.N.; Vulfius, C.A.; Corbacheva, E.V.; Mordvintsev, D.Y.; Utkin, Y.N.; van Elk, R.; Smit, A.B.; Tsetlin, V.I.

    2006-01-01

    α-Conotoxins from Conus snails are indispensable tools for distinguishing various subtypes of nicotinic acetylcholine receptors (nAChRs), and synthesis of α-conotoxin analogs may yield novel antagonists of higher potency and selectivity. We incorporated additional positive charges into α-conotoxins

  18. A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain.

    Science.gov (United States)

    Makino, Hiroto; Seki, Shoji; Yahara, Yasuhito; Shiozawa, Shunichi; Aikawa, Yukihiko; Motomura, Hiraku; Nogami, Makiko; Watanabe, Kenta; Sainoh, Takeshi; Ito, Hisakatsu; Tsumaki, Noriyuki; Kawaguchi, Yoshiharu; Yamazaki, Mitsuaki; Kimura, Tomoatsu

    2017-12-05

    Intervertebral disc (IVD) degeneration is a major cause of low back pain. The transcription factor c-Fos/Activator Protein-1 (AP-1) controls the expression of inflammatory cytokines and matrix metalloproteinases (MMPs) that contribute to the pathogenesis IVD degeneration. We investigated the effects of inhibition of c-Fos/AP-1 on IVD degeneration and associated pain. A selective inhibitor, T-5224, significantly suppressed the interleukin-1β-induced up-regulation of Mmp-3, Mmp-13 and Adamts-5 transcription in human nucleus pulposus cells and in a mouse explant culture model of IVD degeneration. We used a tail disc percutaneous needle puncture method to further assess the effects of oral administration of T-5224 on IVD degeneration. Analysis of disc height, T2-magnetic resonance imaging (MRI) findings, and histology revealed that IVD degeneration was significantly mitigated by T-5224. Further, oral administration of T-5224 ameliorated pain as indicated by the extended tail-flick latency in response to heat stimulation of rats with needle-puncture-induced IVD degeneration. These findings suggest that the inhibition of c-Fos/AP-1 prevents disc degeneration and its associated pain and that T-5224 may serve as a drug for the prevention of IVD degeneration.

  19. Phage display selection of fully human antibody fragments to inhibit growth-promoting effects of glycine-extended gastrin 17 on human colorectal cancer cells.

    Science.gov (United States)

    Khajeh, Shirin; Tohidkia, Mohammad Reza; Aghanejad, Ayuob; Mehdipour, Tayebeh; Fathi, Farzaneh; Omidi, Yadollah

    2018-06-09

    Glycine-extended gastrin 17 (G17-Gly), a dominant processing intermediate of gastrin gene, has been implicated in the development or maintenance of colorectal cancers (CRCs). Hence, neutralizing G17-Gly activity by antibody entities can provide a potential therapeutic strategy in the patients with CRCs. To this end, we isolated fully human antibody fragments from a phage antibody library through biopanning against different epitopes of G17-Gly in order to obtain the highest possible antibody diversity. ELISA screening and sequence analysis identified 2 scFvs and 4 V L antibody fragments. Kinetic analysis of the antibody fragments by SPR revealed K D values to be in the nanomolar range (87.9-334 nM). The selected anti-G17-Gly antibody fragments were analyzed for growth inhibition and apoptotic assays in a CRC cell line, HCT-116, which is well-characterized for expressing gastrin intermediate species but not amidated gastrin. The antibody fragments exhibited significant inhibition of HCT-116 cells proliferation ranging from 36.5 to 73% of controls. Further, Annexin V/PI staining indicated that apoptosis rates of scFv H8 and V L G8 treated cells were 45.8 and 63%, respectively. Based on these results, we for the first time, demonstrated the isolation of anti-G17-Gly human scFv and V L antibodies with potential therapeutic applications in G17-Gly-responsive tumors.

  20. Evaluation of a rapid radiometric differentiation test for the Mycobacterium tuberculosis complex by selective inhibition with p-nitro-alpha-acetylamino-beta-hydroxypropiophenone

    International Nuclear Information System (INIS)

    Laszlo, A.; Siddiqi, S.H.

    1984-01-01

    This study is an evaluation of a rapid technique for the differentiation of the Mycobacterium tuberculosis complex from other mycobacteria, using p-nitro-alpha-acetylamino-beta- hydroxypropiophenone (NAP) as a selective inhibitory agent. A total of 416 coded cultures, 234 cultures belonging to the M. tuberculosis complex and 182 cultures belonging to 35 other mycobacterial species, were tested in two laboratories for p-nitro-alpha-acetylamino-beta- hydroxypropiophenone inhibition to concentrations of 5 and 10 micrograms of NAP per ml in Middlebrook 7H12 liquid medium. Two testing modes were compared: the indirect, in which a large bacterial inoculum was used from an isolated culture on a solid medium, and the direct, which used a small inoculum from 7H12 medium. A decrease or no increase in daily 14 CO 2 output as measured by a BACTEC system was considered evidence of inhibition. The data presented show that a concentration of 5 micrograms of NAP per ml can effectively separate the M. tuberculosis complex from other mycobacterial species in 4 to 6 days. The direct test data show that, unlike other conventional biochemical tests, it does not require a heavy inoculum of mycobacteria and can therefore be performed soon after growth is detected by the radiometric method

  1. Establishment of a luciferase assay-based screening system: Fumitremorgin C selectively inhibits cellular proliferation of immortalized astrocytes expressing an active form of AKT

    International Nuclear Information System (INIS)

    Wang Lei; Sasai, Ken; Akagi, Tsuyoshi; Tanaka, Shinya

    2008-01-01

    The AKT pathway is frequently activated in glioblastoma, and as such, inhibitors of this pathway could prove very useful as anti-glioblastoma therapies. Here we established immortalized astrocytes expressing Renilla luciferase as well as those expressing both an active form of AKT and firefly luciferase. Since both luciferase activities represent the numbers of corresponding cell lines, novel inhibitors of the AKT pathway can be identified by treating co-cultures containing the two types of luciferase-expressing cells with individual compounds. Indeed, such a screening system succeeded in identifying fumitremorgin C as an efficient inhibitor of the AKT pathway, which was further confirmed by the ability of fumitremorgin C to selectively inhibit the growth of immortalized astrocytes expressing an active form of AKT. The present study proposes a broadly applicable approach for identifying therapeutic agents that target the pathways and/or molecules responsible for cancer development

  2. BDNF/TrkB Signaling as a Potential Novel Target in Pediatric Brain Tumors: Anticancer Activity of Selective TrkB Inhibition in Medulloblastoma Cells.

    Science.gov (United States)

    Thomaz, Amanda; Jaeger, Mariane; Buendia, Marienela; Bambini-Junior, Victorio; Gregianin, Lauro José; Brunetto, Algemir Lunardi; Brunetto, André T; de Farias, Caroline Brunetto; Roesler, Rafael

    2016-07-01

    Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling has been associated with increased proliferative capabilities, invasiveness, and chemoresistance in several types of cancer. However, the relevance of this pathway in MB remains unknown. Here, we show that the selective TrkB inhibitor N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide (ANA-12) markedly reduced the viability and survival of human cell lines representative of different MB molecular subgroups. These findings provide the first evidence supporting further investigation of TrkB inhibition as a potential novel strategy for MB treatment.

  3. Selective inhibition of MG-63 osteosarcoma cell proliferation induced by curcumin-loaded self-assembled arginine-rich-RGD nanospheres

    Directory of Open Access Journals (Sweden)

    Chang R

    2015-05-01

    cytotoxicity against MG-63 osteosarcoma cells when compared with normal osteoblasts. We have demonstrated for the first time that APNPs can encapsulate hydrophobic curcumin in their hydrophobic cores, and curcumin-loaded APNPs could be an innovative treatment for the selective inhibition of osteosarcoma cells. Keywords: osteosarcoma, selective inhibition, curcumin, arginine-rich, arginine-glycine-aspartic acid, self-assembly

  4. The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation in the naturally selected dominant follicle in rhesus macaques.

    Science.gov (United States)

    Jensen, Jeffrey T; Zelinski, Mary B; Stanley, Jessica E; Fanton, John W; Stouffer, Richard L

    2008-04-01

    The study was conducted to determine whether the phosphodiesterase (PDE) 3 inhibitor ORG 9935 prevents the resumption of meiosis in primate oocytes during natural menstrual cycles. Regularly cycling adult female macaques (n=8) were followed during the follicular phase and then started on a 2-day treatment regimen of human recombinant gonadotropins to control the timing of ovulation. Monkeys received no further treatment (controls) or ORG 9935. Oocytes were recovered by laparoscopic follicle aspiration 27 h after an ovulatory stimulus, cultured in vitro in the absence of inhibitor and inseminated. The primary outcome was the meiotic stage of the oocyte. In six ORG 9935 cycles, five of the recovered oocytes were germinal vesicle (GV)-intact, and one exhibited GV breakdown (GVBD). In contrast, all three oocytes that recovered during control cycles were GVBD (pORG 9935-treated oocytes underwent fertilization compared with 2/3 (67%) from controls. These results demonstrate that ORG 9935 blocks resumption of meiosis in the naturally selected dominant follicle in primates and suggest that PDE3 inhibitors have potential clinical use as contraceptives in women.

  5. Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition

    Science.gov (United States)

    Frost, Julianty; Galdeano, Carles; Soares, Pedro; Gadd, Morgan S.; Grzes, Katarzyna M.; Ellis, Lucy; Epemolu, Ola; Shimamura, Satoko; Bantscheff, Marcus; Grandi, Paola; Read, Kevin D.; Cantrell, Doreen A.; Rocha, Sonia; Ciulli, Alessio

    2016-11-01

    Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.

  6. Selection Of Employees In The Metal Industry Based On Competences, On The Example Of A Designer Position

    Directory of Open Access Journals (Sweden)

    Skrzypek Katarzyna

    2015-06-01

    Full Text Available The selection of an effective team of employees is crucial to proper management of the company. The success of the project often depends on the competencies of employees who carry out those projects. Therefore, the selection of the workers, whose competences complement each other in terms of subject matter, in terms of personality, and also in practical terms, is very important. This article presents the proposal of applying the FAHP (fuzzy analytic hierarchy process and TOPSIS (technique for order preference by similarity to an ideal solution methods as a tool to facilitate the management of human resources in the metal production factories based on the skills of employees.

  7. HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice.

    Directory of Open Access Journals (Sweden)

    Thaiz Ferraz Borin

    Full Text Available A selective inhibitor of 20-HETE synthesis, HET0016, has been reported to inhibit angiogenesis. 20-HETE has been known as a second mitogenic messenger of angiogenesis inducing growth factors. HET0016 effects were analyzed on MDA-MB-231 derived breast cancer in mouse and in vitro cell line. MDA-MB-231 tumor cells were implanted in animals' right flank and randomly assigned to early (1 and 2, starting treatments on day 0, or delayed groups (3 and 4 on day 8 after implantation of tumor. Animals received HET0016 (10 mg/kg treatment via intraperitoneal injection for 5 days/week for either 3 or 4 weeks. Control group received vehicle treatment. Tumor sizes were measured on days 7, 14, 21, and 28 and the animals were euthanized on day 22 and 29. Proteins were extracted from the whole tumor and from cells treated with 10 µM HET0016 for 4 and 24 hrs. Protein array kits of 20 different cytokines/factors were used. ELISA was performed to observe the HIF-1α and MMP-2 protein expression. Other markers were confirmed by IHC. HET0016 significantly inhibited tumor growth in all treatment groups at all-time points compared to control (p<0.05. Tumor growth was completely inhibited on three of ten animals on early treatment group. Treatment groups showed significantly lower expression of pro-angiogenic factors compared to control at 21 days; however, there was no significant difference in HIF-1α expression after treatments. Similar results were found in vitro at 24 hrs of HET0016 treatment. After 28 days, significant increase of angiogenin, angiopoietin-1/2, EGF-R and IGF-1 pro-angiogenic factors were found (p<0.05 compared to control, as well as an higher intensity of all factors were found when compared to that of 21 day's data, suggesting a treatment resistance. HET0016 inhibited tumor growth by reducing expression of different set of pro-angiogenic factors; however, a resistance to treatment seemed to happen after 21 days.

  8. Sequence-selective topoisomerase II inhibition by anthracycline derivatives in SV40 DNA: Relationship with DNA binding affinity and cytotoxicity

    International Nuclear Information System (INIS)

    Capranico, G.; Kohn, K.W.; Pommier, Y.; Zunino, F.

    1990-01-01

    Topoisomerase II mediated double-strand breaks produced by anthracycline analogues were studied in SV40 DNA. The compounds included doxorubicin, daunorubicin, two doxorubicin stereoisomers (4'-epimer and β-anomer), and five chromophore-modified derivatives, with a wide range of cytotoxic activity and DNA binding affinity. Cleavage of 32 P-end-labeled DNA fragments was visualized by autoradiography of agarose and polyacrylamide gels. Structure-activity relationships indicated that alterations in the chromophore structure greatly affected drug action on topoisomerase II. In particular, removal of substituents on position 4 of the D ring resulted in more active inducers of cleavage with lower DNA binding affinity. The stereochemistry between the sugar and the chromophore was also essential for activity. All the active anthracyclines induced a single region of prominent cleavage in the entire SV40 DNA, which resulted from a cluster of sites between nucleotides 4237 and 4294. DNA cleavage intensity patterns exhibited differences among analogues and were also dependent upon drug concentration. Intensity at a given site dependent on both stimulatory and suppressive effects depending upon drug concentration and DNA sequence. A good correlation was found between cytotoxicity and intensity of topoisomerase II mediated DNA breakage

  9. Positive Side Effects in the Treatment of SIB Using the Self-Injurious Behavior Inhibiting System (SIBIS): Implications for Operant and Biochemical Explanations of SIB.

    Science.gov (United States)

    Linscheid, Thomas R.; And Others

    1994-01-01

    The rate of self-injurious head hitting in an eight-year old with severe/profound mental retardation was reduced using contingent electric shock delivered via the Self Injurious Behavior Inhibiting System. An improved affective state and increased interaction with the environment were documented. Treatment gai