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Sample records for activity modulates codon

  1. Adjacent Codons Act in Concert to Modulate Translation Efficiency in Yeast.

    Science.gov (United States)

    Gamble, Caitlin E; Brule, Christina E; Dean, Kimberly M; Fields, Stanley; Grayhack, Elizabeth J

    2016-07-28

    Translation elongation efficiency is largely thought of as the sum of decoding efficiencies for individual codons. Here, we find that adjacent codon pairs modulate translation efficiency. Deploying an approach in Saccharomyces cerevisiae that scored the expression of over 35,000 GFP variants in which three adjacent codons were randomized, we have identified 17 pairs of adjacent codons associated with reduced expression. For many pairs, codon order is obligatory for inhibition, implying a more complex interaction than a simple additive effect. Inhibition mediated by adjacent codons occurs during translation itself as GFP expression is restored by increased tRNA levels or by non-native tRNAs with exact-matching anticodons. Inhibition operates in endogenous genes, based on analysis of ribosome profiling data. Our findings suggest translation efficiency is modulated by an interplay between tRNAs at adjacent sites in the ribosome and that this concerted effect needs to be considered in predicting the functional consequences of codon choice. PMID:27374328

  2. Suppression of galactocerebrosidase premature termination codon and rescue of galactocerebrosidase activity in twitcher cells.

    Science.gov (United States)

    Luddi, Alice; Crifasi, Laura; Capaldo, Angela; Piomboni, Paola; Costantino-Ceccarini, Elvira

    2016-11-01

    Krabbe's disease (KD) is a degenerative lysosomal storage disease resulting from deficiency of β-galactocerebrosidase activity. Over 100 mutations are known to cause the disease, and these usually occur in compound heterozygote patterns. In affected patients, nonsense mutations leading to a nonfunctional enzyme are often found associated with other mutations. The twitcher mouse is a naturally occurring model of KD, containing in β-galactocerebrosidase a premature stop codon, W339X. Recent studies have shown that selected compounds may induce the ribosomal bypass of premature stop codons without affecting the normal termination codons. The rescue of β-galactocerebrosidase activity induced by treatment with premature termination codon (PTC) 124, a well-characterized compound known to induce ribosomal read-through, was investigated on oligodendrocytes prepared from twitcher mice and on human fibroblasts from patients bearing nonsense mutations. The effectiveness of the nonsense-mediated mRNA decay (NMD) inhibitor 1 (NMDI1), a newly identified inhibitor of NMD, was also tested. Incubation of these cell lines with PTC124 and NMDI1 increased the levels of mRNA and rescued galactocerebrosidase enzymatic activity in a dose-dependent manner. The low but sustained expression of β-galactocerebrosidase in oligodendrocytes was sufficient to improve the morphology of the differentiated cells. Our in vitro approach provides the basis for further investigation of ribosomal read-through as an alternative therapeutic strategy to ameliorate the quality of life in selected KD patients. © 2016 Wiley Periodicals, Inc. PMID:27638609

  3. Exploring codon optimization and response surface methodology to express biologically active transmembrane RANKL in E. coli.

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    Sushila Maharjan

    Full Text Available Receptor activator of nuclear factor (NF-κB ligand (RANKL, a master cytokine that drives osteoclast differentiation, activation and survival, exists in both transmembrane and extracellular forms. To date, studies on physiological role of RANKL have been mainly carried out with extracellular RANKL probably due to difficulties in achieving high level expression of functional transmembrane RANKL (mRANKL. In the present study, we took advantage of codon optimization and response surface methodology to optimize the soluble expression of mRANKL in E. coli. We optimized the codon usage of mRANKL sequence to a preferred set of codons for E. coli changing its codon adaptation index from 0.64 to 0.76, tending to increase its expression level in E. coli. Further, we utilized central composite design to predict the optimum combination of variables (cell density before induction, lactose concentration, post-induction temperature and post-induction time for the expression of mRANKL. Finally, we investigated the effects of various experimental parameters using response surface methodology. The best combination of response variables was 0.6 OD600, 7.5 mM lactose, 26°C post-induction temperature and 5 h post-induction time that produced 52.4 mg/L of fusion mRANKL. Prior to functional analysis of the protein, we purified mRANKL to homogeneity and confirmed the existence of trimeric form of mRANKL by native gel electrophoresis and gel filtration chromatography. Further, the biological activity of mRANKL to induce osteoclast formation on RAW264.7 cells was confirmed by tartrate resistant acid phosphatase assay and quantitative real-time polymerase chain reaction assays. Importantly, a new finding from this study was that the biological activity of mRANKL is higher than its extracellular counterpart. To the best of our knowledge, this is the first time to report heterologous expression of mRANKL in soluble form and to perform a comparative study of functional

  4. Experimentally increased codon bias in the Drosophila Adh gene leads to an increase in larval, but not adult, alcohol dehydrogenase activity.

    Science.gov (United States)

    Hense, Winfried; Anderson, Nathan; Hutter, Stephan; Stephan, Wolfgang; Parsch, John; Carlini, David B

    2010-02-01

    Although most amino acids can be encoded by more than one codon, the synonymous codons are not used with equal frequency. This phenomenon is known as codon bias and appears to be a universal feature of genomes. The translational selection hypothesis posits that the use of optimal codons, which match the most abundant species of isoaccepting tRNAs, results in increased translational efficiency and accuracy. Previous work demonstrated that the experimental reduction of codon bias in the Drosophila alcohol dehydrogenase (Adh) gene led to a significant decrease in ADH protein expression. In this study we performed the converse experiment: we replaced seven suboptimal leucine codons that occur naturally in the Drosophila melanogaster Adh gene with the optimal codon. We then compared the in vivo ADH activities imparted by the wild-type and mutant alleles. The introduction of optimal leucine codons led to an increase in ADH activity in third-instar larvae. In adult flies, however, the introduction of optimal codons led to a decrease in ADH activity. There is no evidence that other selectively constrained features of the Adh gene, or its rate of transcription, were altered by the synonymous replacements. These results are consistent with translational selection for codon bias being stronger in the larval stage and suggest that there may be a selective conflict over optimal codon usage between different developmental stages.

  5. Transforming activity of the c-Ha-ras oncogene having two point mutations in codons 12 and 61.

    Science.gov (United States)

    Sekiya, T; Prassolov, V S; Fushimi, M; Nishimura, S

    1985-09-01

    A recombinant plasmid carrying the human c-Ha-ras gene with two point mutations in codons 12 and 61 was constructed and its transforming activity on mouse NIH 3T3 cells was compared with those of genes with a single mutation in either codon 12 or 61. Quantitative analyses revealed that the gene with two mutations had essentially the same transforming activity as the genes with single mutations. These results indicate that a single mutation of the c-Ha-ras gene in either codon 12 or 61 is sufficient to activate the gene and that neither of the two mutation sites involved in activation of the gene needs to be intact for transforming activity.

  6. Role of codon usage and tRNA changes in rat cytomegalovirus latency and (re)activation.

    Science.gov (United States)

    Kanduc, Darja

    2016-06-01

    Herpesviruses can remain in their hosts by establishing a latent infection with a low pattern of viral gene expression. Passage from latency to reactivation may occur under particular conditions such as immunosuppressive treatments or during fetal development, and often is accompanied by heavy pathologic sequelae. To investigate the molecular basis underlying herpesvirus latency and (re)activation, codon usage of rat cytomegalovirus was comparatively analyzed with respect to the rat codon usage. Two major points stand out as follows: (i) six codons - GCG (Ala), CCG (Pro), CGG (Arg), CGC (Arg), TCG (Ser), and ACG (Thr) - are rare in rat genes and intensively used in rat cytomegalovirus coding sequences; (ii) in many instances, the codons seldom used by the host are clustered along viral sequences coding for single amino acid repeats such as poly-Ala and poly-Thr stretches. The results indicate that rare host codons and their iteration along viral sequences might represent major constraints that lock rat cytomegalovirus translation in its host during the viral latent phase. Consequently, the data also suggest a link between rat cytomegalovirus quiescence/activation and the functional tRNA coadaptation phenomenon. Indeed, increases in minor tRNA species corresponding to rare rat codons mark rat cell proliferation and might rescue difficult viral translational contexts. Ala isoaccepting-tRNA (CGC) is reported as an example. On the whole, the present findings may contribute to explain how the molecular mechanisms that normally control host gene expression can silence/(re)activate viral gene expression, and might address research toward new approaches in anti-viral therapeutics. PMID:26875974

  7. Empirical codon substitution matrix

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    Gonnet Gaston H

    2005-06-01

    Full Text Available Abstract Background Codon substitution probabilities are used in many types of molecular evolution studies such as determining Ka/Ks ratios, creating ancestral DNA sequences or aligning coding DNA. Until the recent dramatic increase in genomic data enabled construction of empirical matrices, researchers relied on parameterized models of codon evolution. Here we present the first empirical codon substitution matrix entirely built from alignments of coding sequences from vertebrate DNA and thus provide an alternative to parameterized models of codon evolution. Results A set of 17,502 alignments of orthologous sequences from five vertebrate genomes yielded 8.3 million aligned codons from which the number of substitutions between codons were counted. From this data, both a probability matrix and a matrix of similarity scores were computed. They are 64 × 64 matrices describing the substitutions between all codons. Substitutions from sense codons to stop codons are not considered, resulting in block diagonal matrices consisting of 61 × 61 entries for the sense codons and 3 × 3 entries for the stop codons. Conclusion The amount of genomic data currently available allowed for the construction of an empirical codon substitution matrix. However, more sequence data is still needed to construct matrices from different subsets of DNA, specific to kingdoms, evolutionary distance or different amount of synonymous change. Codon mutation matrices have advantages for alignments up to medium evolutionary distances and for usages that require DNA such as ancestral reconstruction of DNA sequences and the calculation of Ka/Ks ratios.

  8. Codon Adaptation of Plastid Genes

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    Suzuki, Haruo; Morton, Brian R.

    2016-01-01

    Codon adaptation is codon usage bias that results from selective pressure to increase the translation efficiency of a gene. Codon adaptation has been studied across a wide range of genomes and some early analyses of plastids have shown evidence for codon adaptation in a limited set of highly expressed plastid genes. Here we study codon usage bias across all fully sequenced plastid genomes which includes representatives of the Rhodophyta, Alveolata, Cryptophyta, Euglenozoa, Glaucocystophyceae, Rhizaria, Stramenopiles and numerous lineages within the Viridiplantae, including Chlorophyta and Embryophyta. We show evidence that codon adaptation occurs in all genomes except for two, Theileria parva and Heicosporidium sp., both of which have highly reduced gene contents and no photosynthesis genes. We also show evidence that selection for codon adaptation increases the representation of the same set of codons, which we refer to as the adaptive codons, across this wide range of taxa, which is probably due to common features descended from the initial endosymbiont. We use various measures to estimate the relative strength of selection in the different lineages and show that it appears to be fairly strong in certain Stramenopiles and Chlorophyta lineages but relatively weak in many members of the Rhodophyta, Euglenozoa and Embryophyta. Given these results we propose that codon adaptation in plastids is widespread and displays the same general features as adaptation in eubacterial genomes. PMID:27196606

  9. Codon Adaptation of Plastid Genes.

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    Haruo Suzuki

    Full Text Available Codon adaptation is codon usage bias that results from selective pressure to increase the translation efficiency of a gene. Codon adaptation has been studied across a wide range of genomes and some early analyses of plastids have shown evidence for codon adaptation in a limited set of highly expressed plastid genes. Here we study codon usage bias across all fully sequenced plastid genomes which includes representatives of the Rhodophyta, Alveolata, Cryptophyta, Euglenozoa, Glaucocystophyceae, Rhizaria, Stramenopiles and numerous lineages within the Viridiplantae, including Chlorophyta and Embryophyta. We show evidence that codon adaptation occurs in all genomes except for two, Theileria parva and Heicosporidium sp., both of which have highly reduced gene contents and no photosynthesis genes. We also show evidence that selection for codon adaptation increases the representation of the same set of codons, which we refer to as the adaptive codons, across this wide range of taxa, which is probably due to common features descended from the initial endosymbiont. We use various measures to estimate the relative strength of selection in the different lineages and show that it appears to be fairly strong in certain Stramenopiles and Chlorophyta lineages but relatively weak in many members of the Rhodophyta, Euglenozoa and Embryophyta. Given these results we propose that codon adaptation in plastids is widespread and displays the same general features as adaptation in eubacterial genomes.

  10. Codon Adaptation of Plastid Genes.

    Science.gov (United States)

    Suzuki, Haruo; Morton, Brian R

    2016-01-01

    Codon adaptation is codon usage bias that results from selective pressure to increase the translation efficiency of a gene. Codon adaptation has been studied across a wide range of genomes and some early analyses of plastids have shown evidence for codon adaptation in a limited set of highly expressed plastid genes. Here we study codon usage bias across all fully sequenced plastid genomes which includes representatives of the Rhodophyta, Alveolata, Cryptophyta, Euglenozoa, Glaucocystophyceae, Rhizaria, Stramenopiles and numerous lineages within the Viridiplantae, including Chlorophyta and Embryophyta. We show evidence that codon adaptation occurs in all genomes except for two, Theileria parva and Heicosporidium sp., both of which have highly reduced gene contents and no photosynthesis genes. We also show evidence that selection for codon adaptation increases the representation of the same set of codons, which we refer to as the adaptive codons, across this wide range of taxa, which is probably due to common features descended from the initial endosymbiont. We use various measures to estimate the relative strength of selection in the different lineages and show that it appears to be fairly strong in certain Stramenopiles and Chlorophyta lineages but relatively weak in many members of the Rhodophyta, Euglenozoa and Embryophyta. Given these results we propose that codon adaptation in plastids is widespread and displays the same general features as adaptation in eubacterial genomes. PMID:27196606

  11. The human c-Kirsten ras gene is activated by a novel mutation in codon 13 in the breast carcinoma cell line MDA-MB231.

    OpenAIRE

    Kozma, S C; Bogaard, M E; Buser, K; Saurer, S M; Bos, J. L.; Groner, B; Hynes, N E

    1987-01-01

    We have detected amplified human Ki-ras sequences in tumorigenic NIH 3T3 cells transfected with genomic DNA from the human breast carcinoma cell line MDA-MB231. Hybridization of synthetic oligonucleotides specific for human Ki-ras sequences showed a mutation at codon 13. The polymerase chain reaction with Ki-ras specific amplimers revealed a guanosine to adenosine transition at the second position of codon 13, resulting in a substitution of glycine by aspartic acid. The codon 13 mutation is a...

  12. Modulation of Emotion by Cognitive Activity

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    Saea Iida

    2013-09-01

    Full Text Available While emotions themselves are beneficial for our survival, they are also the targets to be regulated appropriately to adapt to social environments. Previous studies have demonstrated that cognitive strategies such as cognitive reappraisal and expressive suppression can effectively enhance and attenuate emotions. Such cognitive strategies of emotion regulation are based on cortical modulation of sub-cortical emotion-related brain regions. Though in the prior studies emotion regulation was conducted in parallel with or after the emotion elicitation, a series of our studies showed that prior cognitive activities can automatically and unintentionally attenuate subsequent emotional responses. In this article, after reviewing the previous findings about emotion regulation, we introduce our empirical findings showing that cognitive activities where the neural system of emotion regulation would be recruited can unintentionally and automatically dampen psychological and physiological emotional responses. Finally, we propose possible neural mechanisms underlying modulation of emotion by cognitive activity.

  13. Distribution of ADAT-Dependent Codons in the Human Transcriptome

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    Àlbert Rafels-Ybern

    2015-07-01

    Full Text Available Nucleotide modifications in the anticodons of transfer RNAs (tRNA play a central role in translation efficiency, fidelity, and regulation of translation, but, for most of these modifications, the details of their function remain unknown. The heterodimeric adenosine deaminases acting on tRNAs (ADAT2-ADAT3, or ADAT are enzymes present in eukaryotes that convert adenine (A to inosine (I in the first anticodon base (position 34 by hydrolytic deamination. To explore the influence of ADAT activity on mammalian translation, we have characterized the human transcriptome and proteome in terms of frequency and distribution of ADAT-related codons. Eight different tRNAs can be modified by ADAT and, once modified, these tRNAs will recognize NNC, NNU and NNA codons, but not NNG codons. We find that transcripts coding for proteins highly enriched in these eight amino acids (ADAT-aa are specifically enriched in NNC, NNU and NNA codons. We also show that the proteins most enriched in ADAT-aa are composed preferentially of threonine, alanine, proline, and serine (TAPS. We propose that the enrichment in ADAT-codons in these proteins is due to the similarities in the codons that correspond to TAPS.

  14. Comparative analysis of codon usage bias and codon context patterns between dipteran and hymenopteran sequenced genomes.

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    Susanta K Behura

    Full Text Available BACKGROUND: Codon bias is a phenomenon of non-uniform usage of codons whereas codon context generally refers to sequential pair of codons in a gene. Although genome sequencing of multiple species of dipteran and hymenopteran insects have been completed only a few of these species have been analyzed for codon usage bias. METHODS AND PRINCIPAL FINDINGS: Here, we use bioinformatics approaches to analyze codon usage bias and codon context patterns in a genome-wide manner among 15 dipteran and 7 hymenopteran insect species. Results show that GAA is the most frequent codon in the dipteran species whereas GAG is the most frequent codon in the hymenopteran species. Data reveals that codons ending with C or G are frequently used in the dipteran genomes whereas codons ending with A or T are frequently used in the hymenopteran genomes. Synonymous codon usage orders (SCUO vary within genomes in a pattern that seems to be distinct for each species. Based on comparison of 30 one-to-one orthologous genes among 17 species, the fruit fly Drosophila willistoni shows the least codon usage bias whereas the honey bee (Apis mellifera shows the highest bias. Analysis of codon context patterns of these insects shows that specific codons are frequently used as the 3'- and 5'-context of start and stop codons, respectively. CONCLUSIONS: Codon bias pattern is distinct between dipteran and hymenopteran insects. While codon bias is favored by high GC content of dipteran genomes, high AT content of genes favors biased usage of synonymous codons in the hymenopteran insects. Also, codon context patterns vary among these species largely according to their phylogeny.

  15. Solar active envelope module with an adjustable transmittance/absorptance

    OpenAIRE

    C. Villasante Villasante; I. del Hoyo; Pagola, I. (I.); Sanchez, M.; E. Aranzabe

    2015-01-01

    A solar active envelope module with a high flexibility degree is proposed in this paper. The transparent module controls the day-lighting of the room, improving the indoor environment, while absorbing the superfluous solar energy inside. That energy is used to increase the efficiency of heating, ventilation, and the air-conditioning (HVAC) system of the building. This is carried out through a fine control of the absorptance of the envelope module. The active envelope module consists of three ...

  16. Is there a close relationship between synonymous codon bias and codon-anticodon binding strength in human genes?

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Synonymous codon bias has been examined in 78 human genes (19967 codons) and measured by relative synonymous codon usage (RSCU). Relative frequencies of all kinds of dinucleotides in 2,3 or 3,4 codon positions have been calculated, and codon-anticodon binding strength has been estimated by the stacking energies of codon-anticodon bases in Watson-Crick pairs. The data show common features in synonymous codon bias for all codon families in human genes: all C-ending codons, which possess the strongest co-don-anticodon binding energies, are the most favored codons in almost all codon families, and those codons with medium codon-anticodon binding energies are avoided. Data analysis suggests that besides isochore and genome signature , codon-anticodon binding strength may be closely related to syn-onymous codon choice in human genes. The join-effect of these factors on human genes results in the common features in codon bias.

  17. Exploring codon context bias for synthetic gene design of a thermostable invertase in Escherichia coli.

    Science.gov (United States)

    Pek, Han Bin; Klement, Maximilian; Ang, Kok Siong; Chung, Bevan Kai-Sheng; Ow, Dave Siak-Wei; Lee, Dong-Yup

    2015-01-01

    Various isoforms of invertases from prokaryotes, fungi, and higher plants has been expressed in Escherichia coli, and codon optimisation is a widely-adopted strategy for improvement of heterologous enzyme expression. Successful synthetic gene design for recombinant protein expression can be done by matching its translational elongation rate against heterologous host organisms via codon optimization. Amongst the various design parameters considered for the gene synthesis, codon context bias has been relatively overlooked compared to individual codon usage which is commonly adopted in most of codon optimization tools. In addition, matching the rates of transcription and translation based on secondary structure may lead to enhanced protein folding. In this study, we evaluated codon context fitness as design criterion for improving the expression of thermostable invertase from Thermotoga maritima in Escherichia coli and explored the relevance of secondary structure regions for folding and expression. We designed three coding sequences by using (1) a commercial vendor optimized gene algorithm, (2) codon context for the whole gene, and (3) codon context based on the secondary structure regions. Then, the codon optimized sequences were transformed and expressed in E. coli. From the resultant enzyme activities and protein yield data, codon context fitness proved to have the highest activity as compared to the wild-type control and other criteria while secondary structure-based strategy is comparable to the control. Codon context bias was shown to be a relevant parameter for enhancing enzyme production in Escherichia coli by codon optimization. Thus, we can effectively design synthetic genes within heterologous host organisms using this criterion. PMID:26047917

  18. Revision of the DELFIC Particle Activity Module

    Energy Technology Data Exchange (ETDEWEB)

    Hooper, David A [ORNL; Jodoin, Vincent J [ORNL

    2010-09-01

    The Defense Land Fallout Interpretive Code (DELFIC) was originally released in 1968 as a tool for modeling fallout patterns and for predicting exposure rates. Despite the continual advancement of knowledge of fission yields, decay behavior of fission products, and biological dosimetry, the decay data and logic of DELFIC have remained mostly unchanged since inception. Additionally, previous code revisions caused a loss of conservation of radioactive nuclides. In this report, a new revision of the decay database and the Particle Activity Module is introduced and explained. The database upgrades discussed are replacement of the fission yields with ENDF/B-VII data as formatted in the Oak Ridge Isotope Generation (ORIGEN) code, revised decay constants, revised exposure rate multipliers, revised decay modes and branching ratios, and revised boiling point data. Included decay logic upgrades represent a correction of a flaw in the treatment of the fission yields, extension of the logic to include more complex decay modes, conservation of nuclides (including stable nuclides) at all times, and conversion of key variables to double precision for nuclide conservation. Finally, recommended future work is discussed with an emphasis on completion of the overall radiation physics upgrade, particularly for dosimetry, induced activity, decay of the actinides, and fractionation.

  19. Synthetic modulators of TRP channel activity.

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    Harteneck, Christian; Klose, Chihab; Krautwurst, Dietmar

    2011-01-01

    In humans, 27 TRP channels from 6 related families contribute to a broad spectrum of cellular functions, such as thermo-, pressure-, volume-, pain- and chemosensation. Pain and inflammation-inducing compounds represent potent plant and animal defense mechanisms explaining the great variety of the naturally occurring, TRPV1-, TRPM8-, and TRPA1-activating ligands. The discovery of the first vanilloid receptor (TRPV1) and its involvement in nociception triggered the euphoria and the hope in novel therapeutic strategies treating pain, and this clear-cut indication inspired the development of TRPV1-selective ligands. On the other hand the nescience in the physiological role and putative clinical indication hampered the development of a selective drug in the case of the other TRP channels. Therefore, currently only a handful of mostly un-selective blocker is available to target TRP channels. Nevertheless, there is an ongoing quest for new, natural or synthetic ligands and modulators. In this chapter, we will give an overview on available broad-range blocker, as well as first TRP channel-selective compounds. PMID:21290290

  20. Codon optimizing for increased membrane protein production

    DEFF Research Database (Denmark)

    Mirzadeh, K.; Toddo, S.; Nørholm, Morten;

    2016-01-01

    Reengineering a gene with synonymous codons is a popular approach for increasing production levels of recombinant proteins. Here we present a minimalist alternative to this method, which samples synonymous codons only at the second and third positions rather than the entire coding sequence...

  1. Codon information value and codon transition-probability distributions in short-term evolution

    Science.gov (United States)

    Jiménez-Montaño, M. A.; Coronel-Brizio, H. F.; Hernández-Montoya, A. R.; Ramos-Fernández, A.

    2016-07-01

    To understand the way the Genetic Code and the physical-chemical properties of coded amino acids affect accepted amino acid substitutions in short-term protein evolution, taking into account only overall amino acid conservation, we consider an underlying codon-level model. This model employs codon pair-substitution frequencies from an empirical matrix in the literature, modified for single-base mutations only. Ordering the degenerated codons according to their codon information value (Volkenstein, 1979), we found that three-fold and most of four-fold degenerated codons, which have low codon values, were best fitted to rank-frequency distributions with constant failure rate (exponentials). In contrast, almost all two-fold degenerated codons, which have high codon values, were best fitted to rank-frequency distributions with variable failure rate (inverse power-laws). Six-fold degenerated codons are considered to be doubly assigned. The exceptional behavior of some codons, including non-degenerate codons, is discussed.

  2. Activated protein C modulates the proinflammatory activity of dendritic cells

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    Matsumoto T

    2015-05-01

    Full Text Available Takahiro Matsumoto,1,2* Yuki Matsushima,1* Masaaki Toda,1 Ziaurahman Roeen,1 Corina N D'Alessandro-Gabazza,1,5 Josephine A Hinneh,1 Etsuko Harada,1,3 Taro Yasuma,4 Yutaka Yano,4 Masahito Urawa,1,5 Tetsu Kobayashi,5 Osamu Taguchi,5 Esteban C Gabazza1 1Department of Immunology, Mie University Graduate School of Medicine, Tsu, Mie Prefecture, 2BONAC Corporation, BIO Factory 4F, Fukuoka, 3Iwade Research Institute of Mycology, 4Department of Endocrinology, Diabetes and Metabolism, 5Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Mie Prefecture, Japan *These authors contributed equally to this work Background: Previous studies have demonstrated the beneficial activity of activated protein C in allergic diseases including bronchial asthma and rhinitis. However, the exact mechanism of action of activated protein C in allergies is unclear. In this study, we hypothesized that pharmacological doses of activated protein C can modulate allergic inflammation by inhibiting dendritic cells. Materials and methods: Dendritic cells were prepared using murine bone marrow progenitor cells and human peripheral monocytes. Bronchial asthma was induced in mice that received intratracheal instillation of ovalbumin-pulsed dendritic cells. Results: Activated protein C significantly increased the differentiation of tolerogenic plasmacytoid dendritic cells and the secretion of type I interferons, but it significantly reduced lipopolysaccharide-mediated maturation and the secretion of inflammatory cytokines in myeloid dendritic cells. Activated protein C also inhibited maturation and the secretion of inflammatory cytokines in monocyte-derived dendritic cells. Activated protein C-treated dendritic cells were less effective when differentiating naïve CD4 T-cells from Th1 or Th2 cells, and the cellular effect of activated protein C was mediated by its receptors. Mice that received adoptive transfer of activated protein C

  3. Modulation of Emotion by Cognitive Activity

    OpenAIRE

    Saea Iida; Hiroki C. Tanabe; Takashi Nakao; Hideki Ohira

    2013-01-01

    While emotions themselves are beneficial for our survival, they are also the targets to be regulated appropriately to adapt to social environments. Previous studies have demonstrated that cognitive strategies such as cognitive reappraisal and expressive suppression can effectively enhance and attenuate emotions. Such cognitive strategies of emotion regulation are based on cortical modulation of sub-cortical emotion-related brain regions. Though in the prior studies emotion regulation was cond...

  4. Codon Bias and Mutability in HIV Sequences

    CERN Document Server

    Waelbroeck, H

    1997-01-01

    A survey of the patterns of synonymous codon preferences in the HIV env gene reveals a relation between the codon bias and the mutability requirements in different regions in the protein. At hypervariable regions in $gp120$, one finds a greater proportion of codons that tend to mutate non-synonymously, but to a target that is similar in hydrophobicity and volume. We argue that this strategy results from a compromise between the selective pressure placed on the virus by the induced immune response, which favours amino acid substitutions in the complementarity determining regions, and the negative selection against missense mutations that violate structural constraints of the env protein.

  5. A Stable Upstream Stem-loop Structure Enhances Selection of the First 5′-ORF-AUG as a Main Start Codon for Translation Initiation of Human ACAT1 mRNA

    Institute of Scientific and Technical Information of China (English)

    Li YANG; Jiang CHEN; Catherine C. Y. CHANG; Xin-Ying YANG; Zhen-Zhen WANG; Ta-Yuan CHANG; Bo-Liang LI

    2004-01-01

    Human ACAT1 cDNA K1 was first cloned and functionally expressed in 1993. There are two adjacent in-frame AUG codons, AUG1397-1399 and AUG1415-1417, at 5′-terminus of the open reading frame (ORF,nt 1397-3049) of human ACAT1 mRNA corresponding to cDNA K1. In current work, these two adjacent inframe AUGs at 5 ′-terminus of the predicted ORF (5′-ORF-AUGs) as start codons for translation initiation of human ACAT1 mRNA were characterized in detail. Codon mutations indicated that both of these two adjacent 5′-ORF-AUGs can be selected as start codons but the first 5′-ORF-AUG1397-1399 is a main start codon consistent with that of the predicted ORF of human ACAT1 mRNA. Further deletion and mutation analyses demonstrated that a stable upstream stem-loop structure enhanced the selection of the first 5 ′-ORF-AUG1397-1399 as a main start codon, in addition to upstream nucleotide A in the -3 position, which is a key site of Kozak sequence. In addition, result of ACAT1 enzymatic activity assay showed no obvious difference between these two ACAT1 proteins respectively initiated from the two adjacent 5′-ORF-AUGs. This work showed that a stable upstream stem-loop structure could modulate the start codon selection during translation initiation of mRNAs that contain adjacent multi-5′-ORF-AUGs.

  6. Wireless multi-level terahertz amplitude modulator using active metamaterial-based spatial light modulation.

    Science.gov (United States)

    Rout, Saroj; Sonkusale, Sameer

    2016-06-27

    The ever increasing demand for bandwidth in wireless communication systems will inevitably lead to the extension of operating frequencies toward the terahertz (THz) band known as the 'THz gap'. Towards closing this gap, we present a multi-level amplitude shift keying (ASK) terahertz wireless communication system using terahertz spatial light modulators (SLM) instead of traditional voltage mode modulation, achieving higher spectral efficiency for high speed communication. The fundamental principle behind this higher efficiency is the conversion of a noisy voltage domain signal to a noise-free binary spatial pattern for effective amplitude modulation of a free-space THz carrier wave. Spatial modulation is achieved using an an active metamaterial array embedded with pseudomorphic high-electron mobility (pHEMT) designed in a consumer-grade galium-arsenide (GaAs) integrated circuit process which enables electronic control of its THz transmissivity. Each array is assembled as individually controllable tiles for transmissive terahertz spatial modulation. Using the experimental data from our metamaterial based modulator, we show that a four-level ASK digital communication system has two orders of magnitude improvement in symbol error rate (SER) for a degradation of 20 dB in transmit signal-to-noise ratio (SNR) using spatial light modulation compared to voltage controlled modulation. PMID:27410614

  7. Correlation matrix for quartet codon usage

    CERN Document Server

    Frappat, L; Sorba, Paul

    2005-01-01

    It has been argued that the sum of usage probabilities for codons, belonging to quartets, that have as third nucleotide C or A, is independent of the biological species for vertebrates. The comparison between the theoretical correlation matrix derived from these sum rules and the experimentally computed matrix for 26 species shows a satisfactory agreement. The Shannon entropy, weakly depending on the biological species, gives further support. Suppression of codons containing the dinucleotides CG or AU is put in evidence.

  8. Codon usage trend in mitochondrial CYB gene.

    Science.gov (United States)

    Uddin, Arif; Chakraborty, Supriyo

    2016-07-15

    Here we reported the pattern of codon usage and the factors which influenced the codon usage pattern in mitochondrial cytochrome B (MT-CYB) gene among pisces, aves and mammals. The F1 axis of correspondence analysis showed highly significant positive correlation with nucleobases A3, C and C3 and significant negative correlation with T and T3 while F2 of correspondence analysis showed significant positive correlation with C and C3 and significant negative correlation with A and A3. From the neutrality plot, it was evident that the GC12 was influenced by mutation pressure and natural selection with a ratio of 0.10/0.90=0.11 in pisces, 0.024/0.976=0.0245 in aves and in mammals 0.215/0.785=0.273, which indicated that the role of natural selection was more than mutation pressure on structuring the bases at the first and second codon positions. Natural selection played the major role; but compositional constraint and mutation pressure also played a significant role in codon usage pattern. Analysis of codon usage pattern has contributed to the better understanding of the mechanism of distribution of codons and the evolution of MT-CYB gene. PMID:27063508

  9. Emergent rules for codon choice elucidated by editing rare arginine codons in Escherichia coli

    Science.gov (United States)

    Napolitano, Michael G.; Landon, Matthieu; Gregg, Christopher J.; Lajoie, Marc J.; Govindarajan, Lakshmi; Mosberg, Joshua A.; Kuznetsov, Gleb; Goodman, Daniel B.; Vargas-Rodriguez, Oscar; Isaacs, Farren J.; Söll, Dieter; Church, George M.

    2016-01-01

    The degeneracy of the genetic code allows nucleic acids to encode amino acid identity as well as noncoding information for gene regulation and genome maintenance. The rare arginine codons AGA and AGG (AGR) present a case study in codon choice, with AGRs encoding important transcriptional and translational properties distinct from the other synonymous alternatives (CGN). We created a strain of Escherichia coli with all 123 instances of AGR codons removed from all essential genes. We readily replaced 110 AGR codons with the synonymous CGU codons, but the remaining 13 “recalcitrant” AGRs required diversification to identify viable alternatives. Successful replacement codons tended to conserve local ribosomal binding site-like motifs and local mRNA secondary structure, sometimes at the expense of amino acid identity. Based on these observations, we empirically defined metrics for a multidimensional “safe replacement zone” (SRZ) within which alternative codons are more likely to be viable. To evaluate synonymous and nonsynonymous alternatives to essential AGRs further, we implemented a CRISPR/Cas9-based method to deplete a diversified population of a wild-type allele, allowing us to evaluate exhaustively the fitness impact of all 64 codon alternatives. Using this method, we confirmed the relevance of the SRZ by tracking codon fitness over time in 14 different genes, finding that codons that fall outside the SRZ are rapidly depleted from a growing population. Our unbiased and systematic strategy for identifying unpredicted design flaws in synthetic genomes and for elucidating rules governing codon choice will be crucial for designing genomes exhibiting radically altered genetic codes. PMID:27601680

  10. Optimal Coding Predicts Attentional Modulation of Activity in Neural Systems

    OpenAIRE

    Jaramillo, Santiago; Pearlmutter, Barak A.

    2007-01-01

    Neuronal activity in response to a fixed stimulus has been shown to change as a function of attentional state, implying that the neural code also changes with attention. We propose an information-theoretic account of such modulation: that the nervous system adapts to optimally encode sensory stimuli while taking into account the changing relevance of different features. We show using computer simulation that such modulation emerges in a coding system informed about the uneven relevance of ...

  11. Network-dependent modulation of brain activity during sleep

    OpenAIRE

    Watanabe, T.; Kan, S.; Koike, T.; Misaki, M; Konishi, S.; Miyauchi, S; Miyahsita, Y.; Masuda, N.

    2014-01-01

    Brain activity dynamically changes even during sleep. A line of neuroimaging studies has reported changes in functional connectivity and regional activity across different sleep stages such as slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. However, it remains unclear whether and how the large-scale network activity of human brains changes within a given sleep stage. Here, we investigated modulation of network activity within sleep stages by applying the pairwise maximum entropy mod...

  12. Nitroprusside modulates pulmonary vein arrhythmogenic activity

    Directory of Open Access Journals (Sweden)

    Chen Yao-Chang

    2010-03-01

    Full Text Available Abstract Background Pulmonary veins (PVs are the most important sources of ectopic beats with the initiation of paroxysmal atrial fibrillation, or the foci of ectopic atrial tachycardia and focal atrial fibrillation. Elimination of nitric oxide (NO enhances cardiac triggered activity, and NO can decrease PV arrhythmogensis through mechano-electrical feedback. However, it is not clear whether NO may have direct electrophysiological effects on PV cardiomyocytes. This study is aimed to study the effects of nitroprusside (NO donor, on the ionic currents and arrhythmogenic activity of single cardiomyocytes from the PVs. Methods Single PV cardiomyocytes were isolated from the canine PVs. The action potential and ionic currents were investigated in isolated single canine PV cardiomyocytes before and after sodium nitroprusside (80 μM, using the whole-cell patch clamp technique. Results Nitroprusside decreased PV cardiomyocytes spontaneous beating rates from 1.7 ± 0.3 Hz to 0.5 ± 0.4 Hz in 9 cells (P Conclusion Nitroprusside regulates the electrical activity of PV cardiomyocytes, which suggests that NO may play a role in PV arrhythmogenesis.

  13. [Peptidergic modulation of the hippocampus synaptic activity].

    Science.gov (United States)

    Skrebitskiĭ, V G; Kondratenko, R V; Povarov, I S; Dereviagin, V I

    2011-11-01

    Effects of two newly synthesized nootropic and anxiolytic dipeptides: Noopept and Selank on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) or Selank (2 microM) significantly increased the frequency of spike-dependent spontaneous m1PSCs, whereas spike-independent mlPSCs remained unchanged. It was suggested that both peptides mediated their effect sue to activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion, at least for Noonent. PMID:22390072

  14. Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease

    OpenAIRE

    Mittal, Seema; Cai, Yufeng; Nalam, Madhavi N.; Bolon, Daniel N. A.; Schiffer, Celia A.

    2012-01-01

    Human immunodeficiency virus Type-1 (HIV-1) protease is crucial for viral maturation and infectivity. Studies of protease dynamics suggest that the rearrangement of the hydrophobic core is essential for enzyme activity. Many mutations in the hydrophobic core are also associated with drug resistance and may modulate the core flexibility. To test the role of flexibility in protease activity, pairs of cysteines were introduced at the interfaces of flexible regions remote from the active site. Di...

  15. Epithelial sodium channel modulates platelet collagen activation.

    Science.gov (United States)

    Cerecedo, Doris; Martínez-Vieyra, Ivette; Alonso-Rangel, Lea; Benítez-Cardoza, Claudia; Ortega, Arturo

    2014-03-01

    Activated platelets adhere to the exposed subendothelial extracellular matrix and undergo a rapid cytoskeletal rearrangement resulting in shape change and release of their intracellular dense and alpha granule contents to avoid hemorrhage. A central step in this process is the elevation of the intracellular Ca(2+) concentration through its release from intracellular stores and on throughout its influx from the extracellular space. The Epithelial sodium channel (ENaC) is a highly selective Na(+) channel involved in mechanosensation, nociception, fluid volume homeostasis, and control of arterial blood pressure. The present study describes the expression, distribution, and participation of ENaC in platelet migration and granule secretion using pharmacological inhibition with amiloride. Our biochemical and confocal analysis in suspended and adhered platelets suggests that ENaC is associated with Intermediate filaments (IF) and with Dystrophin-associated proteins (DAP) via α-syntrophin and β-dystroglycan. Migration assays, quantification of soluble P-selectin, and serotonin release suggest that ENaC is dispensable for migration and alpha and dense granule secretion, whereas Na(+) influx through this channel is fundamental for platelet collagen activation.

  16. Universality and Shannon entropy of codon usage

    CERN Document Server

    Frappat, L; Sciarrino, A; Sorba, Paul

    2003-01-01

    The distribution functions of the codon usage probabilities, computed over all the available GenBank data, for 40 eukaryotic biological species and 5 chloroplasts, do not follow a Zipf law, but are best fitted by the sum of a constant, an exponential and a linear function in the rank of usage. For mitochondriae the analysis is not conclusive. A quantum-mechanics-inspired model is proposed to describe the observed behaviour. These functions are characterized by parameters that strongly depend on the total GC content of the coding regions of biological species. It is predicted that the codon usage is the same in all exonic genes with the same GC content. The Shannon entropy for codons, also strongly depending on the exonic GC content, is computed.

  17. Total Cellular RNA Modulates Protein Activity.

    Science.gov (United States)

    Majumder, Subhabrata; DeMott, Christopher M; Reverdatto, Sergey; Burz, David S; Shekhtman, Alexander

    2016-08-16

    RNA constitutes up to 20% of a cell's dry weight, corresponding to ∼20 mg/mL. This high concentration of RNA facilitates low-affinity protein-RNA quinary interactions, which may play an important role in facilitating and regulating biological processes. In the yeast Pichia pastoris, the level of ubiquitin-RNA colocalization increases when cells are grown in the presence of dextrose and methanol instead of methanol as the sole carbon source. Total RNA isolated from cells grown in methanol increases β-galactosidase activity relative to that seen with RNA isolated from cells grown in the presence of dextrose and methanol. Because the total cellular RNA content changes with growth medium, protein-RNA quinary interactions can alter in-cell protein biochemistry and may play an important role in cell adaptation, critical to many physiological and pathological states. PMID:27456029

  18. Hand gesture recognition by analysis of codons

    Science.gov (United States)

    Ramachandra, Poornima; Shrikhande, Neelima

    2007-09-01

    The problem of recognizing gestures from images using computers can be approached by closely understanding how the human brain tackles it. A full fledged gesture recognition system will substitute mouse and keyboards completely. Humans can recognize most gestures by looking at the characteristic external shape or the silhouette of the fingers. Many previous techniques to recognize gestures dealt with motion and geometric features of hands. In this thesis gestures are recognized by the Codon-list pattern extracted from the object contour. All edges of an image are described in terms of sequence of Codons. The Codons are defined in terms of the relationship between maxima, minima and zeros of curvature encountered as one traverses the boundary of the object. We have concentrated on a catalog of 24 gesture images from the American Sign Language alphabet (Letter J and Z are ignored as they are represented using motion) [2]. The query image given as an input to the system is analyzed and tested against the Codon-lists, which are shape descriptors for external parts of a hand gesture. We have used the Weighted Frequency Indexing Transform (WFIT) approach which is used in DNA sequence matching for matching the Codon-lists. The matching algorithm consists of two steps: 1) the query sequences are converted to short sequences and are assigned weights and, 2) all the sequences of query gestures are pruned into match and mismatch subsequences by the frequency indexing tree based on the weights of the subsequences. The Codon sequences with the most weight are used to determine the most precise match. Once a match is found, the identified gesture and corresponding interpretation are shown as output.

  19. Chemoprotective activity of boldine: modulation of drug-metabolizing enzymes.

    Science.gov (United States)

    Kubínová, R; Machala, M; Minksová, K; Neca, J; Suchý, V

    2001-03-01

    Possible chemoprotective effects of the naturally occurring alkaloid boldine, a major alkaloid of boldo (Peumus boldus Mol.) leaves and bark, including in vitro modulations of drug-metabolizing enzymes in mouse hepatoma Hepa-1 cell line and mouse hepatic microsomes, were investigated. Boldine manifested inhibition activity on hepatic microsomal CYP1A-dependent 7-ethoxyresorufin O-deethylase and CYP3A-dependent testosterone 6 beta-hydroxylase activities and stimulated glutathione S-transferase activity in Hepa-1 cells. In addition to the known antioxidant activity, boldine could decrease the metabolic activation of other xenobiotics including chemical mutagens. PMID:11265593

  20. Application of Discontinuous PWM Modulation in Active Power Filters

    DEFF Research Database (Denmark)

    Blaabjerg, Frede; Asiminoaei, Lucian; Rodriguez, Pedro

    2008-01-01

    Classical discontinuous pulsewidth modulations (DPWMs) may not be efficiently applied in active power filters (APFs), because it is hard to predict the peak values of the inverter current, and consequently it is difficult to calculate the position of the clamped interval, that minimizes the switc...

  1. Solar active envelope module with an adjustable transmittance/absorptance

    Directory of Open Access Journals (Sweden)

    C. Villasante Villasante

    2015-06-01

    Full Text Available A solar active envelope module with a high flexibility degree is proposed in this paper. The transparent module controls the day-lighting of the room, improving the indoor environment, while absorbing the superfluous solar energy inside. That energy is used to increase the efficiency of heating, ventilation, and the air-conditioning (HVAC system of the building. This is carried out through a fine control of the absorptance of the envelope module. The active envelope module consists of three glazed chambers with advanced coatings and frames to assure a minimum thermal transmittance while allowing transparency. A fluid containing heat-absorbing nanoparticles flows inside the central chamber and is heated up due to the impinging solar energy. Unlike other systems proposed in the past, which included transparency control systems based on complex filters and chemical processes, the absorption of the module is controlled by the variation of the thickness of the central chamber with a mechanical device. That is, varying the thickness of the central chamber, it allows controlling the absorptance of the whole system and, as a result, indoor day-lighting and thermal loads. Therefore, a new system is proposed that enables to:  

  2. Hydrophobic Core Flexibility Modulates Enzyme Activity in HIV-1 Protease

    Energy Technology Data Exchange (ETDEWEB)

    Mittal, Seema; Cai, Yufeng; Nalam, Madhavi N.L.; Bolon, Daniel N.A.; Schiffer, Celia A. (UMASS, MED)

    2012-09-11

    Human immunodeficiency virus Type-1 (HIV-1) protease is crucial for viral maturation and infectivity. Studies of protease dynamics suggest that the rearrangement of the hydrophobic core is essential for enzyme activity. Many mutations in the hydrophobic core are also associated with drug resistance and may modulate the core flexibility. To test the role of flexibility in protease activity, pairs of cysteines were introduced at the interfaces of flexible regions remote from the active site. Disulfide bond formation was confirmed by crystal structures and by alkylation of free cysteines and mass spectrometry. Oxidized and reduced crystal structures of these variants show the overall structure of the protease is retained. However, cross-linking the cysteines led to drastic loss in enzyme activity, which was regained upon reducing the disulfide cross-links. Molecular dynamics simulations showed that altered dynamics propagated throughout the enzyme from the engineered disulfide. Thus, altered flexibility within the hydrophobic core can modulate HIV-1 protease activity, supporting the hypothesis that drug resistant mutations distal from the active site can alter the balance between substrate turnover and inhibitor binding by modulating enzyme activity.

  3. Neuronal modulation of calcium channel activity in cultured rat astrocytes.

    OpenAIRE

    Corvalan, V; Cole, R; de Vellis, J.; Hagiwara, S.

    1990-01-01

    The patch-clamp technique was used to study whether cocultivation of neurons and astrocytes modulates the expression of calcium channel activity in astrocytes. Whole-cell patch-clamp recordings from rat brain astrocytes cocultured with rat embryonic neurons revealed two types of voltage-dependent inward currents carried by Ca2+ and blocked by either Cd2+ or Co2+ that otherwise were not detected in purified astrocytes. This expression of calcium channel activity in astrocytes was neuron depend...

  4. Contextual modulation of hippocampal activity during picture naming.

    Science.gov (United States)

    Llorens, A; Dubarry, A-S; Trébuchon, A; Chauvel, P; Alario, F-X; Liégeois-Chauvel, C

    2016-08-01

    Picture naming is a standard task used to probe language processes in healthy and impaired speakers. It recruits a broad neural network of language related areas, among which the hippocampus is rarely included. However, the hippocampus could play a role during picture naming, subtending, for example, implicit learning of the links between pictured objects and their names. To test this hypothesis, we recorded hippocampal activity during plain picture naming, without memorization requirement; we further assessed whether this activity was modulated by contextual factors such as repetition priming and semantic interference. Local field potentials recorded from intracerebral electrodes implanted in the healthy hippocampi of epileptic patients revealed a specific and reliable pattern of activity, markedly modulated by repetition priming and semantic context. These results indicate that the hippocampus is recruited during picture naming, presumably in relation to implicit learning, with contextual factors promoting differential hippocampal processes, possibly subtended by different sub-circuitries. PMID:27380274

  5. Optimized Pulse Width Modulation for transformerless active-NPC inverters

    DEFF Research Database (Denmark)

    Achilladelis, Nikolaos; Koutroulis, Eftichios; Blaabjerg, Frede

    2014-01-01

    The transformerless DC/AC inverter topologies are employed in Photovoltaic systems in order to improve the power conversion efficiency, power density and cost. The Active-Neutral Point Clamped (Active-NPC) transformerless inverters have the advantage of achieving better thermal balance among...... their power semiconductors. In this paper, a new modulation technique is proposed for optimally controlling the power switches employed in transformerless Active-NPC inverters. The design results demonstrate that compared to the existing PWM strategies, using the proposed method results in lower total power...

  6. Prion protein gene analysis in three kindreds with fatal familial insomnia (FFI): Codon 178 mutation and codon 129 polymorphism

    Energy Technology Data Exchange (ETDEWEB)

    Medori, R.; Tritschler, H.J. (Universita di Bologna (Italy))

    1993-10-01

    Fatal familial insomnia (FFI) is a disease linked to a GAC(Asp) [yields] AAC(Asn) mutation in codon 178 of the prion protein (PrP) gene. FFI is characterized clinically by untreatable progressive insomnia, dysautonomia, and motor dysfunctions and is characterized pathologically by selective thalamic atrophy. The authors confirmed the 178[sup Asn] mutation in the PrP gene of a third FFI family of French ancestry. Three family members who are under 40 years of age and who inherited the mutation showed only reduced perfusion in the basal ganglia on single photon emission computerized tomography. Some FFI features differ from the clinical and neuropathologic findings associated with 178[sup Asn] reported elsewhere. However, additional intragenic mutations accounting for the phenotypic differences were not observed in two affected individuals. In other sporadic and familial forms of Creutzfeldt-Jakob disease and Gerstmann-Straeussler syndrome, Met or Val homozygosity at polymorphic codon 129 is associated with a more severe phenotype, younger age at onset, and faster progression. In FFI, young and old individuals at disease onset had 129[sup Met/Val]. Moreover, of five 178[sup Asn] individuals who are above age-at-onset range and who are well, two have 129[sup Met] and three have 129[sup Met/Val], suggesting that polymorphic site 129 does not modulate FFI phenotypic expression. Genetic heterogeneity and environment may play an important role in inter- and intrafamilial variability of the 178[sup Asn] mutation. 32 refs., 5 figs., 1 tab.

  7. Capsaicin modulates proliferation, migration, and activation of hepatic stellate cells.

    Science.gov (United States)

    Bitencourt, Shanna; Mesquita, Fernanda; Basso, Bruno; Schmid, Júlia; Ferreira, Gabriela; Rizzo, Lucas; Bauer, Moises; Bartrons, Ramon; Ventura, Francesc; Rosa, Jose Luis; Mannaerts, Inge; van Grunsven, Leo Adrianus; Oliveira, Jarbas

    2014-03-01

    Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and anti-inflammatory effects on a variety of cell lines. In the current study, we aimed to investigate the effects of capsaicin during HSC activation and maintenance. Activated and freshly isolated HSCs were treated with capsaicin. Proliferation was measured by incorporation of EdU. Cell cycle arrest and apoptosis were investigated using flow cytometry. The migratory response to chemotactic stimuli was evaluated by a modified Boyden chamber assay. Activation markers and inflammatory cytokines were determined by qPCR, immunocytochemistry, and flow cytometry. Our results show that capsaicin reduces HSC proliferation, migration, and expression of profibrogenic markers of activated and primary mouse HSCs. In conclusion, the present study shows that capsaicin modulates proliferation, migration, and activation of HSC in vitro. PMID:23955514

  8. Active removal of large massive objects by hybrid propulsion module

    OpenAIRE

    Luigi T. De Luca; Lavagna, Mich?le; Maggi, Filippo; Tadini, Pietro; Pardini, Carmen; Anselmo, Luciano; Grassi, Michele; Tancredi, Urbano; Francesconi, Alessandro; Chiesa, Sergio; Viola, Nicole; Bonnal, Christophe

    2013-01-01

    This paper deals with the feasibility study of a mission for the active removal of a large massive object, such as the second stage of the Zenit launcher or the Envisat spacecraft, abandoned in the most populated orbit region in low Earth orbit. Critical mission aspects and related technologies are investigated at a preliminary level. In particular, an innovative electro-adhesive system for target capture, mechanical systems for chaser-debris hard docking and a hybrid propulsion module for re...

  9. Target cell-specific modulation of neuronal activity by astrocytes

    OpenAIRE

    Kozlov, A. S.; Angulo, M. C.; Audinat, E.; Charpak, S

    2006-01-01

    Interaction between astrocytes and neurons enriches the behavior of brain circuits. By releasing glutamate and ATP, astrocytes can directly excite neurons and modulate synaptic transmission. In the rat olfactory bulb, we demonstrate that the release of GABA by astrocytes causes long-lasting and synchronous inhibition of mitral and granule cells. In addition, astrocytes release glutamate, leading to a selective activation of granule-cell NMDA receptors. Thus, by releasing excitatory and inhibi...

  10. Stop Codon Reassignment in the Wild

    Energy Technology Data Exchange (ETDEWEB)

    Ivanova, Natalia [Lawrence Berkeley National Lab. (LBNL), Walnut Creek, CA (United States). Dept. of Energy Joint Genome Inst.; Schwientek, Patrick [Lawrence Berkeley National Lab. (LBNL), Walnut Creek, CA (United States). Dept. of Energy Joint Genome Inst.; Tripp, H. James [Lawrence Berkeley National Lab. (LBNL), Walnut Creek, CA (United States). Dept. of Energy Joint Genome Inst.; Rinke, Christian [Lawrence Berkeley National Lab. (LBNL), Walnut Creek, CA (United States). Dept. of Energy Joint Genome Inst.; Pati, Amrita [Lawrence Berkeley National Lab. (LBNL), Walnut Creek, CA (United States). Dept. of Energy Joint Genome Inst.; Huntemann, Marcel [Lawrence Berkeley National Lab. (LBNL), Walnut Creek, CA (United States). Dept. of Energy Joint Genome Inst.; Visel, Axel [Lawrence Berkeley National Lab. (LBNL), Walnut Creek, CA (United States). Dept. of Energy Joint Genome Inst.; Woyke, Tanja [Lawrence Berkeley National Lab. (LBNL), Walnut Creek, CA (United States). Dept. of Energy Joint Genome Inst.; Kyrpides, Nikos [Lawrence Berkeley National Lab. (LBNL), Walnut Creek, CA (United States). Dept. of Energy Joint Genome Inst.; Rubin, Edward [Lawrence Berkeley National Lab. (LBNL), Walnut Creek, CA (United States). Dept. of Energy Joint Genome Inst.

    2014-03-21

    Since the discovery of the genetic code and protein translation mechanisms (1), a limited number of variations of the standard assignment between unique base triplets (codons) and their encoded amino acids and translational stop signals have been found in bacteria and phages (2-3). Given the apparent ubiquity of the canonical genetic code, the design of genomically recoded organisms with non-canonical codes has been suggested as a means to prevent horizontal gene transfer between laboratory and environmental organisms (4). It is also predicted that genomically recoded organisms are immune to infection by viruses, under the assumption that phages and their hosts must share a common genetic code (5). This paradigm is supported by the observation of increased resistance of genomically recoded bacteria to phages with a canonical code (4). Despite these assumptions and accompanying lines of evidence, it remains unclear whether differential and non-canonical codon usage represents an absolute barrier to phage infection and genetic exchange between organisms. Our knowledge of the diversity of genetic codes and their use by viruses and their hosts is primarily derived from the analysis of cultivated organisms. Advances in single-cell sequencing and metagenome assembly technologies have enabled the reconstruction of genomes of uncultivated bacterial and archaeal lineages (6). These initial findings suggest that large scale systematic studies of uncultivated microorganisms and viruses may reveal the extent and modes of divergence from the canonical genetic code operating in nature. To explore alternative genetic codes, we carried out a systematic analysis of stop codon reassignments from the canonical TAG amber, TGA opal, and TAA ochre codons in assembled metagenomes from environmental and host-associated samples, single-cell genomes of uncultivated bacteria and archaea, and a collection of phage sequences

  11. Abnormal Task Modulation of Oscillatory Neural Activity in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Elisa C Dias

    2013-08-01

    Full Text Available Schizophrenia patients have deficits in cognitive function that are a core feature of the disorder. AX-CPT is commonly used to study cognition in schizophrenia, and patients have characteristic pattern of behavioral and ERP response. In AX-CPT subjects respond when a flashed cue A is followed by a target X, ignoring other letter combinations. Patients show reduced hit rate to go trials, and increased false alarms to sequences that require inhibition of a prepotent response. EEG recordings show reduced sensory (P1/N1, as well as later cognitive components (N2, P3, CNV. Behavioral deficits correlate most strongly with sensory dysfunction. Oscillatory analyses provide critical information regarding sensory/cognitive processing over and above standard ERP analyses. Recent analyses of induced oscillatory activity in single trials during AX-CPT in healthy volunteers showed characteristic response patterns in theta, alpha and beta frequencies tied to specific sensory and cognitive processes. Alpha and beta modulated during the trials and beta modulation over the frontal cortex correlated with reaction time. In this study, EEG data was obtained from 18 schizophrenia patients and 13 controls during AX-CPT performance, and single trial decomposition of the signal yielded power in the target wavelengths.Significant task-related event-related desynchronization (ERD was observed in both alpha and beta frequency bands over parieto-occipital cortex related to sensory encoding of the cue. This modulation was reduced in patients for beta, but not for alpha. In addition, significant beta ERD was observed over motor cortex, related to motor preparation for the response, and was also reduced in patients. These findings demonstrate impaired dynamic modulation of beta frequency rhythms in schizophrenia, and suggest that failures of oscillatory activity may underlie impaired sensory information processing in schizophrenia that in turn contributes to cognitive deficits.

  12. Cloning and expression of codon-optimized recombinant darbepoetin alfa in Leishmania tarentolae T7-TR.

    Science.gov (United States)

    Kianmehr, Anvarsadat; Golavar, Raziyeh; Rouintan, Mandana; Mahrooz, Abdolkarim; Fard-Esfahani, Pezhman; Oladnabi, Morteza; Khajeniazi, Safoura; Mostafavi, Seyede Samaneh; Omidinia, Eskandar

    2016-02-01

    Darbepoetin alfa is an engineered and hyperglycosylated analog of recombinant human erythropoietin (EPO) which is used as a drug in treating anemia in patients with chronic kidney failure and cancer. This study desribes the secretory expression of a codon-optimized recombinant form of darbepoetin alfa in Leishmania tarentolae T7-TR. Synthetic codon-optimized gene was amplified by PCR and cloned into the pLEXSY-I-blecherry3 vector. The resultant expression vector, pLEXSYDarbo, was purified, digested, and electroporated into the L. tarentolae. Expression of recombinant darbepoetin alfa was evaluated by ELISA, reverse-transcription PCR (RT-PCR), Western blotting, and biological activity. After codon optimization, codon adaptation index (CAI) of the gene raised from 0.50 to 0.99 and its GC% content changed from 56% to 58%. Expression analysis confirmed the presence of a protein band at 40 kDa. Furthermore, reticulocyte experiment results revealed that the activity of expressed darbepoetin alfa was similar to that of its equivalent expressed in Chinese hamster ovary (CHO) cells. These data suggested that the codon optimization and expression in L. tarentolae host provided an efficient approach for high level expression of darbepoetin alfa. PMID:26546410

  13. Synonymous codon usage affects the expression of wild type and F508del CFTR.

    Science.gov (United States)

    Shah, Kalpit; Cheng, Yi; Hahn, Brian; Bridges, Robert; Bradbury, Neil A; Mueller, David M

    2015-03-27

    The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel composed of 1480 amino acids. The major mutation responsible for cystic fibrosis results in loss of amino acid residue, F508 (F508del). Loss of F508 in CFTR alters the folding pathway resulting in endoplasmic-reticulum-associated degradation. This study investigates the role of synonymous codon in the expression of CFTR and CFTR F508del in human HEK293 cells. DNA encoding the open reading frame (ORF) for CFTR containing synonymous codon replacements was expressed using a heterologous vector integrated into the genome. The results indicate that the codon usage greatly affects the expression of CFTR. While the promoter strength driving expression of the ORFs was largely unchanged and the mRNA half-lives were unchanged, the steady-state levels of the mRNA varied by as much as 30-fold. Experiments support that this apparent inconsistency is attributed to nonsense mediated decay independent of exon junction complex. The ratio of CFTR/mRNA indicates that mRNA containing native codons was more efficient in expressing mature CFTR as compared to mRNA containing synonymous high-expression codons. However, when F508del CFTR was expressed after codon optimization, a greater percentage of the protein escaped endoplasmic-reticulum-associated degradation resulting in considerable levels of mature F508del CFTR on the plasma membrane, which showed channel activity. These results indicate that codon usage has an effect on mRNA levels and protein expression, for CFTR, and likely on chaperone-assisted folding pathway, for F508del CFTR.

  14. Modulating enzyme activity using ionic liquids or surfactants.

    Science.gov (United States)

    Goldfeder, Mor; Fishman, Ayelet

    2014-01-01

    One of the important strategies for modulating enzyme activity is the use of additives to affect their microenvironment and subsequently make them suitable for use in different industrial processes. Ionic liquids (ILs) have been investigated extensively in recent years as such additives. They are a class of solvents with peculiar properties and a "green" reputation in comparison to classical organic solvents. ILs as co-solvents in aqueous systems have an effect on substrate solubility, enzyme structure and on enzyme-water interactions. These effects can lead to higher reaction yields, improved selectivity, and changes in substrate specificity, and thus there is great potential for IL incorporation in biocatalysis. The use of surfactants, which are usually denaturating agents, as additives in enzymatic reactions is less reviewed in recent years. However, interesting modulations in enzyme activity in their presence have been reported. In the case of surfactants there is a more pronounced effect on the enzyme structure, as can be observed in a number of crystal structures obtained in their presence. For each additive and enzymatic process, a specific optimization process is needed and there is no one-fits-all solution. Combining ILs and surfactants in either mixed micelles or water-in-IL microemulsions for use in enzymatic reaction systems is a promising direction which may further expand the range of enzyme applications in industrial processes. While many reviews exist on the use of ILs in biocatalysis, the present review centers on systems in which ILs or surfactants were able to modulate and improve the natural activity of enzymes in aqueous systems. PMID:24281758

  15. Surface plasmon polariton modulator with optimized active layer

    DEFF Research Database (Denmark)

    Babicheva, Viktoriia; Lavrinenko, Andrei

    2012-01-01

    applying voltage to electrodes the carrier density in the transparent conducting oxide layer (we study indium tin oxide - ITO) changes according to the Thomas-Fermi screening theory. We employ analytical solutions for a multilayered system as well as numerical simulations with the commercial software...... package CST Microwave Studio in the frequency domain. We explore different permittivities of the ITO layer, which can be achieved by utilizing different anneal conditions. To increase transmittance and enhance modulation depth or efficiency, we propose to pattern the continuous active layer. Dependence...

  16. EarthScope Content Module for IRIS Active Earth Monitor

    Science.gov (United States)

    McQuillan, P. J.; Welti, R.; Johnson, J. A.; Shiffman, C. R.; Olds, S. E.

    2012-12-01

    The Active Earth Monitor (AEM) is an interactive computer-based display for university lobbies, museums, visitor centers, schools and libraries. AEM runs in a standard Internet web browser in full screen mode. The display consists of a customizable set of content pages about plate tectonics, earthquakes, volcanoes and tsunamis. Low-cost and simple-to-implement, the Active Earth Monitor provides a way to engage audiences with earth science information without spending resources on a large exhibit. The EarthScope Active Earth Monitor content set highlights the connections between the landscape and the research and monitoring being conducted by EarthScope in partnership with regional monitoring networks. Modules consist of chapters that focus on What is EarthScope?, EarthScope Observatories, and EarthScope Research Results. Content topics are easily explored using a web page button type navigation interface via a touch screen or mouse. A formative evaluation of general public users informed the interface design. Chapters in the modules start with a general overview and proceed to detailed specifics. Each chapter utilizes at least one set of live or near real-time research data (often more than one). This exposes the general public to active ongoing research that is engaging, relevant to the individual user, and explained in easy to understand terms. All live content is updated each time a user accesses the individual page displaying the live data. Leading questions are presented allowing the user to examine the content before accessing the answer via pop-up box. Diagrams and charts of research data have explanatory keys that allow users to self explore all content. Content pages can be created and inserted in the Active Earth Monitor by utilizing the simple HTML/CSS coding.;

  17. Integrated Brain Circuits: Astrocytic Networks Modulate Neuronal Activity and Behavior

    Science.gov (United States)

    Halassa, Michael M.; Haydon, Philip G.

    2011-01-01

    The past decade has seen an explosion of research on roles of neuron-astrocyte interactions in the control of brain function. We highlight recent studies performed on the tripartite synapse, the structure consisting of pre- and postsynaptic elements of the synapse and an associated astrocytic process. Astrocytes respond to neuronal activity and neuro-transmitters, through the activation of metabotropic receptors, and can release the gliotransmitters ATP, D-serine, and glutamate, which act on neurons. Astrocyte-derived ATP modulates synaptic transmission, either directly or through its metabolic product adenosine. D-serine modulates NMDA receptor function, whereas glia-derived glutamate can play important roles in relapse following withdrawal from drugs of abuse. Cell type–specific molecular genetics has allowed a new level of examination of the function of astrocytes in brain function and has revealed an important role of these glial cells that is mediated by adenosine accumulation in the control of sleep and in cognitive impairments that follow sleep deprivation. PMID:20148679

  18. The mechanical environment modulates intracellular calcium oscillation activities of myofibroblasts.

    Directory of Open Access Journals (Sweden)

    Charles Godbout

    Full Text Available Myofibroblast contraction is fundamental in the excessive tissue remodeling that is characteristic of fibrotic tissue contractures. Tissue remodeling during development of fibrosis leads to gradually increasing stiffness of the extracellular matrix. We propose that this increased stiffness positively feeds back on the contractile activities of myofibroblasts. We have previously shown that cycles of contraction directly correlate with periodic intracellular calcium oscillations in cultured myofibroblasts. We analyze cytosolic calcium dynamics using fluorescent calcium indicators to evaluate the possible impact of mechanical stress on myofibroblast contractile activity. To modulate extracellular mechanics, we seeded primary rat subcutaneous myofibroblasts on silicone substrates and into collagen gels of different elastic modulus. We modulated cell stress by cell growth on differently adhesive culture substrates, by restricting cell spreading area on micro-printed adhesive islands, and depolymerizing actin with Cytochalasin D. In general, calcium oscillation frequencies in myofibroblasts increased with increasing mechanical challenge. These results provide new insight on how changing mechanical conditions for myofibroblasts are encoded in calcium oscillations and possibly explain how reparative cells adapt their contractile behavior to the stresses occurring in normal and pathological tissue repair.

  19. Codon Deviation Coefficient: a novel measure for estimating codon usage bias and its statistical significance

    Directory of Open Access Journals (Sweden)

    Zhang Zhang

    2012-03-01

    Full Text Available Abstract Background Genetic mutation, selective pressure for translational efficiency and accuracy, level of gene expression, and protein function through natural selection are all believed to lead to codon usage bias (CUB. Therefore, informative measurement of CUB is of fundamental importance to making inferences regarding gene function and genome evolution. However, extant measures of CUB have not fully accounted for the quantitative effect of background nucleotide composition and have not statistically evaluated the significance of CUB in sequence analysis. Results Here we propose a novel measure--Codon Deviation Coefficient (CDC--that provides an informative measurement of CUB and its statistical significance without requiring any prior knowledge. Unlike previous measures, CDC estimates CUB by accounting for background nucleotide compositions tailored to codon positions and adopts the bootstrapping to assess the statistical significance of CUB for any given sequence. We evaluate CDC by examining its effectiveness on simulated sequences and empirical data and show that CDC outperforms extant measures by achieving a more informative estimation of CUB and its statistical significance. Conclusions As validated by both simulated and empirical data, CDC provides a highly informative quantification of CUB and its statistical significance, useful for determining comparative magnitudes and patterns of biased codon usage for genes or genomes with diverse sequence compositions.

  20. Codon Deviation Coefficient: A novel measure for estimating codon usage bias and its statistical significance

    KAUST Repository

    Zhang, Zhang

    2012-03-22

    Background: Genetic mutation, selective pressure for translational efficiency and accuracy, level of gene expression, and protein function through natural selection are all believed to lead to codon usage bias (CUB). Therefore, informative measurement of CUB is of fundamental importance to making inferences regarding gene function and genome evolution. However, extant measures of CUB have not fully accounted for the quantitative effect of background nucleotide composition and have not statistically evaluated the significance of CUB in sequence analysis.Results: Here we propose a novel measure--Codon Deviation Coefficient (CDC)--that provides an informative measurement of CUB and its statistical significance without requiring any prior knowledge. Unlike previous measures, CDC estimates CUB by accounting for background nucleotide compositions tailored to codon positions and adopts the bootstrapping to assess the statistical significance of CUB for any given sequence. We evaluate CDC by examining its effectiveness on simulated sequences and empirical data and show that CDC outperforms extant measures by achieving a more informative estimation of CUB and its statistical significance.Conclusions: As validated by both simulated and empirical data, CDC provides a highly informative quantification of CUB and its statistical significance, useful for determining comparative magnitudes and patterns of biased codon usage for genes or genomes with diverse sequence compositions. 2012 Zhang et al; licensee BioMed Central Ltd.

  1. Modulation of CD44 Activity by A6-Peptide

    Directory of Open Access Journals (Sweden)

    Malcolm eFinlayson

    2015-03-01

    Full Text Available AbstractHyaluronan (HA is a nonsulfated glycosaminoglycan distributed throughout the extracellular matrix that plays a major role in cell adhesion, migration, and proliferation. CD44, a multifunctional cell surface glycoprotein, is a receptor for HA. In addition, CD44 is known to interact with other receptors and ligands, and to mediate a number of cellular functions as well as disease progression. Studies have shown that binding of HA to CD44 in cancer cells activates survival pathways resulting in cancer cell survival. This effect can be blocked by anti-CD44 monoclonal antibodies. A6 is a capped, 8 L-amino acid peptide (Ac-KPSSPPEE-NH2 derived from the biologically active connecting peptide domain of the serine protease, human urokinase plasminogen activator (uPA. A6 does not bind to the uPA receptor (uPAR nor interfere with uPA/uPAR binding. A6 binds to CD44 resulting in the inhibition of migration, invasion, and metastasis of tumor cells, and the modulation of CD44-mediated cell signaling. A6 has been shown to have no dose-limiting toxicity in animal studies. A6 has demonstrated efficacy and an excellent safety profile in Phase 1a, 1b, and 2 clinical trials. In animal models, A6 has also exhibited promising results for the treatment of diabetic retinopathy and wet age-related macular degeneration through the reduction of retinal vascular permeability and inhibition of choroidal neovascularization, respectively. Recently, A6 has been shown to be directly cytotoxic for B-lymphocytes obtained from patients with chronic lymphocytic leukemia (CLL expressing the kinase, ZAP-70. This review will discuss the activity of A6, A6 modulation of HA and CD44, and a novel strategy for therapeutic intervention in disease.

  2. Prophylactic thyroidectomy for asymptomatic 3-year-old boy with positive multiple endocrine neoplasia type 2A mutation (codon 634)

    OpenAIRE

    Ješić Maja D.; Tančić-Gajić Milina; Ješić Miloš M.; Živaljević Vladan; Sajić Silvija; Vujović Svetlana; Damjanović Svetozar

    2014-01-01

    Introduction. The multiple endocrine neoplasia type 2A (MEN 2A) syndrome, comprising medullary thyroid carcinoma (MTC), pheochromocytoma and primary hyperparathyroidism (PHPT) is most frequently caused by codon 634 activating mutations of the RET (rearranged during transfection) proto-oncogene on chromosome 10. For this codon-mutation carriers, earlier thyroidectomy (before the age of 5 years) would be advantageous in limiting the potential for the developm...

  3. Analysis of Synonymous Codon Usage Bias in Chlamydia

    Institute of Scientific and Technical Information of China (English)

    Hui L(ü); Wei-Ming ZHAO; Yan ZHENG; Hong WANG; Mei QI; Xiu-Ping YU

    2005-01-01

    Chlamydiae are obligate intracellular bacterial pathogens that cause ocular and sexually transmitted diseases, and are associated with cardiovascular diseases. The analysis of codon usage may improve our understanding of the evolution and pathogenesis of Chlamydia and allow reengineering of target genes to improve their expression for gene therapy. Here, we analyzed the codon usage of C. muridarum, C.trachomatis (here indicating biovar trachoma and LGV), C. pneumoniae, and C. psittaci using the codon usage database and the CUSP (Create a codon usage table) program of EMBOSS (The European Molecular Biology Open Software Suite). The results show that the four genomes have similar codon usage patterns,with a strong bias towards the codons with A and T at the third codon position. Compared with Homo sapiens, the four chlamydial species show discordant seven or eight preferred codons. The ENC (effective number of codons used in a gene)-plot reveals that the genetic heterogeneity in Chlamydia is constrained by the G+C content, while translational selection and gene length exert relatively weaker influences. Moreover,mutational pressure appears to be the major determinant of the codon usage variation among the chlamydial genes. In addition, we compared the codon preferences of C. trachomatis with those of E. coli, yeast,adenovirus and Homo sapiens. There are 23 codons showing distinct usage differences between C. trachomatis and E. coli, 24 between C. trachomatis and adenovirus, 21 between C. trachomatis and Homo sapiens, but only six codons between C. trachomatis and yeast. Therefore, the yeast system may be more suitable for the expression of chlamydial genes. Finally, we compared the codon preferences of C. trachomatis with those of six eukaryotes, eight prokaryotes and 23 viruses. There is a strong positive correlation between the differences in coding GC content and the variations in codon bias (r=0.905, P<0.001). We conclude that the variation of codon bias

  4. On ribosome load, codon bias and protein abundance.

    Directory of Open Access Journals (Sweden)

    Stefan Klumpp

    Full Text Available Different codons encoding the same amino acid are not used equally in protein-coding sequences. In bacteria, there is a bias towards codons with high translation rates. This bias is most pronounced in highly expressed proteins, but a recent study of synthetic GFP-coding sequences did not find a correlation between codon usage and GFP expression, suggesting that such correlation in natural sequences is not a simple property of translational mechanisms. Here, we investigate the effect of evolutionary forces on codon usage. The relation between codon bias and protein abundance is quantitatively analyzed based on the hypothesis that codon bias evolved to ensure the efficient usage of ribosomes, a precious commodity for fast growing cells. An explicit fitness landscape is formulated based on bacterial growth laws to relate protein abundance and ribosomal load. The model leads to a quantitative relation between codon bias and protein abundance, which accounts for a substantial part of the observed bias for E. coli. Moreover, by providing an evolutionary link, the ribosome load model resolves the apparent conflict between the observed relation of protein abundance and codon bias in natural sequences and the lack of such dependence in a synthetic gfp library. Finally, we show that the relation between codon usage and protein abundance can be used to predict protein abundance from genomic sequence data alone without adjustable parameters.

  5. Synonymous Codon Usage Analysis of Thirty Two Mycobacteriophage Genomes

    Directory of Open Access Journals (Sweden)

    Sameer Hassan

    2009-01-01

    Full Text Available Synonymous codon usage of protein coding genes of thirty two completely sequenced mycobacteriophage genomes was studied using multivariate statistical analysis. One of the major factors influencing codon usage is identified to be compositional bias. Codons ending with either C or G are preferred in highly expressed genes among which C ending codons are highly preferred over G ending codons. A strong negative correlation between effective number of codons (Nc and GC3s content was also observed, showing that the codon usage was effected by gene nucleotide composition. Translational selection is also identified to play a role in shaping the codon usage operative at the level of translational accuracy. High level of heterogeneity is seen among and between the genomes. Length of genes is also identified to influence the codon usage in 11 out of 32 phage genomes. Mycobacteriophage Cooper is identified to be the highly biased genome with better translation efficiency comparing well with the host specific tRNA genes.

  6. Modulation of cortical oscillatory activity during transcranial magnetic stimulation.

    Science.gov (United States)

    Brignani, Debora; Manganotti, Paolo; Rossini, Paolo M; Miniussi, Carlo

    2008-05-01

    Transcranial magnetic stimulation (TMS) can transiently modulate cortical excitability, with a net effect depending on the stimulation frequency ( or =5 Hz facilitation, at least for the motor cortex). This possibility has generated interest in experiments aiming to improve deficits in clinical settings, as well as deficits in the cognitive domain. The aim of the present study was to investigate the on-line effects of low frequency (1 Hz) TMS on the EEG oscillatory activity in the healthy human brain, focusing particularly on the outcome of these modulatory effects in relation to the duration of the TMS stimulation. To this end, we used the event-related desynchronization/synchronization (ERD/ERS) approach to determine the patterns of oscillatory activity during two consecutive trains of sham and real TMS. Each train of stimulation was delivered to the left primary motor cortex (MI) of healthy subjects over a period of 10 min, while EEG rhythms were simultaneously recorded. Results indicated that TMS induced an increase in the power of brain rhythms that was related to the period of the stimulation, i.e. the synchronization of the alpha band increased with the duration of the stimulation, and this increase was inversely correlated with motor-evoked potentials (MEPs) amplitude. In conclusion, low frequency TMS over primary motor cortex induces a synchronization of the background oscillatory activity on the stimulated region. This induced modulation in brain oscillations seems to increase coherently with the duration of stimulation, suggesting that TMS effects may involve short-term modification of the neural circuitry sustaining MEPs characteristics. PMID:17557296

  7. Fingolimod modulates microglial activation to augment markers of remyelination

    Directory of Open Access Journals (Sweden)

    Baker David

    2011-07-01

    Full Text Available Abstract Introduction Microglial activation in multiple sclerosis has been postulated to contribute to long-term neurodegeneration during disease. Fingolimod has been shown to impact on the relapsing remitting phase of disease by modulating autoreactive T-cell egress from lymph organs. In addition, it is brain penetrant and has been shown to exert multiple effects on nervous system cells. Methods In this study, the impact of fingolimod and other sphingosine-1-phosphate receptor active molecules following lysophosphotidyl choline-induced demyelination was examined in the rat telencephalon reaggregate, spheroid cell culture system. The lack of immune system components allowed elucidation of the direct effects of fingolimod on CNS cell types in an organotypic situation. Results Following demyelination, fingolimod significantly augmented expression of myelin basic protein in the remyelination phase. This increase was not associated with changes in neurofilament levels, indicating de novo myelin protein expression not associated with axonal branching. Myelin wrapping was confirmed morphologically using confocal and electron microscopy. Increased remyelination was associated with down-regulation of microglial ferritin, tumor necrosis factor alpha and interleukin 1 during demyelination when fingolimod was present. In addition, nitric oxide metabolites and apoptotic effectors caspase 3 and caspase 7 were reduced during demyelination in the presence of fingolimod. The sphingosine-1-phosphate receptor 1 and 5 agonist BAF312 also increased myelin basic protein levels, whereas the sphingosine-1-phosphate receptor 1 agonist AUY954 failed to replicate this effect on remyelination. Conclusions The results presented indicate that modulation of S1P receptors can ameliorate pathological effectors associated with microglial activation leading to a subsequent increase in protein and morphological markers of remyelination. In addition, sphingosine-1-phosphate

  8. Mutation-selection models of codon substitution and their use to estimate selective strengths on codon usage

    DEFF Research Database (Denmark)

    Yang, Ziheng; Nielsen, Rasmus

    2008-01-01

    to examine the null hypothesis that codon usage is due to mutation bias alone, not influenced by natural selection. Application of the test to the mammalian data led to rejection of the null hypothesis in most genes, suggesting that natural selection may be a driving force in the evolution of synonymous......Current models of codon substitution are formulated at the levels of nucleotide substitution and do not explicitly consider the separate effects of mutation and selection. They are thus incapable of inferring whether mutation or selection is responsible for evolution at silent sites. Here we...... implement a few population genetics models of codon substitution that explicitly consider mutation bias and natural selection at the DNA level. Selection on codon usage is modeled by introducing codon-fitness parameters, which together with mutation-bias parameters, predict optimal codon frequencies...

  9. Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity.

    Science.gov (United States)

    Xie, Shanshan; Spelmink, Laura; Codemo, Mario; Subramanian, Karthik; Pütsep, Katrin; Henriques-Normark, Birgitta; Olliver, Marie

    2016-01-01

    The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy. PMID:27529866

  10. Superoxide radical and iron modulate aconitase activity in mammalian cells.

    Science.gov (United States)

    Gardner, P R; Raineri, I; Epstein, L B; White, C W

    1995-06-01

    Aconitase is a member of a family of iron-sulfur-containing (de)hydratases whose activities are modulated in bacteria by superoxide radical (O2-.)-mediated inactivation and iron-dependent reactivation. The inactivation-reactivation of aconitase(s) in cultured mammalian cells was explored since these reactions may impact important and diverse aconitase functions in the cytoplasm and mitochondria. Conditions which increase O2-. production including exposure to the redox-cycling agent phenazine methosulfate (PMS), inhibitors of mitochondrial ubiquinol-cytochrome c oxidoreductase, or hyperoxia inactivated aconitase in mammalian cells. Overproduction of mitochondrial Mn-superoxide dismutase protected aconitase from inactivation by PMS or inhibitors of ubiquinol-cytochrome c oxidoreductase, but not from normobaric hyperoxia. Aconitase activity was reactivated (t1/2 of 12 +/- 3 min) upon removal of PMS. The iron chelator deferoxamine impaired reactivation and increased net inactivation of aconitase by O2-.. The ability of ubiquinol-cytochrome c oxidoreductase-generated O2-. to inactivate aconitase in several cell types correlated with the fraction of the aconitase activity localized in mitochondria. Extracellular O2-. generated with xanthine oxidase did not affect aconitase activity nor did exogenous superoxide dismutase decrease aconitase inactivation by PMS. The results demonstrate a dynamic and cyclical O2-.-mediated inactivation and iron-dependent reactivation of the mammalian [4Fe-4S] aconitases under normal and stress conditions and provide further evidence for the membrane compartmentalization of O2-.. PMID:7768942

  11. Gender-specific selection on codon usage in plant genomes

    Directory of Open Access Journals (Sweden)

    Krochko Joan E

    2007-06-01

    Full Text Available Abstract Background Currently, there is little data available regarding the role of gender-specific gene expression on synonymous codon usage (translational selection in most organisms, and particularly plants. Using gender-specific EST libraries (with > 4000 ESTs from Zea mays and Triticum aestivum, we assessed whether gender-specific gene expression per se and gender-specific gene expression level are associated with selection on codon usage. Results We found clear evidence of a greater bias in codon usage for genes expressed in female than in male organs and gametes, based on the variation in GC content at third codon positions and the frequency of species-preferred codons. This finding holds true for both highly and for lowly expressed genes. In addition, we found that highly expressed genes have greater codon bias than lowly expressed genes for both female- and male-specific genes. Moreover, in both species, genes with female-specific expression show a greater usage of species-specific preferred codons for each of the 18 amino acids having synonymous codons. A supplemental analysis of Brassica napus suggests that bias in codon usage could also be higher in genes expressed in male gametophytic tissues than in heterogeneous (flower tissues. Conclusion This study reports gender-specific bias in codon usage in plants. The findings reported here, based on the analysis of 1 497 876 codons, are not caused either by differences in the biological functions of the genes or by differences in protein lengths, nor are they likely attributable to mutational bias. The data are best explained by gender-specific translational selection. Plausible explanations for these findings and the relevance to these and other organisms are discussed.

  12. MCT SWIR modules for passive and active imaging applications

    Science.gov (United States)

    Breiter, R.; Benecke, M.; Eich, D.; Figgemeier, H.; Weber, A.; Wendler, J.; Sieck, A.

    2016-05-01

    Based on AIM's state-of-the-art MCT IR technology, detector modules for the SWIR spectral range have been developed, fabricated and characterized. While LPE grown MCT FPAs with extended 2.5μm cut-off have been fabricated and integrated also MBE grown MCT on GaAs is considered for future production. Two imaging applications have been in focus operating either in passive mode by making use of e.g. the night glow, or in active mode by laser illumination for gated viewing. Dedicated readout integrated circuits (ROIC), realized in 0.18μm Si-CMOS technology providing the required functionality for passive imaging and gated imaging, have been designed and implemented. For both designs a 640x512 15μm pitch format was chosen. The FPAs are integrated in compact dewar cooler configurations using AIM's split linear coolers. A command and control electronics (CCE) provides supply voltages, biasing, clocks, control and video digitization for easy system interfacing. For imaging under low-light conditions a low-noise 640x512 15μm pitch ROIC with CTIA input stages and correlated double sampling was designed. The ROIC provides rolling shutter and snapshot integration. To reduce size, weight, power and cost (SWaP-C) a 640x512 format detector in a 10μm pitch is under development. The module makes use of the extended SWIR spectral cut-off up to 2.5μm. To be used for active gated-viewing operation SWIR MCT avalanche photodiodes have been implemented and characterized on FPA level in a 640x512 15μm pitch format. The specific ROIC provides also the necessary functions for range gate control and triggering by the laser illumination. First lab and field tests of a gated viewing demonstrator have been carried out. The paper will present the development status and performance results of AIM's MCT based SWIR Modules for imaging applications.

  13. Caenorhabditis elegans glia modulate neuronal activity and behavior

    Directory of Open Access Journals (Sweden)

    Randy F Stout

    2014-03-01

    Full Text Available Glial cells of C. elegans can modulate neuronal activity and behavior, which is the focus of this review. Initially, we provide an overview of neuroglial evolution, making a comparison between C. elegans glia and their genealogical counterparts. What follows is a brief discussion on C. elegans glia characteristics in terms of their exact numbers, germ layers origin, their necessity for proper development of sensory organs, and lack of their need for neuronal survival. The more specific roles that various glial cells have on neuron-based activity/behavior are succinctly presented. The cephalic sheath glia are important for development, maintenance and activity of central synapses, whereas the amphid glia seem to set the tone of sensory synapses; these glial cell types are ectoderm-derived. Mesoderm-derived GLR glia appear to be a part of the circuit for production of motor movement of the worm anterior. Finally, we discuss tools and approaches utilized in studying C. elegans glia, which are an extension of those experimental assets available for this animal, making it an appealing model, not only in neurosciences, but in biology in general.

  14. Protein evolution via amino acid and codon elimination

    DEFF Research Database (Denmark)

    Goltermann, Lise; Larsen, Marie Sofie Yoo; Banerjee, Rajat;

    2010-01-01

    correlation between the number of residues randomized and the size of the resulting ensemble. Using GFP as the model protein, we present a strategy, termed protein evolution via amino acid and codon elimination, through which simplified, native-like polypeptides encoded by a reduced genetic code were obtained...... via screening of reduced-size ensembles. METHODOLOGY/PRINCIPAL FINDINGS: The strategy involves combining a sequential mutagenesis scheme to reduce library size with structurally stabilizing mutations, chaperone complementation, and reduced temperature of gene expression. In six steps, we eliminated...... a common buried residue, Phe, from the green fluorescent protein (GFP), while retaining activity. A GFP variant containing 11 Phe residues was used as starting scaffold to generate 10 separate variants in which each Phe was replaced individually (in one construct two adjacent Phe residues were changed...

  15. Nonsense codons trigger an RNA partitioning shift.

    Science.gov (United States)

    Bhalla, Angela D; Gudikote, Jayanthi P; Wang, Jun; Chan, Wai-Kin; Chang, Yao-Fu; Olivas, O Renee; Wilkinson, Miles F

    2009-02-13

    T-cell receptor-beta (TCRbeta) genes naturally acquire premature termination codons (PTCs) as a result of programmed gene rearrangements. PTC-bearing TCRbeta transcripts are dramatically down-regulated to protect T-cells from the deleterious effects of the truncated proteins that would otherwise be produced. Here we provide evidence that two responses collaborate to elicit this dramatic down-regulation. One is rapid mRNA decay triggered by the nonsense-mediated decay (NMD) RNA surveillance pathway. We demonstrate that this occurs in highly purified nuclei lacking detectable levels of three different cytoplasmic markers, but containing an outer nuclear membrane marker, suggesting that decay occurs either in the nucleoplasm or at the outer nuclear membrane. The second response is a dramatic partitioning shift in the nuclear fraction-to-cytoplasmic fraction mRNA ratio that results in few TCRbeta transcripts escaping to the cytoplasmic fraction of cells. Analysis of TCRbeta mRNA kinetics after either transcriptional repression or induction suggested that this nonsense codon-induced partitioning shift (NIPS) response is not the result of cytoplasmic NMD but instead reflects retention of PTC(+) TCRbeta mRNA in the nuclear fraction of cells. We identified TCRbeta sequences crucial for NIPS but found that NIPS is not exclusively a property of TCRbeta transcripts, and we identified non-TCRbeta sequences that elicit NIPS. RNA interference experiments indicated that NIPS depends on the NMD factors UPF1 and eIF4AIII but not the NMD factor UPF3B. We propose that NIPS collaborates with NMD to retain and degrade a subset of PTC(+) transcripts at the outer nuclear membrane and/or within the nucleoplasm. PMID:19091751

  16. The relationship between codon usage bias and cold resistant genes

    International Nuclear Information System (INIS)

    This research is based on synonymous codon usage which has been well-known as a feature that affects typical expression level of protein in an organism. Different organisms prefer different codons for same amino acid and this is called Codon Usage Bias (CUB). The codon usage directly affects the level or even direction of changes in protein expression in responses to environmental stimuli. Cold stress is a major abiotic factor that limits the agricultural productivity of plants. In the recent study CUB has been studied in Arabidopsis thaliana cold resistant and housekeeping genes and their homologs in rice (Oryza sativa) to understand the cold stress and housekeeping genes relation with CUB. Six cold resistant and three housekeeping genes in Arabidopsis thaliana and their homologs in rice, were subjected to CUB analysis. The three cold resistant genes (DREB1B, RCI and MYB15) showed more than 50% (52%, 61% and 66% respectively) similar codon usage bias for Arabidopsis thaliana and rice. On the other hand three cold resistant genes (MPK3, ICE1 and ZAT12) showed less than 50% (38%, 38% and 47% respectively) similar codon usage bias for Arabidopsis thaliana and rice. The three housekeeping genes (Actin, Tubulin and Ubiquitin) showed 76% similar codon usage bias for Arabidopsis thaliana and rice. This study will help to manage the plant gene expression through codon optimization under the cold stress. (author)

  17. Effect of the Flanking Sequence Architecture of Translation Initiation AUG Codon on Gene Expression Level in Rice

    Institute of Scientific and Technical Information of China (English)

    LIU Qing-po; TAN Jun; XUE Qing-zhong

    2004-01-01

    The relationship between the codon usage bias, gene expression level and the AUG context (from -20 to +6 positions relative to the initiator AUG codon) was examined in 541unigene sequences of rice. A significant correlation for CAI values (codon adaptation index) was observed at five nucleotide positions (-19, -18, -9, -4, +5), eight (-19, -18,-14, -9, -6, -4, -1, +5) for CPP (codon preference parameter), and seven (-18, -16, -15,-9, -7, -1, + 6) for mRNA abundance in the flanking sequence of the initiator AUG codon respectively, but a significantly positive correlation for both CAI and CPP at two positions (-4 and +5), indicating that both those positions are evolutionally under the natural selection constraint at the translational level. By site-directed mutagenesis at seven specific positions (-18, -16, -15, -9, -7, -1 and + 6) for allergenic protein that had the highest mRNA abundance in this study, its expression level decreased dramatically 63.3 and 72.5% respectively, indicating the importance of those 7 positions for gene expression. A highly positive correlation (r= 0.625, P< 0.01) between AUGCAI and GC content in the flanking sequence of the initiator AUG codon showed a more effective higher GC content on translation initiation efficiency. The strong preference for G or C at those 8 positions (-6, -5, -3, -2, -1, +4, +5 and +6) in the AUG context suggested that an important factor in modulation of the translation efficiency, as well as synonymous codon usage bias, particularly in highly expressed genes.

  18. Codon Deviation Coefficient: a novel measure for estimating codon usage bias and its statistical significance

    OpenAIRE

    Zhang Zhang; Li Jun; Cui Peng; Ding Feng; Li Ang; Townsend Jeffrey P; Yu Jun

    2012-01-01

    Abstract Background Genetic mutation, selective pressure for translational efficiency and accuracy, level of gene expression, and protein function through natural selection are all believed to lead to codon usage bias (CUB). Therefore, informative measurement of CUB is of fundamental importance to making inferences regarding gene function and genome evolution. However, extant measures of CUB have not fully accounted for the quantitative effect of background nucleotide composition and have not...

  19. Activity of transcription factor JACKDAW is essential for SHR/SCR-dependent activation of SCARECROW and MAGPIE and is modulated by reciprocal interactions with MAGPIE, SCARECROW and SHORT ROOT.

    Science.gov (United States)

    Ogasawara, Hiromi; Kaimi, Ryuji; Colasanti, Joseph; Kozaki, Akiko

    2011-11-01

    Two GRAS family transcription factors, SHORT-ROOT (SHR) and SCARECROW (SCR), are required for ground tissue and quiescent center formation in Arabidopsis roots. The action of SHR and SCR is regulated by two INDETERMINATE DOMAIN (IDD) family proteins, JACKDAW (JKD) and MAGPIE (MGP). Although the reciprocal interaction of these transcription factors is considered to be involved in the modulation of SHR and SCR action by JKD and MGP, the underlying mechanism remains unclear. In this study, we use a transient assay with Arabidopsis culture cells to show that the physical interaction of these transcription factors modulate their transcriptional activity. Transient expression of LUC reporter genes with the proximal sequences upstream from the ATG codon of SCR and MGP in protoplasts were activated by JKD. Moreover, promoter activities were enhanced further by the addition of SHR and SCR to JKD, but not by the combination of SHR and SCR in the absence of JKD. Yeast one-hybrid analysis showed that JKD binds to the SCR and MGP promoter sequences, indicating the existence of another binding sequences of JKD different from the previously determined IDD binding sequence. Our findings suggest that JKD directly regulates SCR and MGP expression in cooperation with SHR, SCR and MGP.

  20. Genomic composition factors affect codon usage in porcine genome

    DEFF Research Database (Denmark)

    Khobondo, J O; Okeno, Tobias O; Kahi, A K

    2015-01-01

    The objective of the study was to determine the codon usage bias in the porcine genome and decipher its determinants. To investigate the underlying mechanisms of codon bias, the coding sequence (CDS) from the swine reference sequence (ssc10.2) was extracted using Biomart. An in house built Perl...... script was used to derive various genomic traits and codon indices. Analysis was done using R statistical package, and correlations and multivariate regressions were performed. We report the existence of codon usage bias that might suggest existence of weak translational selection. The codon bias...... is feebly related to nucleotide composition (GC%, GC3, CDS length). This study can be explored for designing degenerate primers, necessitate selecting appropriate hosts expression systems to manipulate the expression of target genes in vivo or in vitro and improve the accuracy of gene prediction from...

  1. Analysis of synonymous codon usage and evolution of begomoviruses

    Institute of Scientific and Technical Information of China (English)

    Xiao-zhong XU; Qing-po LIU; Long-jiang FAN; Xiao-feng CUI; Xue-ping ZHOU

    2008-01-01

    Begomoviruses are single-stranded DNA viruses and cause severe diseases in major crop plants worldwide. Based on current gcnomc sequcncc analyses, we found that synonymous codon usagc variations in the protein-coding genes of begomoviruses arc mainly influenced by mutation bias. Base composition analysis suggested that the codon usage bias of AV1 and BV1 genes is significant and their expressions are high. Fourteen codons were determined as translational optimal ones according to the comparison of codon usage pattcms bctwccn highly and lowly expressed genes. Interestingly the codon usagcs bctwccn bego moviruses from thc Old and the New Worlds are apparently different, which supports the idea that the bipartite bcgomoviruses of the New World might originate from bipartite ones of the Old World, whereas the latter evolve from the Old World monopartite begomoviruses.

  2. Melatonin modulates aromatase activity and expression in endothelial cells.

    Science.gov (United States)

    Alvarez-García, Virginia; González, Alicia; Martínez-Campa, Carlos; Alonso-González, Carolina; Cos, Samuel

    2013-05-01

    Melatonin is known to suppress the development of endocrine-responsive breast cancers by interacting with the estrogen signaling pathways. Paracrine interactions between malignant epithelial cells and proximal stromal cells are responsible for local estrogen biosynthesis. In human breast cancer cells and peritumoral adipose tissue, melatonin downregulates aromatase, which transforms androgens into estrogens. The presence of aromatase on endothelial cells indicates that endothelial cells may contribute to tumor growth by producing estrogens. Since human umbilical vein endothelial cells (HUVECs) express both aromatase and melatonin receptors, the aim of the present study was to evaluate the ability of melatonin to regulate the activity and expression of aromatase on endothelial cells, thus, modulating local estrogen biosynthesis. In the present study, we demonstrated that melatonin inhibits the growth of HUVECs and reduces the local biosynthesis of estrogens through the downregulation of aromatase. These results are supported by three lines of evidence. Firstly, 1 mM of melatonin counteracted the testosterone-induced cell proliferation of HUVECs, which is dependent on the local biosynthesis of estrogens from testosterone by the aromatase activity of the cells. Secondly, we found that 1 mM of melatonin reduced the aromatase activity of HUVECs. Finally, by real‑time RT-PCR, we demonstrated that melatonin significantly downregulated the expression of aromatase as well as its endothelial-specific aromatase promoter region I.7. We conclude that melatonin inhibits aromatase activity and expression in HUVECs by regulating gene expression of specific aromatase promoter regions, thereby reducing the local production of estrogens. PMID:23450505

  3. Tiazofurin modulates lipopolysaccharide-activated microglia in vitro

    Directory of Open Access Journals (Sweden)

    Savić Danijela

    2014-01-01

    Full Text Available Tiazofurin is a purine nucleoside analogue, with a broad spectrum of antitumoral and anti-inflammatory properties. In the present study, we have investigated the effect of tiazofurin on microglial inflammatory response to lipopolysaccharide in vitro. The cytotoxic effect of the drug was examined by sulforhodamine B assay. The Griess method was used to quantify nitrite production. Microglial morphology was assessed by measuring cell body size. Release of the pro-inflammatory cytokines, tumor necrosis factor-α, interleukin-1β, interleukin-6, and the anti-inflammatory cytokine interleukin- 10, were evaluated by enzyme-linked immunosorbent assay. Our data showed that tiazofurin decreased the number of activated microglia, lowered nitric oxide production and reduced the average cell surface of these cells. Tiazofurin reduced tumor necrosis factor-α, interleukin-6 and increased interleukin-10 secretion. Conversely, this drug promoted the release of interleukin-1β. Results obtained in this study indicate that TR displayed both anti- and pro-inflammatory modulation of activated microglia that could be relevant for its antitumor action within the central nervous system. [Projekat Ministarstva nauke Republike Srbije, br. III41014

  4. Active Desiccant Dehumidification Module Integration with Rooftop Packaged HVAC

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, J

    2002-04-17

    This report summarizes a research and development program that produced a stand-alone active desiccant module (ADM) that can be easily integrated with new or existing packaged cooling equipment. The program also produced a fully integrated hybrid system, combining the active desiccant section with a conventional direct expansion air-conditioning unit, that resulted in a compact, low-cost, energy-efficient end product. Based upon the results of this investigation, both systems were determined to be highly viable products for commercialization. Major challenges--including wheel development, compact packaging, regeneration burner development, control optimization, and low-cost design--were all successfully addressed by the final prototypes produced and tested as part of this program. Extensive laboratory testing was completed in the SEMCO laboratory for each of the two ADM system approaches. This testing confirmed the performance of the ADM systems to be attractive compared with that of alternate approaches currently used to precondition outdoor air, where a return air path is not readily available for passive desiccant recovery or where first cost is the primary design criterion. Photographs, schematics, and performance maps are provided for the ADM systems that were developed; and many of the control advantages are discussed. Based upon the positive results of this research and development program, field tests are under way for fully instrumented pilot installations of ADM systems in both a hotel/motel and a restaurant.

  5. Materials and Process Activities for NASA's Composite Crew Module

    Science.gov (United States)

    Polis, Daniel L.

    2012-01-01

    In January 2007, the NASA Administrator and Associate Administrator for the Exploration Systems Mission Directorate chartered the NASA Engineering and Safety Center (NESC) to design, build, and test a full-scale Composite Crew Module (CCM). The overall goal of the CCM project was to develop a team from the NASA family with hands-on experience in composite design, manufacturing, and testing in anticipation of future space exploration systems being made of composite materials. The CCM project was planned to run concurrently with the Orion project s baseline metallic design within the Constellation Program so that features could be compared and discussed without inducing risk to the overall Program. The materials and process activities were prioritized based on a rapid prototype approach. This approach focused developmental activities on design details with greater risk and uncertainty, such as out-of-autoclave joining, over some of the more traditional lamina and laminate building block levels. While process development and associated building block testing were performed, several anomalies were still observed at the full-scale level due to interactions between process robustness and manufacturing scale-up. This paper describes the process anomalies that were encountered during the CCM development and the subsequent root cause investigations that led to the final design solutions. These investigations highlight the importance of full-scale developmental work early in the schedule of a complex composite design/build project.

  6. Building gene expression signatures indicative of transcription factor activation to predict AOP modulation

    Science.gov (United States)

    Building gene expression signatures indicative of transcription factor activation to predict AOP modulation Adverse outcome pathways (AOPs) are a framework for predicting quantitative relationships between molecular initiatin...

  7. Active space debris removal by a hybrid propulsion module

    Science.gov (United States)

    DeLuca, L. T.; Bernelli, F.; Maggi, F.; Tadini, P.; Pardini, C.; Anselmo, L.; Grassi, M.; Pavarin, D.; Francesconi, A.; Branz, F.; Chiesa, S.; Viola, N.; Bonnal, C.; Trushlyakov, V.; Belokonov, I.

    2013-10-01

    During the last 40 years, the mass of the artificial objects in orbit increased quite steadily at the rate of about 145 metric tons annually, leading to a total tally of approximately 7000 metric tons. Now, most of the cross-sectional area and mass (97% in LEO) is concentrated in about 4600 intact objects, i.e. abandoned spacecraft and rocket bodies, plus a further 1000 operational spacecraft. Simulations and parametric analyses have shown that the most efficient and effective way to prevent the outbreak of a long-term exponential growth of the catalogued debris population would be to remove enough cross-sectional area and mass from densely populated orbits. In practice, according to the most recent NASA results, the active yearly removal of approximately 0.1% of the abandoned intact objects would be sufficient to stabilize the catalogued debris in low Earth orbit, together with the worldwide adoption of mitigation measures. The candidate targets for removal would have typical masses between 500 and 1000 kg, in the case of spacecraft, and of more than 1000 kg, in the case of rocket upper stages. Current data suggest that optimal active debris removal missions should be carried out in a few critical altitude-inclination bands. This paper deals with the feasibility study of a mission in which the debris is removed by using a hybrid propulsion module as propulsion unit. Specifically, the engine is transferred from a servicing platform to the debris target by a robotic arm so to perform a controlled disposal. Hybrid rocket technology for de-orbiting applications is considered a valuable option due to high specific impulse, intrinsic safety, thrust throttle ability, low environmental impact and reduced operating costs. Typically, in hybrid rockets a gaseous or liquid oxidizer is injected into the combustion chamber along the axial direction to burn a solid fuel. However, the use of tangential injection on a solid grain Pancake Geometry allows for more compact design of

  8. Coincident helminth infection modulates systemic inflammation and immune activation in active pulmonary tuberculosis.

    Directory of Open Access Journals (Sweden)

    Parakkal Jovvian George

    Full Text Available Helminth infections are known to modulate innate and adaptive immune responses in active and latent tuberculosis (TB. However, the role of helminth infections in modulating responses associated with inflammation and immune activation (reflecting disease activity and/or severity in TB is not known.We measured markers of inflammation and immune activation in active pulmonary TB individuals (ATB with co-incidental Strongyloides stercoralis (Ss infection. These included systemic levels of acute phase proteins, matrix metalloproteinases and their endogenous inhibitors and immune activation markers. As a control, we measured the systemic levels of the same molecules in TB-uninfected individuals (NTB with or without Ss infection.Our data confirm that ATB is associated with elevated levels of the various measured molecules when compared to those seen in NTB. Our data also reveal that co-incident Ss infection in ATB individuals is associated with significantly decreased circulating levels of acute phase proteins, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases as well as the systemic immune activation markers, sCD14 and sCD163. These changes are specific to ATB since they are absent in NTB individuals with Ss infection.Our data therefore reveal a profound effect of Ss infection on the markers associated with TB disease activity and severity and indicate that co-incidental helminth infections might dampen the severity of TB disease.

  9. Antileishmanial activity of the estrogen receptor modulator raloxifene.

    Directory of Open Access Journals (Sweden)

    Juliana Q Reimão

    2014-05-01

    Full Text Available BACKGROUND: The treatment of leishmaniasis relies mostly on parenteral drugs with potentially serious adverse effects. Additionally, parasite resistance in the treatment of leishmaniasis has been demonstrated for the majority of drugs available, making the search for more effective and less toxic drugs and treatment regimens a priority for the control of leishmaniasis. The aims of this study were to evaluate the antileishmanial activity of raloxifene in vitro and in vivo and to investigate its mechanism of action against Leishmania amazonensis. METHODOLOGY/PRINCIPAL FINDINGS: Raloxifene was shown to possess antileishmanial activity in vitro against several species with EC50 values ranging from 30.2 to 38.0 µM against promastigotes and from 8.8 to 16.2 µM against intracellular amastigotes. Raloxifene's mechanism of action was investigated through transmission electron microscopy and labeling with propidium iodide, DiSBAC2(3, rhodamine 123 and monodansylcadaverine. Microscopic examinations showed that raloxifene treated parasites displayed autophagosomes and mitochondrial damage while the plasma membrane remained continuous. Nonetheless, plasma membrane potential was rapidly altered upon raloxifene treatment with initial hyperpolarization followed by depolarization. Loss of mitochondrial membrane potential was also verified. Treatment of L. amazonensis-infected BALB/c mice with raloxifene led to significant decrease in lesion size and parasite burden. CONCLUSIONS/SIGNIFICANCE: The results of this work extend the investigation of selective estrogen receptor modulators as potential candidates for leishmaniasis treatment. The antileishmanial activity of raloxifene was demonstrated in vitro and in vivo. Raloxifene produces functional disorder on the plasma membrane of L. amazonensis promastigotes and leads to functional and morphological disruption of mitochondria, which culminate in cell death.

  10. Codon-Precise, Synthetic, Antibody Fragment Libraries Built Using Automated Hexamer Codon Additions and Validated through Next Generation Sequencing

    Directory of Open Access Journals (Sweden)

    Laura Frigotto

    2015-05-01

    Full Text Available We have previously described ProxiMAX, a technology that enables the fabrication of precise, combinatorial gene libraries via codon-by-codon saturation mutagenesis. ProxiMAX was originally performed using manual, enzymatic transfer of codons via blunt-end ligation. Here we present Colibra™: an automated, proprietary version of ProxiMAX used specifically for antibody library generation, in which double-codon hexamers are transferred during the saturation cycling process. The reduction in process complexity, resulting library quality and an unprecedented saturation of up to 24 contiguous codons are described. Utility of the method is demonstrated via fabrication of complementarity determining regions (CDR in antibody fragment libraries and next generation sequencing (NGS analysis of their quality and diversity.

  11. CD83 Modulates B Cell Activation and Germinal Center Responses.

    Science.gov (United States)

    Krzyzak, Lena; Seitz, Christine; Urbat, Anne; Hutzler, Stefan; Ostalecki, Christian; Gläsner, Joachim; Hiergeist, Andreas; Gessner, André; Winkler, Thomas H; Steinkasserer, Alexander; Nitschke, Lars

    2016-05-01

    CD83 is a maturation marker for dendritic cells. In the B cell lineage, CD83 is expressed especially on activated B cells and on light zone B cells during the germinal center (GC) reaction. The function of CD83 during GC responses is unclear. CD83(-/-) mice have a strong reduction of CD4(+) T cells, which makes it difficult to analyze a functional role of CD83 on B cells during GC responses. Therefore, in the present study we generated a B cell-specific CD83 conditional knockout (CD83 B-cKO) model. CD83 B-cKO B cells show defective upregulation of MHC class II and CD86 expression and impaired proliferation after different stimuli. Analyses of GC responses after immunization with various Ags revealed a characteristic shift in dark zone and light zone B cell numbers, with an increase of B cells in the dark zone of CD83 B-cKO mice. This effect was not accompanied by alterations in the level of IgG immune responses or by major differences in affinity maturation. However, an enhanced IgE response was observed in CD83 B-cKO mice. Additionally, we observed a strong competitive disadvantage of CD83-cKO B cells in GC responses in mixed bone marrow chimeras. Furthermore, infection of mice with Borrelia burgdorferi revealed a defect in bacterial clearance of CD83 B-cKO mice with a shift toward a Th2 response, indicated by a strong increase in IgE titers. Taken together, our results show that CD83 is important for B cell activation and modulates GC composition and IgE Ab responses in vivo. PMID:26983787

  12. Allergy Enhances Neurogenesis and Modulates Microglial Activation in the Hippocampus

    Science.gov (United States)

    Klein, Barbara; Mrowetz, Heike; Thalhamer, Josef; Scheiblhofer, Sandra; Weiss, Richard; Aigner, Ludwig

    2016-01-01

    Allergies and their characteristic TH2-polarized inflammatory reactions affect a substantial part of the population. Since there is increasing evidence that the immune system modulates plasticity and function of the central nervous system (CNS), we investigated the effects of allergic lung inflammation on the hippocampus—a region of cellular plasticity in the adult brain. The focus of the present study was on microglia, the resident immune cells of the CNS, and on hippocampal neurogenesis, i.e., the generation of new neurons. C57BL/6 mice were sensitized with a clinically relevant allergen derived from timothy grass pollen (Phl p 5). As expected, allergic sensitization induced high serum levels of allergen-specific immunoglobulins (IgG1 and IgE) and of TH2 cytokines (IL-5 and IL-13). Surprisingly, fewer Iba1+ microglia were found in the granular layer (GL) and subgranular zone (SGZ) of the hippocampal dentate gyrus and also the number of Iba1+MHCII+ cells was lower, indicating a reduced microglial surveillance and activation in the hippocampus of allergic mice. Neurogenesis was analyzed by labeling of proliferating cells with bromodeoxyuridine (BrdU) and determining their fate 4 weeks later, and by quantitative analysis of young immature neurons, i.e., cells expressing doublecortin (DCX). The number of DCX+ cells was clearly increased in the allergy animals. Moreover, there were more BrdU+ cells present in the hippocampus of allergic mice, and these newly born cells had differentiated into neurons as indicated by a higher number of BrdU+NeuN+ cells. In summary, allergy led to a reduced microglia presence and activity and to an elevated level of neurogenesis in the hippocampus. This effect was apparently specific to the hippocampus, as we did not observe these alterations in the subventricular zone (SVZ)/olfactory bulb (OB) system, also a region of high cellular plasticity and adult neurogenesis.

  13. Heterologous protein expression is enhanced by harmonizing the codon usage frequencies of the target gene with those of the expression host.

    Directory of Open Access Journals (Sweden)

    Evelina Angov

    Full Text Available Synonymous codon replacement can change protein structure and function, indicating that protein structure depends on DNA sequence. During heterologous protein expression, low expression or formation of insoluble aggregates may be attributable to differences in synonymous codon usage between expression and natural hosts. This discordance may be particularly important during translation of the domain boundaries (link/end segments that separate elements of higher ordered structure. Within such regions, ribosomal progression slows as the ribosome encounters clusters of infrequently used codons that preferentially encode a subset of amino acids. To replicate the modulation of such localized translation rates during heterologous expression, we used known relationships between codon usage frequencies and secondary protein structure to develop an algorithm ("codon harmonization" for identifying regions of slowly translated mRNA that are putatively associated with link/end segments. It then recommends synonymous replacement codons having usage frequencies in the heterologous expression host that are less than or equal to the usage frequencies of native codons in the native expression host. For protein regions other than these putative link/end segments, it recommends synonymous substitutions with codons having usage frequencies matched as nearly as possible to the native expression system. Previous application of this algorithm facilitated E. coli expression, manufacture and testing of two Plasmodium falciparum vaccine candidates. Here we describe the algorithm in detail and apply it to E. coli expression of three additional P. falciparum proteins. Expression of the "recoded" genes exceeded that of the native genes by 4- to 1,000-fold, representing levels suitable for vaccine manufacture. The proteins were soluble and reacted with a variety of functional conformation-specific mAbs suggesting that they were folded properly and had assumed native

  14. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies.

    Science.gov (United States)

    Torika, Nofar; Asraf, Keren; Danon, Abraham; Apte, Ron N; Fleisher-Berkovich, Sigal

    2016-01-01

    The circulating renin-angiotensin system (RAS), including the biologically active angiotensin II, is a fundamental regulatory mechanism of blood pressure conserved through evolution. Angiotensin II components of the RAS have also been identified in the brain. In addition to pro-inflammatory cytokines, neuromodulators, such as angiotensin II can induce (through angiotensin type 1 receptor (AT1R)) some of the inflammatory actions of brain glial cells and influence brain inflammation. Moreover, in Alzheimer's disease (AD) models, where neuroinflammation occurs, increased levels of cortical AT1Rs have been shown. Still, the precise role of RAS in neuroinflammation is not completely clear. The overall aim of the present study was to elucidate the role of RAS in the modulation of glial functions and AD pathology. To reach this goal, the specific aims of the present study were a. to investigate the long term effect of telmisartan (AT1R blocker) on tumor necrosis factor-α (TNF-α), interleukin 1-β (IL1-β) and nitric oxide (NO) release from glial cells. b. to examine the effect of intranasally administered telmisartan on amyloid burden and microglial activation in 5X familial AD (5XFAD) mice. Telmisartan effects in vivo were compared to those of perindopril (angiotensin converting enzyme inhibitor). Long-term-exposure of BV2 microglia to telmisartan significantly decreased lipopolysaccharide (LPS) -induced NO, inducible NO synthase, TNF-α and IL1-β synthesis. The effect of Telmisartan on NO production in BV2 cells was confirmed also in primary neonatal rat glial cells. Intranasal administration of telmisartan (1 mg/kg/day) for up to two months significantly reduced amyloid burden and CD11b expression (a marker for microglia) both in the cortex and hipoccampus of 5XFAD. Based on the current view of RAS and our data, showing reduced amyloid burden and glial activation in the brains of 5XFAD transgenic mice, one may envision potential intervention with the progression of

  15. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies.

    Directory of Open Access Journals (Sweden)

    Nofar Torika

    Full Text Available The circulating renin-angiotensin system (RAS, including the biologically active angiotensin II, is a fundamental regulatory mechanism of blood pressure conserved through evolution. Angiotensin II components of the RAS have also been identified in the brain. In addition to pro-inflammatory cytokines, neuromodulators, such as angiotensin II can induce (through angiotensin type 1 receptor (AT1R some of the inflammatory actions of brain glial cells and influence brain inflammation. Moreover, in Alzheimer's disease (AD models, where neuroinflammation occurs, increased levels of cortical AT1Rs have been shown. Still, the precise role of RAS in neuroinflammation is not completely clear. The overall aim of the present study was to elucidate the role of RAS in the modulation of glial functions and AD pathology. To reach this goal, the specific aims of the present study were a. to investigate the long term effect of telmisartan (AT1R blocker on tumor necrosis factor-α (TNF-α, interleukin 1-β (IL1-β and nitric oxide (NO release from glial cells. b. to examine the effect of intranasally administered telmisartan on amyloid burden and microglial activation in 5X familial AD (5XFAD mice. Telmisartan effects in vivo were compared to those of perindopril (angiotensin converting enzyme inhibitor. Long-term-exposure of BV2 microglia to telmisartan significantly decreased lipopolysaccharide (LPS -induced NO, inducible NO synthase, TNF-α and IL1-β synthesis. The effect of Telmisartan on NO production in BV2 cells was confirmed also in primary neonatal rat glial cells. Intranasal administration of telmisartan (1 mg/kg/day for up to two months significantly reduced amyloid burden and CD11b expression (a marker for microglia both in the cortex and hipoccampus of 5XFAD. Based on the current view of RAS and our data, showing reduced amyloid burden and glial activation in the brains of 5XFAD transgenic mice, one may envision potential intervention with the

  16. Codon Bias Patterns of E. coli’s Interacting Proteins

    OpenAIRE

    Dilucca, Maddalena; Cimini, Giulio; Semmoloni, Andrea; Deiana, Antonio; Giansanti, Andrea

    2015-01-01

    Synonymous codons, i.e., DNA nucleotide triplets coding for the same amino acid, are used differently across the variety of living organisms. The biological meaning of this phenomenon, known as codon usage bias, is still controversial. In order to shed light on this point, we propose a new codon bias index, CompAI, that is based on the competition between cognate and near-cognate tRNAs during translation, without being tuned to the usage bias of highly expressed genes. We perform a genome-wid...

  17. Trm9-Catalyzed tRNA Modifications Regulate Global Protein Expression by Codon-Biased Translation

    Science.gov (United States)

    Deng, Wenjun; Babu, I. Ramesh; Su, Dan; Yin, Shanye; Begley, Thomas J.; Dedon, Peter C.

    2015-01-01

    Post-transcriptional modifications of transfer RNAs (tRNAs) have long been recognized to play crucial roles in regulating the rate and fidelity of translation. However, the extent to which they determine global protein production remains poorly understood. Here we use quantitative proteomics to show a direct link between wobble uridine 5-methoxycarbonylmethyl (mcm5) and 5-methoxy-carbonyl-methyl-2-thio (mcm5s2) modifications catalyzed by tRNA methyltransferase 9 (Trm9) in tRNAArg(UCU) and tRNAGlu(UUC) and selective translation of proteins from genes enriched with their cognate codons. Controlling for bias in protein expression and alternations in mRNA expression, we find that loss of Trm9 selectively impairs expression of proteins from genes enriched with AGA and GAA codons under both normal and stress conditions. Moreover, we show that AGA and GAA codons occur with high frequency in clusters along the transcripts, which may play a role in modulating translation. Consistent with these results, proteins subject to enhanced ribosome pausing in yeast lacking mcm5U and mcm5s2U are more likely to be down-regulated and contain a larger number of AGA/GAA clusters. Together, these results suggest that Trm9-catalyzed tRNA modifications play a significant role in regulating protein expression within the cell. PMID:26670883

  18. Trm9-Catalyzed tRNA Modifications Regulate Global Protein Expression by Codon-Biased Translation.

    Directory of Open Access Journals (Sweden)

    Wenjun Deng

    2015-12-01

    Full Text Available Post-transcriptional modifications of transfer RNAs (tRNAs have long been recognized to play crucial roles in regulating the rate and fidelity of translation. However, the extent to which they determine global protein production remains poorly understood. Here we use quantitative proteomics to show a direct link between wobble uridine 5-methoxycarbonylmethyl (mcm5 and 5-methoxy-carbonyl-methyl-2-thio (mcm5s2 modifications catalyzed by tRNA methyltransferase 9 (Trm9 in tRNAArg(UCU and tRNAGlu(UUC and selective translation of proteins from genes enriched with their cognate codons. Controlling for bias in protein expression and alternations in mRNA expression, we find that loss of Trm9 selectively impairs expression of proteins from genes enriched with AGA and GAA codons under both normal and stress conditions. Moreover, we show that AGA and GAA codons occur with high frequency in clusters along the transcripts, which may play a role in modulating translation. Consistent with these results, proteins subject to enhanced ribosome pausing in yeast lacking mcm5U and mcm5s2U are more likely to be down-regulated and contain a larger number of AGA/GAA clusters. Together, these results suggest that Trm9-catalyzed tRNA modifications play a significant role in regulating protein expression within the cell.

  19. Association between p53 polymorphism at codon 72 and recurrent spontaneous abortion.

    Science.gov (United States)

    Zhang, Ying; Wu, Yuan-Yuan; Qiao, Fu-Yuan; Zeng, Wan-Jiang

    2016-06-01

    p53 gene plays an important role in apoptosis, which is necessary for successful invasion of trophoblast cells. The change from an arginine (Arg) to a proline (Pro) at codon 72 can influence the biological activity of p53, which predisposes to an increased risk of recurrent spontaneous abortion (RSA). In order to investigate the association between p53 polymorphism at codon 72 and RSA, we conducted this meta-analysis. Pubmed, Embase and Web of science were used to identify the eligible studies. Odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the strength of the association. Six studies containing 937 cases of RSA and 830 controls were included, and there was one study deviated from Hardy-Weinberg equilibrium (HWE). There was a significant association between p53 polymorphism at codon 72 and RSA in recessive model (Pro/Pro vs. Pro/Arg+Arg/Arg; OR=1.60, 95% CI: 1.14-2.24) and co-dominant model (Pro/Pro vs. Arg/Arg; OR=1.47, 95% CI: 1.02-2.12) whether the study that was deviated from HWE was eliminated or not. A significant association was observed in allelic model (Pro vs. Arg; OR=1.28, 95% CI: 1.04-1.57) after exclusion of the study that was deviated from HWE. No association was noted in recessive model (Pro/Pro+Pro/Arg vs. Arg/Arg; OR=1.05, 95% CI: 0.86-1.30) and co-dominant model (Pro/Arg vs. Arg/Arg; OR=0.96, 95% CI: 0.77-1.19). Subgroup analysis by ethnicity also indicated a significant association between p53 polymorphism at codon 72 and RSA in Caucasian group. No heterogeneity and publication bias were found. Our meta-analysis implied that p53 polymorphism at codon 72 carries high maternal risk of RSA. PMID:27376811

  20. Regions of extreme synonymous codon selection in mammalian genes

    OpenAIRE

    Schattner, Peter; Diekhans, Mark

    2006-01-01

    Recently there has been increasing evidence that purifying selection occurs among synonymous codons in mammalian genes. This selection appears to be a consequence of either cis-regulatory motifs, such as exonic splicing enhancers (ESEs), or mRNA secondary structures, being superimposed on the coding sequence of the gene. We have developed a program to identify regions likely to be enriched for such motifs by searching for extended regions of extreme codon conservation between homologous genes...

  1. 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

  2. Codon Usage Bias and Determining Forces in Taenia solium Genome.

    Science.gov (United States)

    Yang, Xing; Ma, Xusheng; Luo, Xuenong; Ling, Houjun; Zhang, Xichen; Cai, Xuepeng

    2015-12-01

    The tapeworm Taenia solium is an important human zoonotic parasite that causes great economic loss and also endangers public health. At present, an effective vaccine that will prevent infection and chemotherapy without any side effect remains to be developed. In this study, codon usage patterns in the T. solium genome were examined through 8,484 protein-coding genes. Neutrality analysis showed that T. solium had a narrow GC distribution, and a significant correlation was observed between GC12 and GC3. Examination of an NC (ENC vs GC3s)-plot showed a few genes on or close to the expected curve, but the majority of points with low-ENC (the effective number of codons) values were detected below the expected curve, suggesting that mutational bias plays a major role in shaping codon usage. The Parity Rule 2 plot (PR2) analysis showed that GC and AT were not used proportionally. We also identified 26 optimal codons in the T. solium genome, all of which ended with either a G or C residue. These optimal codons in the T. solium genome are likely consistent with tRNAs that are highly expressed in the cell, suggesting that mutational and translational selection forces are probably driving factors of codon usage bias in the T. solium genome. PMID:26797435

  3. Codon Usage Bias and Determining Forces in Taenia solium Genome.

    Science.gov (United States)

    Yang, Xing; Ma, Xusheng; Luo, Xuenong; Ling, Houjun; Zhang, Xichen; Cai, Xuepeng

    2015-12-01

    The tapeworm Taenia solium is an important human zoonotic parasite that causes great economic loss and also endangers public health. At present, an effective vaccine that will prevent infection and chemotherapy without any side effect remains to be developed. In this study, codon usage patterns in the T. solium genome were examined through 8,484 protein-coding genes. Neutrality analysis showed that T. solium had a narrow GC distribution, and a significant correlation was observed between GC12 and GC3. Examination of an NC (ENC vs GC3s)-plot showed a few genes on or close to the expected curve, but the majority of points with low-ENC (the effective number of codons) values were detected below the expected curve, suggesting that mutational bias plays a major role in shaping codon usage. The Parity Rule 2 plot (PR2) analysis showed that GC and AT were not used proportionally. We also identified 26 optimal codons in the T. solium genome, all of which ended with either a G or C residue. These optimal codons in the T. solium genome are likely consistent with tRNAs that are highly expressed in the cell, suggesting that mutational and translational selection forces are probably driving factors of codon usage bias in the T. solium genome.

  4. Surfactant Protein A integrates activation signal strength to differentially modulate T cell proliferation

    OpenAIRE

    Mukherjee, Sambuddho; Giamberardino, Charles; Thomas, Joseph; Evans, Kathy; GOTO, HISATSUGU; Ledford, Julie G.; Hsia, Bethany; Pastva, Amy M.; Wright, Jo Rae

    2012-01-01

    Pulmonary surfactant lipoproteins lower the surface tension at the alveolar:airway interface of the lung and participate in host defense. Previous studies reported that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that SP-A mediated modulation of T cell activation depends upon the strength, duration and type of lymphocyte activating signals. Modulation of T cell signal strength imparted by different activating agents ex and in vivo in different mouse models, ...

  5. Active cancellation of residual amplitude modulation in a frequency-modulation based Fabry-Perot interferometer

    Science.gov (United States)

    Yu, Yinan; Wang, Yicheng; Pratt, Jon R.

    2016-03-01

    Residual amplitude modulation (RAM) is one of the most common noise sources known to degrade the sensitivity of frequency modulation spectroscopy. RAM can arise as a result of the temperature dependent birefringence of the modulator crystal, which causes the orientation of the crystal's optical axis to shift with respect to the polarization of the incident light with temperature. In the fiber-based optical interferometer used on the National Institute of Standards and Technology calculable capacitor, RAM degrades the measured laser frequency stability and correlates with the environmental temperature fluctuations. We have demonstrated a simple approach that cancels out excessive RAM due to polarization mismatch between the light and the optical axis of the crystal. The approach allows us to measure the frequency noise of a heterodyne beat between two lasers individually locked to different resonant modes of a cavity with an accuracy better than 0.5 ppm, which meets the requirement to further determine the longitudinal mode number of the cavity length. Also, this approach has substantially mitigated the temperature dependency of the measurements of the cavity length and consequently the capacitance.

  6. Energy-Storage Modules for Active Solar Heating and Cooling

    Science.gov (United States)

    Parker, J. C.

    1982-01-01

    34 page report describes a melting salt hydrate that stores 12 times as much heat as rocks and other heavy materials. Energy is stored mostly as latent heat; that is, heat that can be stored and recovered without any significant change in temperature. Report also describes development, evaluation and testing of permanently sealed modules containing salt hydrate mixture.

  7. Task-dependent modulation of oscillatory neural activity during movements

    DEFF Research Database (Denmark)

    Herz, D. M.; Christensen, M. S.; Reck, C.;

    2011-01-01

    -dependent modulation of frequency coupling within this network. To this end we recorded 122-multichannel EEG in 13 healthy subjects while they performed three simple motor tasks. EEG data source modeling using individual MR images was carried out with a multiple source beamformer approach. A bilateral motor network...

  8. Studying modulation on simultaneously activated SSVEP neural networks by a cognitive task.

    Science.gov (United States)

    Wu, Zhenghua

    2014-01-01

    Since the discovery of steady-state visually evoked potential (SSVEP), it has been used in many fields. Numerous studies suggest that there exist three SSVEP neural networks in different frequency bands. An obvious phenomenon has been observed, that the amplitude and phase of SSVEP can be modulated by a cognitive task. Previous works have studied this modulation on separately activated SSVEP neural networks by a cognitive task. If two or more SSVEP neural networks are activated simultaneously in the process of a cognitive task, is the modulation on different SSVEP neural networks the same? In this study, two different SSVEP neural networks were activated simultaneously by two different frequency flickers, with a working memory task irrelevant to the flickers being conducted at the same time. The modulated SSVEP waves were compared with each other and to those only under one flicker in previous studies. The comparison results show that the cognitive task can modulate different SSVEP neural networks with a similar style.

  9. Seasonal Modulation of Earthquake Swarm Activity Near Maupin, Oregon

    Science.gov (United States)

    Braunmiller, J.; Nabelek, J.; Trehu, A. M.

    2012-12-01

    Between December 2006 and November 2011, the Pacific Northwest Seismic Network (PNSN) reported 464 earthquakes in a swarm about 60 km east-southeast of Mt. Hood near the town of Maupin, Oregon. Relocation of forty-five MD≥2.5 earthquakes and regional moment tensor analysis of nine 3.3≤Mw≤3.9 earthquakes reveals a north-northwest trending, less than 1 km2 sized active fault patch on a 70° west dipping fault. At about 17 km depth, the swarm occurred at or close to the bottom of the seismogenic crust. The swarm's cumulative seismic moment release, equivalent to an Mw=4.4 earthquake, is not dominated by a single shock; it is rather mainly due to 20 MD≥3.0 events, which occurred throughout the swarm. The swarm started at the southern end and, during the first 18 months of activity, migrated to the northwest at a rate of about 1-2 m/d until reaching its northern terminus. A 10° fault bend, inferred from locations and fault plane solutions, acted as geometrical barrier that temporarily halted event migration in mid-2007 before continuing north in early 2008. The slow event migration points to a pore pressure diffusion process suggesting the swarm onset was triggered by fluid inflow into the fault zone. At 17 km depth, triggering by meteoritic water seems unlikely for a normal crustal permeability. The double couple source mechanisms preclude a magmatic intrusion at the depth of the earthquakes. However, fluids (or gases) associated with a deeper, though undocumented, magma injection beneath the Cascade Mountains, could trigger seismicity in a pre-stressed region when they have migrated upward and reached the seismogenic crust. Superimposed on overall swarm evolution, we found a statistically significant annual seismicity variation, which is likely surface driven. The annual seismicity peak during spring (March-May) coincides with the maximum snow load on the near-by Cascades. The load corresponds to a surface pressure variation of about 6 kPa, which likely

  10. Signal Modulation of Super Read Only Memory with Thermally Activated Aperture Model

    Science.gov (United States)

    Kim, June Seo; Kwak, Keumcheol; You, Chun-Yeol

    2008-07-01

    We describe the signal modulation of super read only memory (ROM) with thermally activated aperture model using a three-dimensional finite-difference time-domain method. The thermally activated aperture is modeled using a spatially varied refractive indices of the GeSbTe layer. No meaningful signal modulation is observed without thermally activated aperture below the resolution limit of 120 nm. When we open the thermally activated aperture by considering the temperature dependence of the refractive indices in the GeSbTe layer, the 2.8 and 1.7% signal modulations are observed for 120 and 80 nm pits, respectively. The experimentally observed signal modulation under the resolution limit can be explained using the thermally activated aperture model.

  11. M19 modulates skeletal muscle differentiation and insulin secretion in pancreatic β-cells through modulation of respiratory chain activity.

    Directory of Open Access Journals (Sweden)

    Linda Cambier

    Full Text Available Mitochondrial dysfunction due to nuclear or mitochondrial DNA alterations contributes to multiple diseases such as metabolic myopathies, neurodegenerative disorders, diabetes and cancer. Nevertheless, to date, only half of the estimated 1,500 mitochondrial proteins has been identified, and the function of most of these proteins remains to be determined. Here, we characterize the function of M19, a novel mitochondrial nucleoid protein, in muscle and pancreatic β-cells. We have identified a 13-long amino acid sequence located at the N-terminus of M19 that targets the protein to mitochondria. Furthermore, using RNA interference and over-expression strategies, we demonstrate that M19 modulates mitochondrial oxygen consumption and ATP production, and could therefore regulate the respiratory chain activity. In an effort to determine whether M19 could play a role in the regulation of various cell activities, we show that this nucleoid protein, probably through its modulation of mitochondrial ATP production, acts on late muscle differentiation in myogenic C2C12 cells, and plays a permissive role on insulin secretion under basal glucose conditions in INS-1 pancreatic β-cells. Our results are therefore establishing a functional link between a mitochondrial nucleoid protein and the modulation of respiratory chain activities leading to the regulation of major cellular processes such as myogenesis and insulin secretion.

  12. Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity

    OpenAIRE

    Gemayel, Rita; Chavali, Sreenivas; Pougach, Ksenia; Legendre, Matthieu; Zhu, Bo; Boeynaems, Steven; van der Zande, Elisa; Gevaert, Kris; Rousseau, Frederic; Schymkowitz, Joost; Babu, M Madan; Verstrepen, Kevin J.

    2015-01-01

    Summary Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington’s disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats i...

  13. Modulated spectral activity (MSA) - Implications for planetary radio sources

    Science.gov (United States)

    Thieman, James R.; Alexander, Joseph K.; Staelin, David H.

    1988-01-01

    The properties of the Jovian and Saturnian MSA, modulation patterns within the normally diffuse nonthermal radio emission that are characterized by distinctive banded structures of enhanced intensity fluctuations in frequency over time scales of minutes to tens of minutes, are discussed. Although Jovian and Saturnian MSA are both normally observed in the 0.2-1.3-MHz frequency range, similar pattern have been noted in Jovian decametric emission above 30 MHz. The MSA properties are used to constrain the possible source mechanism.

  14. Same modulation but different starting points: performance modulates age differences in inferior frontal cortex activity during word-retrieval.

    Directory of Open Access Journals (Sweden)

    Marcus Meinzer

    Full Text Available The neural basis of word-retrieval deficits in normal aging has rarely been assessed and the few previous functional imaging studies found enhanced activity in right prefrontal areas in healthy older compared to younger adults. However, more pronounced right prefrontal recruitment has primarily been observed during challenging task conditions. Moreover, increased task difficulty may result in enhanced activity in the ventral inferior frontal gyrus (vIFG bilaterally in younger participants as well. Thus, the question arises whether increased activity in older participants represents an age-related phenomenon or reflects task difficulty effects. In the present study, we manipulated task difficulty during overt semantic and phonemic word-generation and used functional magnetic resonance imaging to assess activity patterns in the vIFG in healthy younger and older adults (N = 16/group; mean age: 24 vs. 69 years. Both groups produced fewer correct responses during the more difficult task conditions. Overall, older participants produced fewer correct responses and showed more pronounced task-related activity in the right vIFG. However, increased activity during the more difficult conditions was found in both groups. Absolute degree of activity was correlated with performance across groups, tasks and difficulty levels. Activity modulation (difficult vs. easy conditions was correlated with the respective drop in performance across groups and tasks. In conclusion, vIFG activity levels and modulation of activity were mediated by performance accuracy in a similar way in both groups. Group differences in the right vIFG activity were explained by performance accuracy which needs to be considered in future functional imaging studies of healthy and pathological aging.

  15. XPD codon 312 and 751 polymorphisms, and AFB1 exposure, and hepatocellular carcinoma risk

    Directory of Open Access Journals (Sweden)

    Huang Yong

    2009-11-01

    Full Text Available Abstract Background Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of hepatocellular carcinoma (HCC related to the exposure of aflatoxin B1 (AFB1. In this study, we have focused on the polymorphisms of xeroderma pigmentosum complementation group D (XPD codon 312 and 751 (namely Asp312Asn and Lys751Gln, involved in nucleotide excision repair. Methods We conducted a case-control study including 618 HCC cases and 712 controls to evaluate the associations between these two polymorphisms and HCC risk for Guangxi population by means of TaqMan-PCR and PCR-RFLP analysis. Results We found that individuals featuring the XPD genotypes with codon 751 Gln alleles (namely XPD-LG or XPD-GG were related to an elevated risk of HCC compared to those with the homozygote of XPD codon 751 Lys alleles [namely XPD-LL, adjusted odds ratios (ORs were 1.75 and 2.47; 95% confidence interval (CIs were 1.30-2.37 and 1.62-3.76, respectively]. A gender-specific role was evident that showed an higher risk for women (adjusted OR was 8.58 for XPD-GG than for men (adjusted OR = 2.90 for XPD-GG. Interestingly, the interactive effects of this polymorphism and AFB1-exposure information showed the codon 751 Gln alleles increase the risk of HCC for individuals facing longer exposure years (Pinteraction = 0.011, OR = 0.85. For example, long-exposure-years (> 48 years individuals who carried XDP-GG had an adjusted OR of 470.25, whereas long-exposure-years people with XDP-LL were at lower risk (adjusted OR = 149.12. However, we did not find that XPD codon 312 polymorphism was significantly associated with HCC risk. Conclusion These findings suggest that XPD Lys751Gln polymorphism is an important modulator of AFB1 related-HCC development in Guangxi population.

  16. Modulation of pulmonary macrophage superoxide release and tumoricidal activity following activation by biological response modifiers.

    Science.gov (United States)

    Drath, D B

    1986-10-01

    Following immunologic activation, pulmonary macrophages may prevent or cause regression of lung metastases by mechanisms which remain largely unknown. The studies described here were designed to determine if enhanced oxygen metabolite release was related to postactivation tumoricidal activity. We have shown that in vitro activation of Fischer 344 rat pulmonary macrophages by either free or liposome-encapsulated muramyl dipeptide leads to both enhanced release of superoxide anions and marked tumoricidal activity against syngenic (Fischer 13762), allogeneic (Schmidt-Ruppin RR 1022) and xenogeneic (Fibrosarcoma MCA-F) 125I-deoxyuridine-labeled target cells. This immune modulator did not, however, metabolically activate pulmonary macrophages as effectively as liposome-encapsulated lipopolysaccharide. A 24-h in vitro incubation with either 150 U or 300 U of interferon-gamma (3 X 10(6) U/mg) or 30 U, 150 U or 300 U of interferon-alpha (6 X 10(5) U/mg) caused a significant elevation in superoxide release above controls, whereas short-term exposure (2 or 4 h) had little or no effect. Free or encapsulated 6-O-stearoyl muramyl dipeptide, on the other hand, did increase superoxide levels at all 3 time periods. When either interferon-gamma or free or encapsulated muramyl dipeptide derivative were administered to intact rats by either i.v. injection, intratracheal instillation or osmotic minipump infusion, pulmonary macrophage tumoricidal activity was observed 96 h after cell harvesting. Zymosan-stimulated superoxide release, however, was not consistently elevated above control or empty liposome treatment following this course of in vivo activation. The data collectively suggest that in vivo pulmonary macrophage activation to a tumoricidal state and metabolic activation resulting in enhanced superoxide may be separable events. PMID:3021650

  17. Familial Creutzfeldt-Jakob disease associated with a point mutation at codon 210 of the prion protein gene

    Directory of Open Access Journals (Sweden)

    Huang Nancy

    2001-01-01

    Full Text Available Creutzfeldt-Jakob disease (CJD, the most known human prion disease, is usually sporadic but approximately 15% of the cases are familial. To date, seven CJD cases with codon 210 mutation (GTT to ATT have been reported in the literature. We describe a case of a 57 year-old woman who presented gait disturbances and rapidly progressive dementia, leading to death four months after onset. Electroencephalogram revealed periodic activity, diffusion-weighted magnetic resonance imaging showed hypersignal in basal ganglia, and test for 14-3-3 protein was strongly positive in the CSF. The complete prion protein gene coding region was sequenced after PCR amplification, showing a point mutation in codon 210. This is the first case of CJD with codon 210 mutation diagnosed in Brazil. We emphasize the role of genetic search for prion protein gene mutation, even in patients presenting clinical features resembling sporadic CJD.

  18. Genome-Wide Analysis of Codon Usage Bias in Epichloë festucae

    Directory of Open Access Journals (Sweden)

    Xiuzhang Li

    2016-07-01

    Full Text Available Analysis of codon usage data has both practical and theoretical applications in understanding the basics of molecular biology. Differences in codon usage patterns among genes reflect variations in local base compositional biases and the intensity of natural selection. Recently, there have been several reports related to codon usage in fungi, but little is known about codon usage bias in Epichloë endophytes. The present study aimed to assess codon usage patterns and biases in 4870 sequences from Epichloë festucae, which may be helpful in revealing the constraint factors such as mutation or selection pressure and improving the bioreactor on the cloning, expression, and characterization of some special genes. The GC content with 56.41% is higher than the AT content (43.59% in E. festucae. The results of neutrality and effective number of codons plot analyses showed that both mutational bias and natural selection play roles in shaping codon usage in this species. We found that gene length is strongly correlated with codon usage and may contribute to the codon usage patterns observed in genes. Nucleotide composition and gene expression levels also shape codon usage bias in E. festucae. E. festucae exhibits codon usage bias based on the relative synonymous codon usage (RSCU values of 61 sense codons, with 25 codons showing an RSCU larger than 1. In addition, we identified 27 optimal codons that end in a G or C.

  19. Genome-Wide Analysis of Codon Usage Bias in Epichloë festucae.

    Science.gov (United States)

    Li, Xiuzhang; Song, Hui; Kuang, Yu; Chen, Shuihong; Tian, Pei; Li, Chunjie; Nan, Zhibiao

    2016-01-01

    Analysis of codon usage data has both practical and theoretical applications in understanding the basics of molecular biology. Differences in codon usage patterns among genes reflect variations in local base compositional biases and the intensity of natural selection. Recently, there have been several reports related to codon usage in fungi, but little is known about codon usage bias in Epichloë endophytes. The present study aimed to assess codon usage patterns and biases in 4870 sequences from Epichloë festucae, which may be helpful in revealing the constraint factors such as mutation or selection pressure and improving the bioreactor on the cloning, expression, and characterization of some special genes. The GC content with 56.41% is higher than the AT content (43.59%) in E. festucae. The results of neutrality and effective number of codons plot analyses showed that both mutational bias and natural selection play roles in shaping codon usage in this species. We found that gene length is strongly correlated with codon usage and may contribute to the codon usage patterns observed in genes. Nucleotide composition and gene expression levels also shape codon usage bias in E. festucae. E. festucae exhibits codon usage bias based on the relative synonymous codon usage (RSCU) values of 61 sense codons, with 25 codons showing an RSCU larger than 1. In addition, we identified 27 optimal codons that end in a G or C. PMID:27428961

  20. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

    OpenAIRE

    J. Abraham Domínguez-Avila; Gustavo A. González-Aguilar; Emilio Alvarez-Parrilla; de la Rosa, Laura A.

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered...

  1. [Change of cholinesterase relative activity under modulated ultra high frequency electromagnetic radiation in experiments in vitro].

    Science.gov (United States)

    Pashovkina, M S; Pashovkin, T N

    2011-01-01

    Changes in the activity of enzyme cholinesterase (ChE) have been experimentally investigated under the influence of amplitude-modulated super-high-frequency electromagnetic radiation (carrier frequency of 2.375 MHz; power flux density of 8 mW/cm2, 20 mW/cm2 and 50 mW/cm2; modulation frequency range 10 to 210 Hz; exposure time 5 min). The appearance of peaks of the cholinesterase increased relative activity, as well as the changes in the direction and intensity of the reaction associated with the modulation frequency and power flux are observed at equal power flux densities and exposure times.

  2. P-value based visualization of codon usage data

    Directory of Open Access Journals (Sweden)

    Fricke Wolfgang

    2006-06-01

    Full Text Available Abstract Two important and not yet solved problems in bacterial genome research are the identification of horizontally transferred genes and the prediction of gene expression levels. Both problems can be addressed by multivariate analysis of codon usage data. In particular dimensionality reduction methods for visualization of multivariate data have shown to be effective tools for codon usage analysis. We here propose a multidimensional scaling approach using a novel similarity measure for codon usage tables. Our probabilistic similarity measure is based on P-values derived from the well-known chi-square test for comparison of two distributions. Experimental results on four microbial genomes indicate that the new method is well-suited for the analysis of horizontal gene transfer and translational selection. As compared with the widely-used correspondence analysis, our method did not suffer from outlier sensitivity and showed a better clustering of putative alien genes in most cases.

  3. A model for codon position bias in RNA editing

    CERN Document Server

    Liu, T; Liu, Tsunglin; Bundschuh, Ralf

    2005-01-01

    RNA editing can be crucial for the expression of genetic information via inserting, deleting, or substituting a few nucleotides at specific positions in an RNA sequence. Within coding regions in an RNA sequence, editing usually occurs with a certain bias in choosing the positions of the editing sites. In the mitochondrial genes of {\\it Physarum polycephalum}, many more editing events have been observed at the third codon position than at the first and second, while in some plant mitochondria the second codon position dominates. Here we propose an evolutionary model that explains this bias as the basis of selection at the protein level. The model predicts a distribution of the three positions rather close to the experimental observation in {\\it Physarum}. This suggests that the codon position bias in {\\it Physarum} is mainly a consequence of selection at the protein level.

  4. Design, synthesis, and testing toward a 57-codon genome.

    Science.gov (United States)

    Ostrov, Nili; Landon, Matthieu; Guell, Marc; Kuznetsov, Gleb; Teramoto, Jun; Cervantes, Natalie; Zhou, Minerva; Singh, Kerry; Napolitano, Michael G; Moosburner, Mark; Shrock, Ellen; Pruitt, Benjamin W; Conway, Nicholas; Goodman, Daniel B; Gardner, Cameron L; Tyree, Gary; Gonzales, Alexandra; Wanner, Barry L; Norville, Julie E; Lajoie, Marc J; Church, George M

    2016-08-19

    Recoding--the repurposing of genetic codons--is a powerful strategy for enhancing genomes with functions not commonly found in nature. Here, we report computational design, synthesis, and progress toward assembly of a 3.97-megabase, 57-codon Escherichia coli genome in which all 62,214 instances of seven codons were replaced with synonymous alternatives across all protein-coding genes. We have validated 63% of recoded genes by individually testing 55 segments of 50 kilobases each. We observed that 91% of tested essential genes retained functionality with limited fitness effect. We demonstrate identification and correction of lethal design exceptions, only 13 of which were found in 2229 genes. This work underscores the feasibility of rewriting genomes and establishes a framework for large-scale design, assembly, troubleshooting, and phenotypic analysis of synthetic organisms. PMID:27540174

  5. Codon Optimizing for Increased Membrane Protein Production: A Minimalist Approach.

    Science.gov (United States)

    Mirzadeh, Kiavash; Toddo, Stephen; Nørholm, Morten H H; Daley, Daniel O

    2016-01-01

    Reengineering a gene with synonymous codons is a popular approach for increasing production levels of recombinant proteins. Here we present a minimalist alternative to this method, which samples synonymous codons only at the second and third positions rather than the entire coding sequence. As demonstrated with two membrane-embedded transporters in Escherichia coli, the method was more effective than optimizing the entire coding sequence. The method we present is PCR based and requires three simple steps: (1) the design of two PCR primers, one of which is degenerate; (2) the amplification of a mini-library by PCR; and (3) screening for high-expressing clones. PMID:27485329

  6. Optimized codon usage enhances the expression and immunogenicity of DNA vaccine encoding Taenia solium oncosphere TSOL18 gene.

    Science.gov (United States)

    Wang, Yuan-Yuan; Chang, Xue-Lian; Tao, Zhi-Yong; Wang, Xiao-Li; Jiao, Yu-Meng; Chen, Yong; Qi, Wen-Juan; Xia, Hui; Yang, Xiao-Di; Sun, Xin; Shen, Ji-Long; Fang, Qiang

    2015-07-01

    Cysticercosis due to larval cysts of Taenia solium, is a serious public health problem affecting humans in numerous regions worldwide. The oncospheral stage-specific TSOL18 antigen is a promising candidate for an anti-cysticercosis vaccine. It has been reported that the immunogenicity of the DNA vaccine may be enhanced through codon optimization of candidate genes. The aim of the present study was to further increase the efficacy of the cysticercosis DNA vaccine; therefore, a codon optimized recombinant expression plasmid pVAX1/TSOL18 was developed in order to enhance expression and immunogenicity of TSOL18. The gene encoding TSOL18 of Taenia solium was optimized, and the resulting opt-TSOL18 gene was amplified and expressed. The results of the present study showed that the codon-optimized TSOL18 gene was successfully expressed in CHO-K1 cells, and immunized mice vaccinated with opt-TSOL18 recombinant expression plasmids demonstrated opt‑TSOL18 expression in muscle fibers, as determined by immunohistochemistry. In addition, the codon-optimized TSOL18 gene produced a significantly greater effect compared with that of TSOL18 and active spleen cells were markedly stimulated in vaccinated mice. 3H-thymidine incorporation was significantly greater in the opt-TSOL18 group compared with that of the TSOL18, pVAX and blank control groups (P<0.01). In conclusion, the eukaryotic expression vector containing the codon-optimized TSOL18 gene was successfully constructed and was confirmed to be expressed in vivo and in vitro. The expression and immunogenicity of the codon-optimized TSOL18 gene were markedly greater compared with that of the un-optimized gene. Therefore, these results may provide the basis for an optimized TSOL18 gene vaccine against cysticercosis.

  7. Staphylococcal Enterotoxin O Exhibits Cell Cycle Modulating Activity

    Science.gov (United States)

    Hodille, Elisabeth; Alekseeva, Ludmila; Berkova, Nadia; Serrier, Asma; Badiou, Cedric; Gilquin, Benoit; Brun, Virginie; Vandenesch, François; Terman, David S.; Lina, Gerard

    2016-01-01

    Maintenance of an intact epithelial barrier constitutes a pivotal defense mechanism against infections. Staphylococcus aureus is a versatile pathogen that produces multiple factors including exotoxins that promote tissue alterations. The aim of the present study is to investigate the cytopathic effect of staphylococcal exotoxins SEA, SEG, SEI, SElM, SElN and SElO on the cell cycle of various human cell lines. Among all tested exotoxins only SEIO inhibited the proliferation of a broad panel of human tumor cell lines in vitro. Evaluation of a LDH release and a DNA fragmentation of host cells exposed to SEIO revealed that the toxin does not induce necrosis or apoptosis. Analysis of the DNA content of tumor cells synchronized by serum starvation after exposure to SEIO showed G0/G1 cell cycle delay. The cell cycle modulating feature of SEIO was confirmed by the flow cytometry analysis of synchronized cells exposed to supernatants of isogenic S. aureus strains wherein only supernatant of the SElO producing strain induced G0/G1 phase delay. The results of yeast-two-hybrid analysis indicated that SEIO’s potential partner is cullin-3, involved in the transition from G1 to S phase. In conclusion, we provide evidence that SEIO inhibits cell proliferation without inducing cell death, by delaying host cell entry into the G0/G1 phase of the cell cycle. We speculate that this unique cell cycle modulating feature allows SEIO producing bacteria to gain advantage by arresting the cell cycle of target cells as part of a broader invasive strategy. PMID:27148168

  8. Glucose Enhances Leptin Signaling through Modulation of AMPK Activity

    OpenAIRE

    Haoran Su; Lin Jiang; Christin Carter-Su; Liangyou Rui

    2012-01-01

    Leptin exerts its action by binding to and activating the long form of leptin receptors (LEPRb). LEPRb activates JAK2 that subsequently phosphorylates and activates STAT3. The JAK2/STAT3 pathway is required for leptin control of energy balance and body weight. Defects in leptin signaling lead to leptin resistance, a primary risk factor for obesity. Body weight is also regulated by nutrients, including glucose. Defects in glucose sensing also contribute to obesity. Here we report crosstalk bet...

  9. Genome-wide prediction of stop codon readthrough during translation in the yeast Saccharomyces cerevisiae

    OpenAIRE

    Williams, I; Richardson, J.; Starkey, A.; Stansfield, I

    2004-01-01

    In-frame stop codons normally signal termination during mRNA translation, but they can be read as ‘sense’ (readthrough) depending on their context, comprising the 6 nt preceding and following the stop codon. To identify novel contexts directing readthrough, under-represented 5′ and 3′ stop codon contexts from Saccharomyces cerevisiae were identified by genome-wide survey in silico. In contrast with the nucleotide bias 3′ of the stop codon, codon bias in the two codon positions 5′ of the termi...

  10. ROMA: representation and quantification of module activity from target expression data

    Directory of Open Access Journals (Sweden)

    Loredana eMartignetti

    2016-02-01

    Full Text Available In many analysis of high-throughput data in systems biology, there is a need to quantify the activity of a set of genes in individual samples. A typical example is the case where it is necessary to estimate the activity of a transcription factor (which is often not directly measurable from the expression of its target genes. We present here ROMA (Representation and quantification Of Module Activities Java software, designed for fast and robust computation of the activity of gene sets (or modules with coordinated expression. ROMA activity quantification is based on the simplest uni-factor linear model of gene regulation that approximates the expression data of a gene set by its first principal component.The proposed algorithm implements novel functionalities: it provides several method modifications for principal components computation, including weighted, robust and centered methods; it distinguishes overdispersed modules (based on the variance explained by the first principal component and coordinated modules (based on the significance of the spectral gap; finally, it computes statistical significance of the estimated module overdispersion or coordination.ROMA can be applied in many contexts, from estimating differential activities of transcriptional factors to findingoverdispersed pathways in single-cell transcriptomics data. We describe here the principles of ROMA providing several practical examples of its use.ROMA source code is available at https://github.com/sysbio-curie/Roma.

  11. Learning new gait patterns: Exploratory muscle activity during motor learning is not predicted by motor modules.

    Science.gov (United States)

    Ranganathan, Rajiv; Krishnan, Chandramouli; Dhaher, Yasin Y; Rymer, William Z

    2016-03-21

    The motor module hypothesis in motor control proposes that the nervous system can simplify the problem of controlling a large number of muscles in human movement by grouping muscles into a smaller number of modules. Here, we tested one prediction of the modular organization hypothesis by examining whether there is preferential exploration along these motor modules during the learning of a new gait pattern. Healthy college-aged participants learned a new gait pattern which required increased hip and knee flexion during the swing phase while walking in a lower-extremity robot (Lokomat). The new gait pattern was displayed as a foot trajectory in the sagittal plane and participants attempted to match their foot trajectory to this template. We recorded EMG from 8 lower-extremity muscles and we extracted motor modules during both baseline walking and target-tracking using non-negative matrix factorization (NMF). Results showed increased trajectory variability in the first block of learning, indicating that participants were engaged in exploratory behavior. Critically, when we examined the muscle activity during this exploratory phase, we found that the composition of motor modules changed significantly within the first few strides of attempting the new gait pattern. The lack of persistence of the motor modules under even short time scales suggests that motor modules extracted during locomotion may be more indicative of correlated muscle activity induced by the task constraints of walking, rather than reflecting a modular control strategy.

  12. Program-Controlled High Voltage Module in Active Voltage Dividers(AVD) for MPGD

    CERN Document Server

    Ginting, Muhammad Fadhil

    2016-01-01

    Micro Pattern Gas Detectors (MPGD) applications are rapidly developing and became an important part of upgrades for the LHC detectors. RD51/CERN have worked on Active Voltage Divider (AVD) technology for multistage MPGDs, One of the next developments for the AVD is to design and integrate high voltage module in a single box. The Program-Controlled High Voltage Module, part of one AIDA2020 project, has been successfully designed and developed, and can be integrated in AVD design.

  13. Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines

    OpenAIRE

    Spurny, R.; Ramerstorfer, J.; Price, K; Brams, M.; M. Ernst; Nury, H.; Verheij, M.; Legrand, P.; Bertrand, D.; Bertrand, S.; Dougherty, D A; de Esch, I. J. P.; Corringer, P.-J.; Sieghart, W.; Lummis, S. C. R.

    2012-01-01

    GABA_A receptors are pentameric ligand-gated ion channels involved in fast inhibitory neurotransmission and are allosterically modulated by the anxiolytic, anticonvulsant, and sedative-hypnotic benzodiazepines. Here we show that the prokaryotic homolog ELIC also is activated by GABA and is modulated by benzodiazepines with effects comparable to those at GABA_A receptors. Crystal structures reveal important features of GABA recognition and indicate that benzodiazepines, depending on their conc...

  14. Modulation of bulbospinal RVLM neurons by hypoxia/hypercapnia but not medullary respiratory activity

    OpenAIRE

    Boychuk, Carie R.; Woerman, Amanda L.; Mendelowitz, David

    2012-01-01

    Although sympathetic vasomotor discharge has respiratory modulation, the site(s) responsible for this cardiorespiratory interaction are unknown. One likely source for this coupling is the RVLM where pre-sympathetic neurons originate in close apposition to respiratory neurons. The current study tested the hypothesis that RVLM bulbospinal neurons are modulated by medullary respiratory network activity using whole-cell patch-clamp electrophysiological recordings of RVLM neurons while simultaneou...

  15. Reward Sensitivity Modulates Brain Activity in the Prefrontal Cortex, ACC and Striatum during Task Switching

    Science.gov (United States)

    Fuentes-Claramonte, Paola; Ávila, César; Rodríguez-Pujadas, Aina; Ventura-Campos, Noelia; Bustamante, Juan C.; Costumero, Víctor; Rosell-Negre, Patricia; Barrós-Loscertales, Alfonso

    2015-01-01

    Current perspectives on cognitive control acknowledge that individual differences in motivational dispositions may modulate cognitive processes in the absence of reward contingencies. This work aimed to study the relationship between individual differences in Behavioral Activation System (BAS) sensitivity and the neural underpinnings involved in processing a switching cue in a task-switching paradigm. BAS sensitivity was hypothesized to modulate brain activity in frontal regions, ACC and the striatum. Twenty-eight healthy participants underwent fMRI while performing a switching task, which elicited activity in fronto-striatal regions during the processing of the switch cue. BAS sensitivity was negatively associated with activity in the lateral prefrontal cortex, anterior cingulate cortex and the ventral striatum. Combined with previous results, our data indicate that BAS sensitivity modulates the neurocognitive processes involved in task switching in a complex manner depending on task demands. Therefore, individual differences in motivational dispositions may influence cognitive processing in the absence of reward contingencies. PMID:25875640

  16. Development and construction of a thermoelectric active facade module

    OpenAIRE

    Marıa Ibanez-Puy; Jose Antonio Fernandez Sacristan; Cesar Martın-Gomez; Marina Vidaurre-Arbizu

    2015-01-01

    In order to fulfil the current challenges for the European building sector, building design has diverged into two alternative directions: active technologies and passive design strategies. In the last few years, advanced and responsive building envelope components have represented a promising answer to these challenges. This paper presents the design and construction process of a project that aims to design, build and control the energy performance of an industrial-scale modular active ventil...

  17. Fuzzy Behavior Modulation with Threshold Activation for Autonomous Vehicle Navigation

    Science.gov (United States)

    Tunstel, Edward

    2000-01-01

    This paper describes fuzzy logic techniques used in a hierarchical behavior-based architecture for robot navigation. An architectural feature for threshold activation of fuzzy-behaviors is emphasized, which is potentially useful for tuning navigation performance in real world applications. The target application is autonomous local navigation of a small planetary rover. Threshold activation of low-level navigation behaviors is the primary focus. A preliminary assessment of its impact on local navigation performance is provided based on computer simulations.

  18. Activity-dependent modulation of neural circuit synaptic connectivity

    OpenAIRE

    Tessier, Charles R.; Kendal Broadie

    2009-01-01

    In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; 1) early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and 2) subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circ...

  19. Codon usage determines translation rate in Escherichia coli

    DEFF Research Database (Denmark)

    Sørensen, Michael Askvad; Kurland, C G; Pedersen, Steen

    1989-01-01

    We wish to determine whether differences in translation rate are correlated with differences in codon usage or with differences in mRNA secondary structure. We therefore inserted a small DNA fragment in the lacZ gene either directly or flanked by a few frame-shifting bases, leaving the reading...

  20. Modulation of KCNQ4 channel activity by changes in cell volume

    DEFF Research Database (Denmark)

    Hougaard, Charlotte; Klaerke, Dan A; Hoffmann, Else K;

    2004-01-01

    KCNQ4 channels expressed in HEK 293 cells are sensitive to cell volume changes, being activated by swelling and inhibited by shrinkage, respectively. The KCNQ4 channels contribute significantly to the regulatory volume decrease (RVD) process following cell swelling. Under isoosmotic conditions......, the KCNQ4 channel activity is modulated by protein kinases A and C, G protein activation, and a reduction in the intracellular Ca2+ concentration, but these signalling pathways are not responsible for the increased channel activity during cell swelling....

  1. Construction and characterization of mutations at codon 751 of the Escherichia coli gyrB gene that confer resistance to the antimicrobial peptide microcin B17 and alter the activity of DNA gyrase.

    Science.gov (United States)

    del Castillo, F J; del Castillo, I; Moreno, F

    2001-03-01

    Microcin B17 is a peptide antibiotic that inhibits DNA replication in Escherichia coli by targeting DNA gyrase. Previously, two independently isolated microcin B17-resistant mutants were shown to harbor the same gyrB point mutation that results in the replacement of tryptophan 751 by arginine in the GyrB polypeptide. We used site-directed mutagenesis to construct mutants in which tryptophan 751 was deleted or replaced by other amino acids. These mutants exhibit altered DNA gyrase activity and different levels of resistance to microcin B17.

  2. Modulation of Motor Area Activity during Observation of Unnatural Body Movements

    Science.gov (United States)

    Shimada, Sotaro; Oki, Kazuma

    2012-01-01

    The mirror neuron system (MNS) is activated when observing the actions of others. However, it remains unclear whether the MNS responds more strongly to natural bodily actions in the observer's motor repertoire than to unnatural actions. We investigated whether MNS activity is modulated by the unnaturalness of an observed action by inserting short…

  3. Modulation of the protein kinase activity of mTOR.

    Science.gov (United States)

    Lawrence, J C; Lin, T A; McMahon, L P; Choi, K M

    2004-01-01

    mTOR is a founding member of a family of protein kinases having catalytic domains homologous to those in phosphatidylinositol 3-OH kinase. mTOR participates in the control by insulin of the phosphorylation of lipin, which is required for adipocyte differentiation, and the two translational regulators, p70S6K and PHAS-I. The phosphorylation of mTOR, itself, is stimulated by insulin in Ser2448, a site that is also phosphorylated by protein kinase B (PKB) in vitro and in response to activation of PKB activity in vivo. Ser2448 is located in a short stretch of amino acids not found in the two TOR proteins in yeast. A mutant mTOR lacking this stretch exhibited increased activity, and binding of the antibody, mTAb-1, to this region markedly increased mTOR activity. In contrast, rapamycin-FKBP12 inhibited mTOR activity towards both PHAS-I and p70S6K, although this complex inhibited the phosphorylation of some sites more than that of others. Mutating Ser2035 to Ile in the FKBP12-rapamycin binding domain rendered mTOR resistant to inhibition by rapamycin. Unexpectedly, this mutation markedly decreased the ability of mTOR to phosphorylate certain sites in both PHAS-I and p70S6K. The results support the hypotheses that rapamycin disrupts substrate recognition instead of directly inhibiting phosphotransferase activity and that mTOR activity in cells is controlled by the phosphorylation of an inhibitory regulatory domain containing the mTAb-1 epitope. PMID:14560959

  4. Modulation of β-catenin signaling by glucagon receptor activation.

    Directory of Open Access Journals (Sweden)

    Jiyuan Ke

    Full Text Available The glucagon receptor (GCGR is a member of the class B G protein-coupled receptor family. Activation of GCGR by glucagon leads to increased glucose production by the liver. Thus, glucagon is a key component of glucose homeostasis by counteracting the effect of insulin. In this report, we found that in addition to activation of the classic cAMP/protein kinase A (PKA pathway, activation of GCGR also induced β-catenin stabilization and activated β-catenin-mediated transcription. Activation of β-catenin signaling was PKA-dependent, consistent with previous reports on the parathyroid hormone receptor type 1 (PTH1R and glucagon-like peptide 1 (GLP-1R receptors. Since low-density-lipoprotein receptor-related protein 5 (Lrp5 is an essential co-receptor required for Wnt protein mediated β-catenin signaling, we examined the role of Lrp5 in glucagon-induced β-catenin signaling. Cotransfection with Lrp5 enhanced the glucagon-induced β-catenin stabilization and TCF promoter-mediated transcription. Inhibiting Lrp5/6 function using Dickkopf-1(DKK1 or by expression of the Lrp5 extracellular domain blocked glucagon-induced β-catenin signaling. Furthermore, we showed that Lrp5 physically interacted with GCGR by immunoprecipitation and bioluminescence resonance energy transfer assays. Together, these results reveal an unexpected crosstalk between glucagon and β-catenin signaling, and may help to explain the metabolic phenotypes of Lrp5/6 mutations.

  5. How Orthography Modulates Morphological Priming: Subliminal Kanji Activation in Japanese

    Science.gov (United States)

    Nakano, Yoko; Ikemoto, Yu; Jacob, Gunnar; Clahsen, Harald

    2016-01-01

    The current study investigates to what extent masked morphological priming is modulated by language-particular properties, specifically by its writing system. We present results from two masked priming experiments investigating the processing of complex Japanese words written in less common (moraic) scripts. In Experiment 1, participants performed lexical decisions on target verbs; these were preceded by primes which were either (i) a past-tense form of the same verb, (ii) a stem-related form with the epenthetic vowel -i, (iii) a semantically-related form, and (iv) a phonologically-related form. Significant priming effects were obtained for prime types (i), (ii), and (iii), but not for (iv). This pattern of results differs from previous findings on languages with alphabetic scripts, which found reliable masked priming effects for morphologically related prime/target pairs of type (i), but not for non-affixal and semantically-related primes of types (ii), and (iii). In Experiment 2, we measured priming effects for prime/target pairs which are neither morphologically, semantically, phonologically nor - as presented in their moraic scripts—orthographically related, but which—in their commonly written form—share the same kanji, which are logograms adopted from Chinese. The results showed a significant priming effect, with faster lexical-decision times for kanji-related prime/target pairs relative to unrelated ones. We conclude that affix-stripping is insufficient to account for masked morphological priming effects across languages, but that language-particular properties (in the case of Japanese, the writing system) affect the processing of (morphologically) complex words. PMID:27065895

  6. How Orthography Modulates Morphological Priming: Subliminal Kanji Activation in Japanese

    Directory of Open Access Journals (Sweden)

    Yoko eNakano

    2016-03-01

    Full Text Available The current study investigates to what extent masked morphological priming is modulated by language-particular properties, specifically by its writing system. We present results from two masked priming experiments investigating the processing of complex Japanese words written in less common (moraic scripts. In Experiment 1, participants performed lexical decisions on target verbs; these were preceded by primes which were either (i a past-tense form of the same verb, (ii a stem-related form with the epenthetic vowel -i, (iii a semantically-related form, and (iv a phonologically-related form. Significant priming effects were obtained for prime types (i, (ii and (iii, but not for (iv. This pattern of results differs from previous findings on languages with alphabetic scripts, which found reliable masked priming effects for morphologically related prime/target pairs of type (i, but not for non-affixal and semantically-related primes of types (ii and (iii. In Experiment 2, we measured priming effects for prime/target pairs which are neither morphologically, semantically, phonologically nor - as presented in their moraic scripts – orthographically related, but which - in their commonly written form - share the same kanji, which are logograms adopted from Chinese. The results showed a significant priming effect, with faster lexical-decision times for kanji-related prime/target pairs relative to unrelated ones. We conclude that affix-stripping is insufficient to account for masked morphological priming effects across languages, but that language-particular properties (in the case of Japanese, the writing system affect the processing of (morphologically complex words.

  7. How Orthography Modulates Morphological Priming: Subliminal Kanji Activation in Japanese.

    Science.gov (United States)

    Nakano, Yoko; Ikemoto, Yu; Jacob, Gunnar; Clahsen, Harald

    2016-01-01

    The current study investigates to what extent masked morphological priming is modulated by language-particular properties, specifically by its writing system. We present results from two masked priming experiments investigating the processing of complex Japanese words written in less common (moraic) scripts. In Experiment 1, participants performed lexical decisions on target verbs; these were preceded by primes which were either (i) a past-tense form of the same verb, (ii) a stem-related form with the epenthetic vowel -i, (iii) a semantically-related form, and (iv) a phonologically-related form. Significant priming effects were obtained for prime types (i), (ii), and (iii), but not for (iv). This pattern of results differs from previous findings on languages with alphabetic scripts, which found reliable masked priming effects for morphologically related prime/target pairs of type (i), but not for non-affixal and semantically-related primes of types (ii), and (iii). In Experiment 2, we measured priming effects for prime/target pairs which are neither morphologically, semantically, phonologically nor - as presented in their moraic scripts-orthographically related, but which-in their commonly written form-share the same kanji, which are logograms adopted from Chinese. The results showed a significant priming effect, with faster lexical-decision times for kanji-related prime/target pairs relative to unrelated ones. We conclude that affix-stripping is insufficient to account for masked morphological priming effects across languages, but that language-particular properties (in the case of Japanese, the writing system) affect the processing of (morphologically) complex words. PMID:27065895

  8. Activity-dependent modulation of neural circuit synaptic connectivity

    Directory of Open Access Journals (Sweden)

    Charles R Tessier

    2009-07-01

    Full Text Available In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; 1 early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and 2 subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circuits are “hard-wired” in a purely activity-independent manner. This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution. These recent studies reveal that activity-dependent mechanisms are indeed required to refine circuit maps in Drosophila during precise, restricted windows of late-phase development. Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function. This review focuses on our current understanding of activity-dependent synaptic connectivity in Drosophila, primarily through analyzing the role of the fragile X mental retardation protein (FMRP in the Drosophila FXS disease model. The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail.

  9. Expression of a Chimeric Allergen with High Rare Codons Content in Codon Bias-Adjusted Escherichia coli: Escherichia coli BL21 (DE3)-Codon Plus RIL as an Efficient Host.

    Science.gov (United States)

    Nouri, Hamid Reza; Karkhah, Ahmad; Varasteh, Abdolreza; Sankian, Mojtaba

    2016-07-01

    The expression of heterologous proteins in Escherichia coli (E. coli) is importantly affected by codon bias. Hence, the aim of the current study was to determine which codon bias-adjusted E. coli strain is sufficient for expression of a chimeric allergen coded by high rare codon content. To investigate the expression level, a chimeric protein of Chenopodium album (C. album) was used as an appropriate model. An expression construct was assembled and was transformed to four strains of codon bias-adjusted E. coli including origami, BL21 (DE3), BL21 (DE3)-codon plus RIL, and Rosetta. The level of expression and solubility of the chimeric allergen was analyzed by SDS-PAGE. In addition, the allergenicity of chimeric allergen was determined using immunoblotting. Our results showed that the chimeric allergen was expressed at high level in E. coli BL21 (DE3)-codon plus RIL and Rosetta. In detail, this recombinant allergen was isolated from soluble fraction in the codon bias-adjusted strains of E. coli BL21 (DE3)-codon plus RIL and Rosetta. Moreover, some lower molecular weight proteins were observed in Rosetta, which could be related to inappropriate expression or broken compartments of the chimeric allergen. The immunoblotting assay confirmed that the IgE-specific immune reactivity of our chimeric allergen expressed in BL21 (DE3)-codon plus RIL was significantly higher than the other strains. Our results showed that the expression of the chimeric allergen with high rare codons content in a codon bias-adjusted strain E. coli BL21 (DE3)-codon plus RIL improves the quality and solubility of the heterologous protein production. PMID:27040822

  10. Modulation of Erythrocyte Plasma Membrane Redox System Activity by Curcumin.

    Science.gov (United States)

    Singh, Prabhakar; Kesharwani, Rajesh Kumar; Misra, Krishna; Rizvi, Syed Ibrahim

    2016-01-01

    Plasma membrane redox system (PMRS) is an electron transport chain system ubiquitously present throughout all cell types. It transfers electron from intracellular substrates to extracellular acceptors for regulation of redox status. Curcumin, isolated from Curcuma longa, has modulatory effects on cellular physiology due to its membrane interaction ability and antioxidant potential. The present study investigates the effect of curcumin on PMRS activity of erythrocytes isolated from Wistar rats in vitro and in vivo and validated through an in silico docking simulation study using Molegro Virtual Docker (MVD). Effects of curcumin were also evaluated on level of glutathione (GSH) and the oxidant potential of plasma measured in terms of plasma ferric equivalent oxidative potentials (PFEOP). Results show that curcumin significantly (p < 0.01) downregulated the PMRS activity in a dose-dependent manner. Molecular docking results suggest that curcumin interacts with amino acids at the active site cavity of cytochrome b 5 reductase, a key constituent of PMRS. Curcumin also increased the GSH level in erythrocytes and plasma while simultaneously decreasing the oxidant potential (PFEOP) of plasma. Altered PMRS activity and redox status are associated with the pathophysiology of several health complications including aging and diabetes; hence, the above finding may explain part of the role of curcumin in health beneficial effects. PMID:26904287

  11. Modulation of Erythrocyte Plasma Membrane Redox System Activity by Curcumin

    Directory of Open Access Journals (Sweden)

    Prabhakar Singh

    2016-01-01

    Full Text Available Plasma membrane redox system (PMRS is an electron transport chain system ubiquitously present throughout all cell types. It transfers electron from intracellular substrates to extracellular acceptors for regulation of redox status. Curcumin, isolated from Curcuma longa, has modulatory effects on cellular physiology due to its membrane interaction ability and antioxidant potential. The present study investigates the effect of curcumin on PMRS activity of erythrocytes isolated from Wistar rats in vitro and in vivo and validated through an in silico docking simulation study using Molegro Virtual Docker (MVD. Effects of curcumin were also evaluated on level of glutathione (GSH and the oxidant potential of plasma measured in terms of plasma ferric equivalent oxidative potentials (PFEOP. Results show that curcumin significantly (p<0.01 downregulated the PMRS activity in a dose-dependent manner. Molecular docking results suggest that curcumin interacts with amino acids at the active site cavity of cytochrome b5 reductase, a key constituent of PMRS. Curcumin also increased the GSH level in erythrocytes and plasma while simultaneously decreasing the oxidant potential (PFEOP of plasma. Altered PMRS activity and redox status are associated with the pathophysiology of several health complications including aging and diabetes; hence, the above finding may explain part of the role of curcumin in health beneficial effects.

  12. Genome-wide analysis of the synonymous codon usage patterns in apple

    Institute of Scientific and Technical Information of China (English)

    LI Ning; SUN Mei-hong; JIANG Ze-sheng; SHU Huai-rui; ZHANG Shi-zhong

    2016-01-01

    Apple (Malus×domestica) has been proposed as an important woody plant and the major cultivated fruit trees in temperate regions. Apple whole genome sequencing has been completed, which provided an excelent opportunity for genome-wide analysis of the synonymous codon usage patterns. In this study, a multivariate bioinformatics analysis was performed to reveal the characteristics of synonymous codon usage and the main factors affecting codon bias in apple. The neutrality, correspondence, and correlation analyses were performed by CodonW and SPSS (Statistical Product and Service Solu-tions) programs, indicating that the apple genome codon usage patterns were affected by mutational pressure and selective constraint. Meanwhile, coding sequence length and the hydrophobicity of proteins could also inlfuence the codon usage patterns. In short, codon usage pattern analysis and determination of optimal codons has laid an important theoretical basis for genetic engineering, gene prediction and molecular evolution studies in apple.

  13. Crystallinity Modulation of Layered Carbon Nitride for Enhanced Photocatalytic Activities.

    Science.gov (United States)

    Wang, Jianhai; Shen, Yanfei; Li, Ying; Liu, Songqin; Zhang, Yuanjian

    2016-08-22

    As an emerging metal-free semiconductor, covalently bonded carbon nitride (CN) has attracted much attention in photocatalysis. However, drawbacks such as a high recombination rate of excited electrons and holes hinder its potential applications. Tailoring the crystallinity of semiconductors is an important way to suppress unwanted charge recombination, but has rarely been applied to CN so far. Herein, a simple method to synthesize CN of high crystallinity by protonation of specific intermediate species during conventional polymerization is reported. Interestingly, the as-obtained CN exhibited improved photocatalytic activities of up to seven times those of the conventional bulk CN. This approach, with only a slight change to the conventional method, provides a facile way to effectively regulate the crystallinity of bulk CN to improve its photocatalytic activities and sheds light on large-scale industrial applications of CN with high efficiency for sustainable energy.

  14. Substrate modulation of enzyme activity in the herpesvirus protease family

    OpenAIRE

    Lazic, Ana; Goetz, David H.; Nomura, Anson M.; Marnett, Alan B.; Craik, Charles S.

    2007-01-01

    The herpesvirus proteases are an example in which allosteric regulation of an enzyme activity is achieved through the formation of quaternary structure. Here, we report a 1.7 Å resolution structure of Kaposi’s Sarcoma herpesvirus protease in complex with a hexapeptide transition state analogue that stabilizes the dimeric state of the enzyme. Extended substrate binding sites are induced upon peptide binding. In particular, 104 Å2 of surface are buried in the newly formed S4 pocket when tyrosin...

  15. Modulation of insulin degrading enzyme activity and liver cell proliferation

    OpenAIRE

    Pivovarova, Olga; von Loeffelholz, Christian; Ilkavets, Iryna; Sticht, Carsten; Zhuk, Sergei; Murahovschi, Veronica; Lukowski, Sonja; Döcke, Stephanie; Kriebel, Jennifer; de las Heras Gala, Tonia; Malashicheva, Anna; Kostareva, Anna; Lock, Johan F; Stockmann, Martin; Grallert, Harald

    2015-01-01

    Diabetes mellitus type 2 (T2DM), insulin therapy, and hyperinsulinemia are independent risk factors of liver cancer. Recently, the use of a novel inhibitor of insulin degrading enzyme (IDE) was proposed as a new therapeutic strategy in T2DM. However, IDE inhibition might stimulate liver cell proliferation via increased intracellular insulin concentration. The aim of this study was to characterize effects of inhibition of IDE activity in HepG2 hepatoma cells and to analyze liver specific expre...

  16. Reconstituted high-density lipoprotein modulates activation of human leukocytes.

    Directory of Open Access Journals (Sweden)

    Rolf Spirig

    Full Text Available An anti-inflammatory effect of reconstituted High Density Lipoprotein (rHDL has been demonstrated in atherosclerosis and in sepsis models. An increase of adhesion molecules as well as tissue factor expression on endothelial cells in response to inflammatory or danger signals are attenuated by the treatment with rHDL. Here we show the inhibitory effect of rHDL on the activation of human leukocytes in a whole blood assay as well as on monocyte-derived human dendritic cells (DC. Multiplex analysis of human whole blood showed that phytohaemagglutinin (PHA-induced secretion of the cytokines IL-1β, IL-1RA, IL-2R, IL-6, IL-7, IL-12(p40, IL-15 and IFN-α was inhibited. Furthermore, an inhibitory effect on the production of the chemokines CCL-2, CCL-4, CCL-5, CXCL-9 and CXCL-10 was observed. Activation of granulocytes and CD14+ monocytes by PHA is inhibited dose-dependently by rHDL shown as decreased up-regulation of ICAM-1 surface expression. In addition, we found a strong inhibitory effect of rHDL on toll-like receptor 2 (TLR2- and TLR4-mediated maturation of DC. Treatment of DC with rHDL prevented the up-regulation of cell surface molecules CD80, CD83 and CD86 and it inhibited the TLR-driven activation of inflammatory transcription factor NF-κB. These findings suggest that rHDL prevents activation of crucial cellular players of cellular immunity and could therefore be a useful reagent to impede inflammation as well as the link between innate and adaptive immunity.

  17. Sendai Virus Fusion Activity as Modulated by Target Membrane Components

    OpenAIRE

    Nunes-Correia, Isabel; Ramalho-Santos, João; Maria C Pedroso de Lima

    1998-01-01

    We have studied the differences between erythrocytes and erythrocyte ghosts as target membranes for the study of Sendai virus fusion activity. Fusion was monitored continuously by fluorescence dequenching of R18-labeled virus. Experiments were carried out either with or without virus/target membrane prebinding. When Sendai virus was added directly to a erythrocyte/erythrocyte ghost suspension, fusion was always lower than that obtained when experiments were carried out with virus already boun...

  18. Implicitly perceived vocal attractiveness modulates prefrontal cortex activity.

    Science.gov (United States)

    Bestelmeyer, Patricia E G; Latinus, Marianne; Bruckert, Laetitia; Rouger, Julien; Crabbe, Frances; Belin, Pascal

    2012-06-01

    Social interactions involve more than "just" language. As important is a more primitive nonlinguistic mode of communication acting in parallel with linguistic processes and driving our decisions to a much higher degree than is generally suspected. Amongst the "honest signals" that influence our behavior is perceived vocal attractiveness. Not only does vocal attractiveness reflect important biological characteristics of the speaker, it also influences our social perceptions according to the "what sounds beautiful is good" phenomenon. Despite the widespread influence of vocal attractiveness on social interactions revealed by behavioral studies, its neural underpinnings are yet unknown. We measured brain activity while participants listened to a series of vocal sounds ("ah") and performed an unrelated task. We found that voice-sensitive auditory and inferior frontal regions were strongly correlated with implicitly perceived vocal attractiveness. While the involvement of auditory areas reflected the processing of acoustic contributors to vocal attractiveness ("distance to mean" and spectrotemporal regularity), activity in inferior prefrontal regions (traditionally involved in speech processes) reflected the overall perceived attractiveness of the voices despite their lack of linguistic content. These results suggest the strong influence of hidden nonlinguistic aspects of communication signals on cerebral activity and provide an objective measure of this influence.

  19. Implicitly perceived vocal attractiveness modulates prefrontal cortex activity.

    Science.gov (United States)

    Bestelmeyer, Patricia E G; Latinus, Marianne; Bruckert, Laetitia; Rouger, Julien; Crabbe, Frances; Belin, Pascal

    2012-06-01

    Social interactions involve more than "just" language. As important is a more primitive nonlinguistic mode of communication acting in parallel with linguistic processes and driving our decisions to a much higher degree than is generally suspected. Amongst the "honest signals" that influence our behavior is perceived vocal attractiveness. Not only does vocal attractiveness reflect important biological characteristics of the speaker, it also influences our social perceptions according to the "what sounds beautiful is good" phenomenon. Despite the widespread influence of vocal attractiveness on social interactions revealed by behavioral studies, its neural underpinnings are yet unknown. We measured brain activity while participants listened to a series of vocal sounds ("ah") and performed an unrelated task. We found that voice-sensitive auditory and inferior frontal regions were strongly correlated with implicitly perceived vocal attractiveness. While the involvement of auditory areas reflected the processing of acoustic contributors to vocal attractiveness ("distance to mean" and spectrotemporal regularity), activity in inferior prefrontal regions (traditionally involved in speech processes) reflected the overall perceived attractiveness of the voices despite their lack of linguistic content. These results suggest the strong influence of hidden nonlinguistic aspects of communication signals on cerebral activity and provide an objective measure of this influence. PMID:21828348

  20. Lipid metabolizing enzyme activities modulated by phospholipid substrate lateral distribution.

    Science.gov (United States)

    Salinas, Dino G; Reyes, Juan G; De la Fuente, Milton

    2011-09-01

    Biological membranes contain many domains enriched in phospholipid lipids and there is not yet clear explanation about how these domains can control the activity of phospholipid metabolizing enzymes. Here we used the surface dilution kinetic theory to derive general equations describing how complex substrate distributions affect the activity of enzymes following either the phospholipid binding kinetic model (which assumes that the enzyme molecules directly bind the phospholipid substrate molecules), or the surface-binding kinetic model (which assumes that the enzyme molecules bind to the membrane before binding the phospholipid substrate). Our results strongly suggest that, if the enzyme follows the phospholipid binding kinetic model, any substrate redistribution would increase the enzyme activity over than observed for a homogeneous distribution of substrate. Besides, enzymes following the surface-binding model would be independent of the substrate distribution. Given that the distribution of substrate in a population of micelles (each of them a lipid domain) should follow a Poisson law, we demonstrate that the general equations give an excellent fit to experimental data of lipases acting on micelles, providing reasonable values for kinetic parameters--without invoking special effects such as cooperative phenomena. Our theory will allow a better understanding of the cellular-metabolism control in membranes, as well as a more simple analysis of the mechanisms of membrane acting enzymes. PMID:21108012

  1. Multifractal detrended fluctuation analysis of optogenetic modulation of neural activity

    Science.gov (United States)

    Kumar, S.; Gu, L.; Ghosh, N.; Mohanty, S. K.

    2013-02-01

    Here, we introduce a computational procedure to examine whether optogenetically activated neuronal firing recordings could be characterized as multifractal series. Optogenetics is emerging as a valuable experimental tool and a promising approach for studying a variety of neurological disorders in animal models. The spiking patterns from cortical region of the brain of optogenetically-stimulated transgenic mice were analyzed using a sophisticated fluctuation analysis method known as multifractal detrended fluctuation analysis (MFDFA). We observed that the optogenetically-stimulated neural firings are consistent with a multifractal process. Further, we used MFDFA to monitor the effect of chemically induced pain (formalin injection) and optogenetic treatment used to relieve the pain. In this case, dramatic changes in parameters characterizing a multifractal series were observed. Both the generalized Hurst exponent and width of singularity spectrum effectively differentiates the neural activities during control and pain induction phases. The quantitative nature of the analysis equips us with better measures to quantify pain. Further, it provided a measure for effectiveness of the optogenetic stimulation in inhibiting pain. MFDFA-analysis of spiking data from other deep regions of the brain also turned out to be multifractal in nature, with subtle differences in the parameters during pain-induction by formalin injection and inhibition by optogenetic stimulation. Characterization of neuronal firing patterns using MFDFA will lead to better understanding of neuronal response to optogenetic activation and overall circuitry involved in the process.

  2. Detection and characterisation of delamination in PV modules by active infrared thermography

    Science.gov (United States)

    Sinha, A.; Sastry, O. S.; Gupta, R.

    2016-01-01

    The paper presents a fast and efficient method for the detection and characterisation of delamination in photovoltaic (PV) modules by using active infrared thermography approach. A discrete part of PV module was irradiated by step heating and its thermal image sequence was used to detect and analyse delamination. Different types of heating source for thermal excitation for this application have been studied. An electro-thermal model was developed to simulate the active thermography approach for the characterisation of delamination in PV module by equivalent resistance-capacitance (RC) network using a circuit simulator. This simulation approach was used to estimate the extent of delamination in the module and to determine the optimum parameters for the characterisation of delamination. Different applications based on front and backsides of heating the module were also proposed in this paper. The proposed method has the potential to be employed for the quality check of PV modules during inline production as well as for the predictive maintenance of outdoor PV plants.

  3. Hybrid Modulation of Bidirectional Three-Phase Dual-Active-Bridge DC Converters for Electric Vehicles

    Directory of Open Access Journals (Sweden)

    Yen-Ching Wang

    2016-06-01

    Full Text Available Bidirectional power converters for electric vehicles (EVs have received much attention recently, due to either grid-supporting requirements or emergent power supplies. This paper proposes a hybrid modulation of the three-phase dual-active bridge (3ΦDAB converter for EV charging systems. The designed hybrid modulation allows the converter to switch its modulation between phase-shifted and trapezoidal modes to increase the conversion efficiency, even under light-load conditions. The mode transition is realized in a real-time manner according to the charging or discharging current. The operation principle of the converter is analyzed in different modes and thus design considerations of the modulation are derived. A lab-scaled prototype circuit with a 48V/20Ah LiFePO4 battery is established to validate the feasibility and effectiveness.

  4. Clustering of classical swine fever virus isolates by codon pair bias

    Directory of Open Access Journals (Sweden)

    Leifer Immanuel

    2011-11-01

    Full Text Available Abstract Background The genetic code consists of non-random usage of synonymous codons for the same amino acids, termed codon bias or codon usage. Codon juxtaposition is also non-random, referred to as codon context bias or codon pair bias. The codon and codon pair bias vary among different organisms, as well as with viruses. Reasons for these differences are not completely understood. For classical swine fever virus (CSFV, it was suggested that the synonymous codon usage does not significantly influence virulence, but the relationship between variations in codon pair usage and CSFV virulence is unknown. Virulence can be related to the fitness of a virus: Differences in codon pair usage influence genome translation efficiency, which may in turn relate to the fitness of a virus. Accordingly, the potential of the codon pair bias for clustering CSFV isolates into classes of different virulence was investigated. Results The complete genomic sequences encoding the viral polyprotein of 52 different CSFV isolates were analyzed. This included 49 sequences from the GenBank database (NCBI and three newly sequenced genomes. The codon usage did not differ among isolates of different virulence or genotype. In contrast, a clustering of isolates based on their codon pair bias was observed, clearly discriminating highly virulent isolates and vaccine strains on one side from moderately virulent strains on the other side. However, phylogenetic trees based on the codon pair bias and on the primary nucleotide sequence resulted in a very similar genotype distribution. Conclusion Clustering of CSFV genomes based on their codon pair bias correlate with the genotype rather than with the virulence of the isolates.

  5. Multiple Evolutionary Selections Involved in Synonymous Codon Usages in the Streptococcus agalactiae Genome

    OpenAIRE

    Yan-Ping Ma; Hao Ke; Zhi-Ling Liang; Zhen-Xing Liu; Le Hao; Jiang-Yao Ma; Yu-Gu Li

    2016-01-01

    Streptococcus agalactiae is an important human and animal pathogen. To better understand the genetic features and evolution of S. agalactiae, multiple factors influencing synonymous codon usage patterns in S. agalactiae were analyzed in this study. A- and U-ending rich codons were used in S. agalactiae function genes through the overall codon usage analysis, indicating that Adenine (A)/Thymine (T) compositional constraints might contribute an important role to the synonymous codon usage patte...

  6. Respiratory modulation of sympathetic nerve activity is enhanced in male rat offspring following uteroplacental insufficiency.

    Science.gov (United States)

    Menuet, C; Wlodek, M E; Fong, A Y; Allen, A M

    2016-06-01

    Sympathetic nerve activity to the cardiovascular system displays prominent respiratory-related modulation which leads to the generation of rhythmic oscillations in blood pressure called Traube-Hering waves. An amplification of this respiratory modulation of sympathetic activity is observed in hypertension of both genetic, the spontaneously hypertensive rat, and induced, chronic intermittent hypoxia or maternal protein restriction during gestation, origin. Male offspring of mothers with uteroplacental insufficiency, induced by bilateral uterine vessel ligation at 18 days of gestation, are also hypertensive in adulthood. In this study we examined whether these male offspring display altered respiratory modulation of sympathetic activity at pre-hypertensive ages compared to controls. Respiratory, cardiovascular and sympathetic parameters were examined using the working heart-brainstem preparation in 35 day old male rats that had reduced birth weight due to uteroplacental insufficiency. Whilst all respiratory parameters were not different between groups, we observed an enhanced respiratory-related burst of thoracic sympathetic nerve activity and amplified Traube-Hering waves in the growth-restricted group. This group also showed an increased sympathetic and bradycardic response to activation of peripheral chemoreceptors. The observations add support to the view that altered respiratory modulation of sympathetic activity represents a common mechanism involved in the development of several forms of hypertension. PMID:26593642

  7. Comparative investigation of the various determinants that influence the codon and amino acid usage patterns in the genus Bifidobacterium.

    Science.gov (United States)

    Roy, Ayan; Mukhopadhyay, Subhasish; Sarkar, Indrani; Sen, Arnab

    2015-06-01

    Various strains of the genus Bifidobacterium are crucial members of the human, animal and insect gut, associated with beneficial probiotic activities. An extensive analysis on codon and amino acid usage of the GC rich genus Bifidobacterium has been executed in the present study. Multivariate statistical analysis revealed a coupled effect of GC compositional constraint and natural selection for translational efficiency to be operative in producing the observed codon usage variations. Gene expression level was inferred to be the most crucial factor governing the codon usage patterns. Amino acid usage was found to be influenced significantly by hydrophobic and aromatic character of the encoded proteins. Gene expressivity and protein energetic cost also had considerable impact on the differential mode of amino acid usage. The genus was found to strictly obey the cost-minimization hypothesis as was reflected from the amino acid usage patterns of the potential highly expressed gene products. Evolutionary analysis revealed that the highly expressed genes were candidates to extreme evolutionary selection pressure and indicated a high degree of conservation at the proteomic level. Interestingly, the complimentary strands of replication appeared to evolve under similar evolutionary constraints which might be addressed as a consequence of absence of replicational selection and lack of strand-specific asymmetry among the members of the genus. Thus, the present endeavor confers considerable know-how pertaining to the codon and amino acid usage intricacies in Bifidobacterium and might prove handy for further scientific investigations associated with the concerned domain. PMID:25842224

  8. Development and construction of a thermoelectric active facade module

    Directory of Open Access Journals (Sweden)

    Marıa Ibanez-Puy

    2015-06-01

    Full Text Available In order to fulfil the current challenges for the European building sector, building design has diverged into two alternative directions: active technologies and passive design strategies. In the last few years, advanced and responsive building envelope components have represented a promising answer to these challenges. This paper presents the design and construction process of a project that aims to design, build and control the energy performance of an industrial-scale modular active ventilated facade prototype with a new Themoelectric Peltier System (TPS. The TPS is a thermoelectric HVAC heat pump system designed to be located in the building envelope and providing a high comfort level. Trying to optimize the energy performance of the traditional ventilated opaque facade, and make more efficient the energy performance of the TPS, the concept of adaptability has been applied to ventilated opaque facades. The essential research theme is to control the natural phenomena that take place inside the ventilated air cavity of the facade: taking advantage when heat dissipation is needed, and avoiding it when heat losses are not welcome. In order to quantify the previous statements, some facade prototypes are being built in Pamplona (Spain and their energy performance is going to be analyzed during a year.  

  9. Modulation of zinc toxicity by tissue plasminogen activator.

    Science.gov (United States)

    Siddiq, Mustafa M; Tsirka, Stella E

    2004-01-01

    The tissue plasminogen activator (tPA)-plasmin proteolytic system mediates excitotoxin-induced neurodegeneration in vivo and in cell culture. tPA also confers neuroprotection from zinc toxicity in cell culture through a proteolysis-independent mechanism. This raises two questions: what is this non-enzymatic mechanism, and why tPA does not synergize with zinc to promote neuronal cell death? We show here that zinc binds to tPA and inhibits its activity in a dose-dependent fashion, thus terminating its protease-dependent neurotoxic capacity. We extend the previously reported culture findings to demonstrate that elevated zinc is neurotoxic in vivo, and even more so when tPA is absent. Thus, physiological levels of tPA confer protection from elevated free zinc. Mechanistically, tPA promotes movement of zinc into hippocampal neuron cells through voltage-sensitive Ca(2+) channels and Ca(2+)-permeable AMPA/KA channels. Therefore, zinc and tPA each appear to be able to limit the potential of the other to facilitate neurodegeneration, a reciprocal set of actions that may be critical in the hippocampus where tPA is secreted during the nonpathological conditions of learning and memory at sites known to be repositories of free and sequestered zinc.

  10. Codon Bias as a Means to Fine-Tune Gene Expression

    NARCIS (Netherlands)

    Quax, T.E.F.; Claassens, N.J.H.P.; Söll, D.; Oost, van der J.

    2015-01-01

    The redundancy of the genetic code implies that most amino acids are encoded by multiple synonymous codons. In all domains of life, a biased frequency of synonymous codons is observed at the genome level, in functionally related genes (e.g., in operons), and within single genes. Other codon bias var

  11. Codon Usage Bias in Two Hemipteran Insect Species: Bemisia tabaci and Homalodisca coagulata

    Directory of Open Access Journals (Sweden)

    Jyotika Sharma

    2014-01-01

    Full Text Available Codon bias is the nonuniform use of synonymous codons which encode the same amino acid. Some codons are more frequently used than others in several organisms, particularly in the highly expressed genes. The spectacular diversity of insects makes them a suitable candidate for analyzing the codon usage bias. Recent expansion in genome sequencing of different insect species provides an opportunity for studying the codon usage bias. Several works on patterns of codon usage bias were done on Drosophila and other related species but only few works were found in Hemiptera order. We analyzed codon usage in two Hemipteran insect species namely Bemisia tabaci and Homalodisca coagulata. Most frequent codons end with A or C at the 3rd codon position. The ENC (a measure of codon bias value ranges from 43 to 60 (52.80 in B. tabaci but from 49 to 60 (56.69 in H. coagulata. In both insect species, a significant positive correlation was observed between A and A3%, C and C3%, and GC and GC3%, respectively. Our findings suggest that codon usage bias in two Hemipteran insect species is not remarkable and that mutation pressure causes the codon usage pattern in two Hemipteran insect species.

  12. Dopaminergic Activity in the Medial Prefrontal Cortex Modulates Fear Conditioning

    Directory of Open Access Journals (Sweden)

    Parvin Babaei

    2011-07-01

    Full Text Available "nThe purpose of the present study was to determine the role of medial prefrontal cortex (mPFC dopaminergic system in fear conditioning response considering individual differences. Animals were initially counterbalanced and classified based on open field test, and then were given a single infusion of the dopamine agonist, amphetamine (AMPH and antagonist, clozapine (CLZ into the medial prefrontal cortex. Rats received tone-shock pairing in a classical fear conditioning test and then exposed to the tone alone. Freezing responses were measured as conditioned fear index. The results showed that both AMPH and CLZ infusion in mPFC reduced the expression of conditioned fear. This finding indicates that elevation or reduction in the dopaminergic activity is associated with the decrease of fear responses, despite preexisting individual-typological differences.

  13. Activities of nicotinic acetylcholine receptors modulate neurotransmission and synaptic architecture

    Institute of Scientific and Technical Information of China (English)

    Akira Oda; Hidekazu Tanaka

    2014-01-01

    The cholinergic system is involved in a broad spectrum of brain function, and its failure has been implicated in Alzheimer’s disease. Acetylcholine transduces signals through muscarinic and nicotinic acetylcholine receptors, both of which inlfuence synaptic plasticity and cognition. However, the mechanisms that relate the rapid gating of nicotinic acetylcholine receptors to per-sistent changes in brain function have remained elusive. Recent evidence indicates that nicotinic acetylcholine receptors activities affect synaptic morphology and density, which result in per-sistent rearrangements of neural connectivity. Further investigations of the relationships between nicotinic acetylcholine receptors and rearrangements of neural circuitry in the central nervous system may help understand the pathogenesis of Alzheimer’s disease.

  14. Modulation of P-glycoprotein ATPase activity by some phytoconstituents.

    Science.gov (United States)

    Najar, I A; Sachin, B S; Sharma, S C; Satti, N K; Suri, K A; Johri, R K

    2010-03-01

    In the present investigation 16 phytoconstituents, which are active moieties found in several medicinal herbs, have been evaluated for their P-glycoprotein (P-gp) stimulation/inhibition profiles using a P-gp-dependent ATPase assay in rat jejunal membrane (in vitro). Acteoside, agnuside, catechin, chlorogenic acid, picroside -II and santonin showed an inhibitory effect. Negundoside, picroside -I and oleanolic acid caused a stimulatory effect. Andrographolide, apocyanin, berberine, glycyrrhizin, magniferin and piperine produced a biphasic response (stimulation at low concentration and inhibition at high concentration). The results suggested that a possible interaction of these phytoconstituents at the level of P-gp, could be an important parameter in determining their role in several key pharmacodynamic events. PMID:19653312

  15. A primary cardiac leiomyosarcoma with mutation at H-ras codon 12.

    Science.gov (United States)

    Parissis, J; Arvanitis, D; Sourvinos, G; Spandidos, D

    1997-01-01

    The presence of activating ras mutations in a cardiac leiomyosarcoma which occurred in the right atrium of the heart of a female patient was examined. The tumor had the appearance of leiomyosarcoma in rutine histopathological examination and the definite diagnosis was confirmed by a positive immunohistochemical reaction to smooth muscle actin. Molecular analysis by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) technique showed a point mutation of H-ras gene at codon 12. To the best of our knowledge, this is the first report describing ras gene mutation in a cardiac leiomyosarcoma implying a role for the ras oncogenes in the development of this tumor.

  16. CCL2/MCP-1 modulation of microglial activation and proliferation

    Directory of Open Access Journals (Sweden)

    Garcia-Bueno Borja

    2011-07-01

    Full Text Available Abstract Background Monocyte chemoattractant protein (CCL2/MCP-1 is a chemokine that attracts cells involved in the immune/inflammatory response. As microglia are one of the main cell types sustaining inflammation in brain, we proposed here to analyze the direct effects of MCP-1 on cultured primary microglia. Methods Primary microglia and neuronal cultures were obtained from neonatal and embryonic Wistar rats, respectively. Microglia were incubated with different concentrations of recombinant MCP-1 and LPS. Cell proliferation was quantified by measuring incorporation of bromodeoxyuridine (BrdU. Nitrite accumulation was measured using the Griess assay. The expression and synthesis of different proteins was measured by RT-PCR and ELISA. Cell death was quantified by measuring release of LDH into the culture medium. Results MCP-1 treatment (50 ng/ml, 24 h did not induce morphological changes in microglial cultures. Protein and mRNA levels of different cytokines were measured, showing that MCP-1 was not able to induce proinflammatory cytokines (IL-1β, IL6, MIP-1α, either by itself or in combination with LPS. A similar lack of effect was observed when measuring inducible nitric oxide synthase (NOS2 expression or accumulation of nitrites in the culture media as a different indicator of microglial activation. MCP-1 was also unable to alter the expression of different trophic factors that were reduced by LPS treatment. In order to explore the possible release of other products by microglia and their potential neurotoxicity, neurons were co-cultured with microglia: no death of neurons could be detected when treated with MCP-1. However, the presence of MCP-1 induced proliferation of microglia, an effect opposite to that observed with LPS. Conclusion These data indicate that, while causing migration and proliferation of microglia, MCP-1 does not appear to directly activate an inflammatory response in this cell type, and therefore, other factors may be

  17. Individually Tailored Screening of Susceptibility to Sarcopenia Using p53 Codon 72 Polymorphism, Phenotypes, and Conventional Risk Factors

    OpenAIRE

    Laura Di Renzo; Santo Gratteri; Francesca Sarlo; Andrea Cabibbo; Carmen Colica; Antonino De Lorenzo

    2014-01-01

    Background and Aim. p53 activity plays a role in muscle homeostasis and skeletal muscle differentiation; all pathways that lead to sarcopenia are related to p53 activities. We investigate the allelic frequency of the TP53 codon 72 in exon 4 polymorphism in the Italian female population and the association with appendicular skeletal muscle mass index in normal weight (NW), normal weight obese (NWO), and preobese-obese (Preob-Ob) subjects. Methods. We evaluated anthropometry, body composition, ...

  18. Isolated PWM DC-AC SICAM with an active capacitive voltage clamp[Pulse Density Modulated; Pulse Width Modulation

    Energy Technology Data Exchange (ETDEWEB)

    Ljusev, P.

    2004-03-15

    In this report an isolated PWM DC-AC SICAM with an active capacitive voltage clamp is presented. AC-DC power supply is implemented in its simplest form: diode rectifier followed by a medium-size charge-storage capacitors and possibly with an EMC filter on the mains entrance. Isolation from the AC mains is achieved using a high frequency (HF) transformer, whose voltages are not audio-modulated. The latter simplifies the design and is expected to have many advantages over the approach where the transformer voltages are modulated in regards to the audio signal reference. Input stage is built as a DC-AC inverter (push-pull, half-bridge or a full-bridge) and operated with 50% duty cycle, with all the challenges to avoid transformer saturation and obtain symmetrical operation. On the secondary side the output section is implemented as rectifier+inverter AC-AC stage, i.e. a true bidirectional bridge, which operation is aimed towards amplification of the audio signal. In order to solve the problem with the commutation of the load current, a dead time between the incoming and outgoing bidirectional switch is implemented, while a capacitive voltage clamp is used to keep the induced overvoltage to reasonable levels. The energy stored in the clamping capacitor is not wasted as in the dissipative clamps, but is rather transferred back to the primary side for further processing using an auxiliary isolated single-switch converter, i.e. an active clamping technique is used. (au)

  19. Comparative Analysis of Codon Usage Bias Patterns in Microsporidian Genomes

    OpenAIRE

    Xiang, Heng; Zhang, Ruizhi; Butler, Robert R.; Liu, Tie; Zhang, Li; Pombert, Jean-François; Zhou, Zeyang

    2015-01-01

    The sub-3 Mbp genomes from microsporidian species of the Encephalitozoon genus are the smallest known among eukaryotes and paragons of genomic reduction and compaction in parasites. However, their diminutive stature is not characteristic of all Microsporidia, whose genome sizes vary by an order of magnitude. This large variability suggests that different evolutionary forces are applied on the group as a whole. In this study, we have compared the codon usage bias (CUB) between eight taxonomica...

  20. Nonsense Codons Trigger an RNA Partitioning Shift*S⃞

    OpenAIRE

    Bhalla, Angela D.; Gudikote, Jayanthi P.; Wang, Jun; Chan, Wai-kin; Chang, Yao-Fu; Olivas, O. Renee; Wilkinson, Miles F

    2009-01-01

    T-cell receptor-β (TCRβ) genes naturally acquire premature termination codons (PTCs) as a result of programmed gene rearrangements. PTC-bearing TCRβ transcripts are dramatically down-regulated to protect T-cells from the deleterious effects of the truncated proteins that would otherwise be produced. Here we provide evidence that two responses collaborate to elicit this dramatic down-regulation. One is rapid mRNA decay triggered by the nonsense-mediated decay (NMD) RNA ...

  1. The fungus Candida albicans tolerates ambiguity at multiple codons

    Directory of Open Access Journals (Sweden)

    João Salvador Simões

    2016-03-01

    Full Text Available The ascomycete Candida albicans is a normal resident of the gastrointestinal tract of humans and other warm-blooded animals. It occurs in a broad range of body sites and has high capacity to survive and proliferate in adverse environments with drastic changes in oxygen, carbon dioxide, pH, osmolarity, nutrients and temperature. Its biology is unique due to flexible reassignment of the leucine CUG codon to serine and synthesis of statistical proteins. Under standard growth conditions 3% of leucine and 97% of serine are incorporated at CUG sites on a proteome wide scale, but leucine incorporation fluctuates in response to environmental stressors and can be artificially increased up to 98%. In order to determine whether such flexibility also exists at other codons, we have constructed several serine tRNAs that decode various non-cognate codons. Expression of these tRNAs had minor effects on fitness, but growth of the mistranslating strains at different temperatures, in medium with different pH and nutrients composition was often enhanced relatively to the wild type (WT strain, supporting our previous data on adaptive roles of CUG ambiguity in variable growth conditions. Parallel evolution of the recombinant strains (100 generations followed by full genome resequencing identified various strain specific single nucleotide polymorphisms (SNP and one SNP in the deneddylase (JAB1 gene in all strains. Since JAB1 is a subunit of the COP9 signalosome complex, which interacts with cullin (Cdc53p to mediate degradation of a variety of cellular proteins, our data suggest that neddylation plays a key role in tolerance and adaptation to codon ambiguity in C. albicans.

  2. Human SNPs resulting in premature stop codons and protein truncation

    OpenAIRE

    Savas Sevtap; Tuzmen Sukru; Ozcelik Hilmi

    2006-01-01

    Abstract Single nucleotide polymorphisms (SNPs) constitute the most common type of genetic variation in humans. SNPs introducing premature termination codons (PTCs), herein called X-SNPs, can alter the stability and function of transcripts and proteins and thus are considered to be biologically important. Initial studies suggested a strong selection against such variations/mutations. In this study, we undertook a genome-wide systematic screening to identify human X-SNPs using the dbSNP databa...

  3. Vestibular activation differentially modulates human early visual cortex and V5/MT excitability and response entropy.

    Science.gov (United States)

    Seemungal, Barry M; Guzman-Lopez, Jessica; Arshad, Qadeer; Schultz, Simon R; Walsh, Vincent; Yousif, Nada

    2013-01-01

    Head movement imposes the additional burdens on the visual system of maintaining visual acuity and determining the origin of retinal image motion (i.e., self-motion vs. object-motion). Although maintaining visual acuity during self-motion is effected by minimizing retinal slip via the brainstem vestibular-ocular reflex, higher order visuovestibular mechanisms also contribute. Disambiguating self-motion versus object-motion also invokes higher order mechanisms, and a cortical visuovestibular reciprocal antagonism is propounded. Hence, one prediction is of a vestibular modulation of visual cortical excitability and indirect measures have variously suggested none, focal or global effects of activation or suppression in human visual cortex. Using transcranial magnetic stimulation-induced phosphenes to probe cortical excitability, we observed decreased V5/MT excitability versus increased early visual cortex (EVC) excitability, during vestibular activation. In order to exclude nonspecific effects (e.g., arousal) on cortical excitability, response specificity was assessed using information theory, specifically response entropy. Vestibular activation significantly modulated phosphene response entropy for V5/MT but not EVC, implying a specific vestibular effect on V5/MT responses. This is the first demonstration that vestibular activation modulates human visual cortex excitability. Furthermore, using information theory, not previously used in phosphene response analysis, we could distinguish between a specific vestibular modulation of V5/MT excitability from a nonspecific effect at EVC.

  4. Vestibular Activation Differentially Modulates Human Early Visual Cortex and V5/MT Excitability and Response Entropy

    Science.gov (United States)

    Guzman-Lopez, Jessica; Arshad, Qadeer; Schultz, Simon R; Walsh, Vincent; Yousif, Nada

    2013-01-01

    Head movement imposes the additional burdens on the visual system of maintaining visual acuity and determining the origin of retinal image motion (i.e., self-motion vs. object-motion). Although maintaining visual acuity during self-motion is effected by minimizing retinal slip via the brainstem vestibular-ocular reflex, higher order visuovestibular mechanisms also contribute. Disambiguating self-motion versus object-motion also invokes higher order mechanisms, and a cortical visuovestibular reciprocal antagonism is propounded. Hence, one prediction is of a vestibular modulation of visual cortical excitability and indirect measures have variously suggested none, focal or global effects of activation or suppression in human visual cortex. Using transcranial magnetic stimulation-induced phosphenes to probe cortical excitability, we observed decreased V5/MT excitability versus increased early visual cortex (EVC) excitability, during vestibular activation. In order to exclude nonspecific effects (e.g., arousal) on cortical excitability, response specificity was assessed using information theory, specifically response entropy. Vestibular activation significantly modulated phosphene response entropy for V5/MT but not EVC, implying a specific vestibular effect on V5/MT responses. This is the first demonstration that vestibular activation modulates human visual cortex excitability. Furthermore, using information theory, not previously used in phosphene response analysis, we could distinguish between a specific vestibular modulation of V5/MT excitability from a nonspecific effect at EVC. PMID:22291031

  5. General and efficient method for calculating modulation ressponses and noise spectra of active semiconductor waveguides

    DEFF Research Database (Denmark)

    Blaaberg, Søren; Öhman, Filip; Mørk, Jesper

    2008-01-01

    We present a theoretical method for obtaining small-signal responses in a spatially resolved active semiconductor waveguide including finite end-facet reflectivities and amplified spontaneous emission. RF-modulation responses and output noise spectra of an SOA are shown....

  6. Real-time MEG neurofeedback training of posterior alpha activity modulates subsequent visual detection performance

    NARCIS (Netherlands)

    Okazaki, Y.O.; Horschig, J.; Luther, L.M.; Oostenveld, R.; Murakami, I.; Jensen, O.

    2015-01-01

    It has been demonstrated that alpha activity is lateralized when attention is directed to the left or right visual hemifield. We investigated whether real-time neurofeedback training of the alpha lateralization enhances participants' ability to modulate posterior alpha lateralization and causes subs

  7. Effect of modulated photo-activation on polymerization shrinkage behavior of dental restorative resin composites

    NARCIS (Netherlands)

    T.T. Tauböck; A.J. Feilzer; W. Buchalla; C.J. Kleverlaan; I. Krejci; T. Attin

    2014-01-01

    This study investigated the influence of modulated photo-activation on axial polymerization shrinkage, shrinkage force, and hardening of light- and dual-curing resin-based composites. Three light-curing resin composites (SDR bulk-fill, Esthet X flow, and Esthet X HD) and one dual-curing material (Re

  8. Modulators of membrane drug transporters potentiate the activity of the DMI fungicide oxpoconazole against Botrytis cinerea

    NARCIS (Netherlands)

    Hayashi, K.; Schoonbeek, H.; Waard, de M.A.

    2003-01-01

    Modulators known to reduce multidrug resistance in tumour cells were tested for their potency to synergize the fungitoxic activity of the fungicide oxpoconazole, a sterol demethylation inhibitor (DMI), against Botrytis cinerea Pers. Chlorpromazine, a phenothiazine compound known as a calmodulin anta

  9. MODULATION BREATHING OF THE ELECTRICAL ACTIVITY IN THE PHRENIC NERVE DURING STARTLES REFLEXES

    OpenAIRE

    Emanov, Sergey

    2006-01-01

    In the paper the reflex activity in the phrenic nerve is studied in chloralose anesthetized cats during development of somatic startle reflexes. Modulation of responses during the respiratory cycle is described. Organization of possible neurophysiologic mechanisms of phrenic responses during startle reflexes is discussed

  10. Effect of hypnotic pain modulation on brain activity in patients with temporomandibular disorder pain

    DEFF Research Database (Denmark)

    Abrahamsen, Randi; Dietz, Martin; Lodahl, Sanne;

    2010-01-01

    Hypnosis modulates pain perception but the associated brain mechanisms in chronic pain conditions are poorly understood. Brain activity evoked by painful repetitive pin-prick stimulation of the left mental nerve region was investigated with use of fMRI in 19 patients with painful temporomandibular...

  11. Codon Distribution in Error-Detecting Circular Codes

    Directory of Open Access Journals (Sweden)

    Elena Fimmel

    2016-03-01

    Full Text Available In 1957, Francis Crick et al. suggested an ingenious explanation for the process of frame maintenance. The idea was based on the notion of comma-free codes. Although Crick’s hypothesis proved to be wrong, in 1996, Arquès and Michel discovered the existence of a weaker version of such codes in eukaryote and prokaryote genomes, namely the so-called circular codes. Since then, circular code theory has invariably evoked great interest and made significant progress. In this article, the codon distributions in maximal comma-free, maximal self-complementary C3 and maximal self-complementary circular codes are discussed, i.e., we investigate in how many of such codes a given codon participates. As the main (and surprising result, it is shown that the codons can be separated into very few classes (three, or five, or six with respect to their frequency. Moreover, the distribution classes can be hierarchically ordered as refinements from maximal comma-free codes via maximal self-complementary C3 codes to maximal self-complementary circular codes.

  12. Tracing specific synonymous codon-secondary structure correlations through evolution.

    Science.gov (United States)

    Oresic, Matej; Dehn, Michael; Korenblum, Daniel; Shalloway, David

    2003-04-01

    We previously showed that GAU codons are preferred (relative to synonymous GAC codons) for encoding aspartates specifically at the N-termini of alpha-helices in human, but not in E. coli, proteins. To test if this difference reflected a general difference between eucaryotes and procaryotes, we now extended the analysis to include the proteins and coding sequences of mammals, vertebrates, S. cerevisiae, and plants. We found that the GAU-alpha-helix correlation is also strong in non-human mammalian and vertebrate proteins but is much weaker or insignificant in S. cerevisiae and plants. The vertebrate correlations are of sufficient strength to enhance alpha-helix N-terminus prediction. Additional results, including the observation that the correlation is significantly enhanced when proteins that are known to be correctly expressed in recombinant procaryotic systems are excluded, suggest that the correlation is induced at the level of protein translation and folding and not at the nucleic acid level. To the best of our knowledge, it is not explicable by the canonical picture of protein expression and folding, suggesting the existence of a novel evolutionary selection mechanism. One possible explanation is that some alpha-helix N-terminal GAU codons may facilitate correct co-translational folding in vertebrates.

  13. HCN channels contribute to serotonergic modulation of ventral surface chemosensitive neurons and respiratory activity.

    Science.gov (United States)

    Hawkins, Virginia E; Hawryluk, Joanna M; Takakura, Ana C; Tzingounis, Anastasios V; Moreira, Thiago S; Mulkey, Daniel K

    2015-02-15

    Chemosensitive neurons in the retrotrapezoid nucleus (RTN) provide a CO2/H(+)-dependent drive to breathe and function as an integration center for the respiratory network, including serotonergic raphe neurons. We recently showed that serotonergic modulation of RTN chemoreceptors involved inhibition of KCNQ channels and activation of an unknown inward current. Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels are the molecular correlate of the hyperpolarization-activated inward current (Ih) and have a high propensity for modulation by serotonin. To investigate whether HCN channels contribute to basal activity and serotonergic modulation of RTN chemoreceptors, we characterize resting activity and the effects of serotonin on RTN chemoreceptors in vitro and on respiratory activity of anesthetized rats in the presence or absence of blockers of KCNQ (XE991) and/or HCN (ZD7288, Cs(+)) channels. We found in vivo that bilateral RTN injections of ZD7288 increased respiratory activity and in vitro HCN channel blockade increased activity of RTN chemoreceptors under control conditions, but this was blunted by KCNQ channel inhibition. Furthermore, in vivo unilateral RTN injection of XE991 plus ZD7288 eliminated the serotonin response, and in vitro serotonin sensitivity was eliminated by application of XE991 and ZD7288 or SQ22536 (adenylate cyclase blocker). Serotonin-mediated activation of RTN chemoreceptors was blocked by a 5-HT7-receptor blocker and mimicked by a 5-HT7-receptor agonist. In addition, serotonin caused a depolarizing shift in the voltage-dependent activation of Ih. These results suggest that HCN channels contribute to resting chemoreceptor activity and that serotonin activates RTN chemoreceptors and breathing in part by a 5-HT7 receptor-dependent mechanism and downstream activation of Ih.

  14. Engineering a hyper-catalytic enzyme by photo-activated conformation modulation

    Energy Technology Data Exchange (ETDEWEB)

    Agarwal, Pratul K [ORNL

    2012-01-01

    Enzyme engineering for improved catalysis has wide implications. We describe a novel chemical modification of Candida antarctica lipase B that allows modulation of the enzyme conformation to promote catalysis. Computational modeling was used to identify dynamical enzyme regions that impact the catalytic mechanism. Surface loop regions located distal to active site but showing dynamical coupling to the reaction were connected by a chemical bridge between Lys136 and Pro192, containing a derivative of azobenzene. The conformational modulation of the enzyme was achieved using two sources of light that alternated the azobenzene moiety in cis and trans conformations. Computational model predicted that mechanical energy from the conformational fluctuations facilitate the reaction in the active-site. The results were consistent with predictions as the activity of the engineered enzyme was found to be enhanced with photoactivation. Preliminary estimations indicate that the engineered enzyme achieved 8-52 fold better catalytic activity than the unmodulated enzyme.

  15. 5-HT1A receptors modulate small-conductance Ca2+-activated K+ channels

    DEFF Research Database (Denmark)

    Grunnet, Morten; Jespersen, Thomas; Perrier, Jean-François

    2004-01-01

    Small-conductance calcium-activated potassium channels (SK) are responsible for the medium afterhyperpolarisation (mAHP) following action potentials in neurons. Here we tested the ability of serotonin (5-HT) to modulate the activity of SK channels by coexpressing 5-HT1A receptors with different...... and the ion channel. To investigate the physiological relevance of this pathway, we characterized the mAHP present after action potentials in spinal motoneurons recorded in a slice preparation from the lumbar spinal cord of the adult turtle. By performing current and voltage clamp recordings, we showed that 8......-OH-DPAT specifically inhibited the fraction of the AHP mediated by SK channels. We conclude that the activity of SK channels is modulated by activation of serotonergic receptors....

  16. Novel Active Bouncer Topology for Klystron Modulators based on Pulsed Transformers

    CERN Document Server

    AUTHOR|(CDS)2079689; Aguglia, Davide; Viarouge, Philippe; Cros, Jérôme

    2015-01-01

    Active droop compensation systems, so called active bouncers, for klystron modulators based on monolithic pulse transformers perform the regulation of the output pulse voltage while simultaneously withstand all the primary current of the modulator. This imposes the utilization of high power semiconductors which can produce high switching losses and degrade the overall system efficiency. In order to overcome this issue, this paper proposes a new active bouncer topology based on the parallel connection of two different power converters: the first one is in charge of handling the majority of the primary current at high efficiency, and the second one is used to fine tune the bouncer voltage via a high bandwidth converter rated at a fraction of the first parallel connected converter. Detailed comparison between a classical active bouncer and two variants of the proposed topology are presented and based on numerical simulations.

  17. Accessible cultural mind-set modulates default mode activity: evidence for the culturally situated brain.

    Science.gov (United States)

    Wang, Chenbo; Oyserman, Daphna; Liu, Qiang; Li, Hong; Han, Shihui

    2013-01-01

    Self-construal priming modulates human behavior and associated neural activity. However, the neural activity associated with the self-construal priming procedure itself remains unknown. It is also unclear whether and how self-construal priming affects neural activity prior to engaging in a particular task. To address this gap, we scanned Chinese adults, using functional magnetic resonance imaging, during self-construal priming and a following resting state. We found that, relative to a calculation task, both interdependent and independent self-construal priming activated the ventral medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC). The contrast of interdependent vs. independent self-construal priming also revealed increased activity in the dorsal MPFC and left middle frontal cortex. The regional homogeneity analysis of the resting-state activity revealed increased local synchronization of spontaneous activity in the dorsal MPFC but decreased local synchronization of spontaneous activity in the PCC when contrasting interdependent vs. independent self-construal priming. The functional connectivity analysis of the resting-state activity, however, did not show significant difference in synchronization of activities in remote brain regions between different priming conditions. Our findings suggest that accessible collectivistic/individualistic mind-set induced by self-construal priming is associated with modulations of both task-related and resting-state activity in the default mode network.

  18. Noradrenergic Activation of the Basolateral Amygdala Modulates Consolidation of Object Recognition Memory

    OpenAIRE

    Roozendaal, Benno; Castello, Nicholas A.; Vedana, Gustavo; Barsegyan, Areg; McGaugh, James L.

    2008-01-01

    Noradrenergic activation of the basolateral complex of the amygdala (BLA) modulates the consolidation of memory for many kinds of highly emotionally arousing training tasks. The present experiments investigated whether posttraining noradrenergic activation of the BLA is sufficient to enable memory consolidation of a low-arousing training experience. Sprague-Dawley rats received intra-BLA infusions of norepinephrine, the β-adrenoceptor antagonist propranolol or saline immediately after either ...

  19. Dopamine Modulates Reward System Activity During Subconscious Processing of Sexual Stimuli

    OpenAIRE

    Oei, Nicole Y. L.; Rombouts, Serge ARB; Soeter, Roelof P.; van Gerven, Joop M; Both, Stephanie

    2012-01-01

    Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive–compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the ‘reward system'. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. You...

  20. Copper modulates the phenotypic response of activated BV2 microglia through the release of nitric oxide

    OpenAIRE

    Rossi-George, Alba; GUO, CHANG-JIANG; Oakes, Benjamin L.; Gow, Andrew J.

    2012-01-01

    Microglia are resident immune cells of the central nervous system. Their persistent activation in neurodegenerative diseases, traditionally attributed to neuronal dysfunction, may be due to a microglial failure to modulate the release of cytotoxic mediators such as nitric oxide (NO). The persistent activation of microglia with the subsequent release of NO vis-á-vis the accumulation of redox transition metals such as copper (Cu) in neurodegenerative diseases, prompted the hypothesis that coppe...

  1. Identification of Functionally Relevant Lysine Residues That Modulate Human Farnesoid X Receptor Activation

    OpenAIRE

    Sun, An-Qiang; Luo, Yuhuan; Backos, Donald S.; Xu, Shuhua; Balasubramaniyan, Natarajan; Reigan, Philip; Suchy, Frederick J.

    2013-01-01

    Base amino acid lysine residues play an important role in regulation of nuclear receptors [e.g., farnesyl X receptor (FXR)], leading to enhanced or suppressed biologic activity. To understand the molecular mechanisms and the subsequent effects in modulating FXR functions in diverse biologic processes, we individually replaced eight highly conserved lysine residues of human FXR (hFXR) with arginine. The effects of each mutated FXR on target gene activation, subcellular localization, protein-pr...

  2. Plasmonic modulator optimized by patterning of active layer and tuning permittivity

    DEFF Research Database (Denmark)

    Babicheva, Viktoriia; Lavrinenko, Andrei

    2012-01-01

    -dimension periodic stripes increases transmittance through the device and keeps the modulator's performance at the same level. The dependence on the pattern size and filling factor of the active material is analyzed and optimum parameters are found. Patterned ITO layers allow us to design a Bragg grating inside the...... waveguide. The grating can be turned on and off, thus modulating reflection from the structure. The considered structure with electrical control possesses a high performance and can efficiently work as a plasmonic component in nanophotonic architectures....

  3. The p53 Codon 72 Polymorphism Modifies the Cellular Response to Inflammatory Challenge in the Liver.

    Science.gov (United States)

    Leu, Julia I-Ju; Murphy, Maureen E; George, Donna L

    2013-01-01

    The p53 protein is a critical stress-response mediator and signal coordinator in cellular metabolism and environmental exposure to deleterious agents. In human populations, the p53 gene contains a common single nucleotide polymorphism (SNP) affecting codon 72 that determines whether a proline (P72) or an arginine (R72) is present at this amino acid position of the polypeptide. Previous studies carried out using human populations, mouse models, and cell culture analyses have provided evidence that this amino acid difference can alter p53 functional activities, and potentially also can affect clinical presentation of disease. The clinical presentation associated with many forms of liver disease is variable, but few of the responsible underlying genetic factors or molecular pathways have been identified. The aim of the present study was to investigate whether the p53 codon 72 polymorphism influences the cellular response to hepatic stresses. A humanized p53 knock-in (Hupki) mouse model was used to address this issue. Mice expressing either the P72 or R72 normal variation of p53 were given an acute-, intermittent- or a chronic challenge, associated with exposure to lipopolysaccharide, D-galactosamine, or a high-fat diet. The results reveal that the livers of the P72 and R72 mice exhibit notable differences in inflammatory and apoptotic response to these distinct forms of stress. Interestingly the influence of this polymorphism on the response to stress is context dependent, with P72 showing increased response to liver toxins (lipopolysaccharide and D-galactosamine), but R72 showing increased response to metabolic stress (high fat diet). When taken together, these data point to the p53 codon 72 polymorphism as an important molecular mediator of events contributing to hepatic inflammation and metabolic homeostasis.

  4. Bicarbonate and Ca(2+) Sensing Modulators Activate Photoreceptor ROS-GC1 Synergistically.

    Science.gov (United States)

    Duda, Teresa; Pertzev, Alexandre; Makino, Clint L; Sharma, Rameshwar K

    2016-01-01

    Photoreceptor ROS-GC1, a prototype subfamily member of the membrane guanylate cyclase family, is a central component of phototransduction. It is a single transmembrane-spanning protein, composed of modular blocks. In rods, guanylate cyclase activating proteins (GCAPs) 1 and 2 bind to its juxtamembrane domain (JMD) and the C-terminal extension, respectively, to accelerate cyclic GMP synthesis when Ca(2+) levels are low. In cones, the additional expression of the Ca(2+)-dependent guanylate cyclase activating protein (CD-GCAP) S100B which binds to its C-terminal extension, supports acceleration of cyclic GMP synthesis at high Ca(2+) levels. Independent of Ca(2+), ROS-GC1 activity is also stimulated directly by bicarbonate binding to the core catalytic domain (CCD). Several enticing molecular features of this transduction system are revealed in the present study. In combination, bicarbonate and Ca(2+)-dependent modulators raised maximal ROS-GC activity to levels that exceeded the sum of their individual effects. The F(514)S mutation in ROS-GC1 that causes blindness in type 1 Leber's congenital amaurosis (LCA) severely reduced basal ROS-GC1 activity. GCAP2 and S100B Ca(2+) signaling modes remained functional, while the GCAP1-modulated mode was diminished. Bicarbonate nearly restored basal activity as well as GCAP2- and S100B-stimulated activities of the F(514)S mutant to normal levels but could not resurrect GCAP1 stimulation. We conclude that GCAP1 and GCAP2 forge distinct pathways through domain-specific modules of ROS-GC1 whereas the S100B and GCAP2 pathways may overlap. The synergistic interlinking of bicarbonate to GCAPs- and S100B-modulated pathways intensifies and tunes the dependence of cyclic GMP synthesis on intracellular Ca(2+). Our study challenges the recently proposed GCAP1 and GCAP2 "overlapping" phototransduction model (Peshenko et al., 2015b). PMID:26858600

  5. Modulation of WNT/β-catenin pathway in melanoma by biologically active components derived from plants.

    Science.gov (United States)

    Gajos-Michniewicz, Anna; Czyz, Malgorzata

    2016-03-01

    Metastatic melanoma is an aggressive cancer, often resistant to treatment. Therefore, it is essential to determine the molecular mechanisms leading to melanoma or underlying resistance to therapy, and the response to targeted inhibition of the RAS/BRAF/MEK/ERK pathway was a good lesson in this respect. Aberrant WNT/β-catenin pathway is observed in melanoma, and the modulators of this signaling cascade have been under investigation in the context of therapy as well as chemoprevention. Several natural compounds were recognized as being capable of targeting elements of the WNT/β-catenin pathway in various cancers, however, only a few of them can modulate this pathway in melanoma. This review examines recent research on the role of the WNT/β-catenin pathway in tumor development and maintenance, as well as summarizes the current knowledge concerning the modulation of this pathway in melanoma by active compounds of natural origin. PMID:26851176

  6. Performance Evaluation of a High Bandwidth Liquid Fuel Modulation Valve for Active Combustion Control

    Science.gov (United States)

    Saus, Joseph R.; DeLaat, John C.; Chang, Clarence T.; Vrnak, Daniel R.

    2012-01-01

    At the NASA Glenn Research Center, a characterization rig was designed and constructed for the purpose of evaluating high bandwidth liquid fuel modulation devices to determine their suitability for active combustion control research. Incorporated into the rig s design are features that approximate conditions similar to those that would be encountered by a candidate device if it were installed on an actual combustion research rig. The characterized dynamic performance measures obtained through testing in the rig are planned to be accurate indicators of expected performance in an actual combustion testing environment. To evaluate how well the characterization rig predicts fuel modulator dynamic performance, characterization rig data was compared with performance data for a fuel modulator candidate when the candidate was in operation during combustion testing. Specifically, the nominal and off-nominal performance data for a magnetostrictive-actuated proportional fuel modulation valve is described. Valve performance data were collected with the characterization rig configured to emulate two different combustion rig fuel feed systems. Fuel mass flows and pressures, fuel feed line lengths, and fuel injector orifice size was approximated in the characterization rig. Valve performance data were also collected with the valve modulating the fuel into the two combustor rigs. Comparison of the predicted and actual valve performance data show that when the valve is operated near its design condition the characterization rig can appropriately predict the installed performance of the valve. Improvements to the characterization rig and accompanying modeling activities are underway to more accurately predict performance, especially for the devices under development to modulate fuel into the much smaller fuel injectors anticipated in future lean-burning low-emissions aircraft engine combustors.

  7. Inhibitory short-term plasticity modulates neuronal activity in the rat entopeduncular nucleus in vitro.

    Science.gov (United States)

    Lavian, Hagar; Korngreen, Alon

    2016-04-01

    The entopeduncular nucleus (EP) is one of the basal ganglia output nuclei integrating synaptic information from several pathways within the basal ganglia. The firing of EP neurons is modulated by two streams of inhibitory synaptic transmission, the direct pathway from the striatum and the indirect pathway from the globus pallidus. These two inhibitory pathways continuously modulate the firing of EP neurons. However, the link between these synaptic inputs to neuronal firing in the EP is unclear. To investigate this input-output transformation we performed whole-cell and perforated-patch recordings from single neurons in the entopeduncular nucleus in rat brain slices during repetitive stimulation of the striatum and the globus pallidus at frequencies within the in vivo activity range of these neurons. These recordings, supplemented by compartmental modelling, showed that GABAergic synapses from the striatum, converging on EP dendrites, display short-term facilitation and that somatic or proximal GABAergic synapses from the globus pallidus show short-term depression. Activation of striatal synapses during low presynaptic activity decreased postsynaptic firing rate by continuously increasing the inter-spike interval. Conversely, activation of pallidal synapses significantly affected postsynaptic firing during high presynaptic activity. Our data thus suggest that low-frequency striatal output may be encoded as progressive phase shifts in downstream nuclei of the basal ganglia while high-frequency pallidal output may continuously modulate EP firing.

  8. Leishmania amazonensis: PKC-like protein kinase modulates the (Na++K+)ATPase activity.

    Science.gov (United States)

    Almeida-Amaral, Elmo Eduardo de; Caruso-Neves, Celso; Lara, Lucienne Silva; Pinheiro, Carla Mônica; Meyer-Fernandes, José Roberto

    2007-08-01

    The present study aimed to identify the presence of protein kinase C-like (PKC-like) in Leishmania amazonensis and to elucidate its possible role in the modulation of the (Na(+)+K(+))ATPase activity. Immunoblotting experiments using antibody against a consensus sequence (Ac 543-549) of rabbit protein kinase C (PKC) revealed the presence of a protein kinase of 80 kDa in L. amazonensis. Measurements of protein kinase activity showed the presence of both (Ca(2+)-dependent) and (Ca(2+)-independent) protein kinase activity in plasma membrane and cytosol. Phorbol ester (PMA) activation of the Ca(2+)-dependent protein kinase stimulated the (Na(+)+K(+))ATPase activity, while activation of the Ca(2+)-independent protein kinase was inhibitory. Both effects of protein kinase on the (Na(+)+K(+))ATPase of the plasma membrane were lower than that observed in intact cells. PMA induced the translocation of protein kinase from cytosol to plasma membrane, indicating that the maximal effect of protein kinase on the (Na(+)+K(+))ATPase activity depends on the synergistic action of protein kinases from both plasma membrane and cytosol. This is the first demonstration of a protein kinase activated by PMA in L. amazonensis and the first evidence for a possible role in the regulation of the (Na(+)+K(+))ATPase activity in this trypanosomatid. Modulation of the (Na(+)+K(+))ATPase by protein kinase in a trypanosomatid opens up new possibilities to understand the regulation of ion homeostasis in this parasite. PMID:17475255

  9. Impact of bias discrepancy and amino acid usage on estimates of the effective number of codons used in a gene, and a test for selection on codon usage

    DEFF Research Database (Denmark)

    Fuglsang, Anders

    2007-01-01

    The effective number of codons (Nc) used in a gene is one of the most commonly used measures of synonymous codon usage bias, owing much of its popularity to the fact that it is species independent and that simulation studies have shown that it is less dependent of gene length than other measures....... literature that exists for Buchnera sp. APS and Borrelia burgdorferi....

  10. Improved prognostic classification of breast cancer defined by antagonistic activation patterns of immune response pathway modules

    International Nuclear Information System (INIS)

    Elucidating the activation pattern of molecular pathways across a given tumour type is a key challenge necessary for understanding the heterogeneity in clinical response and for developing novel more effective therapies. Gene expression signatures of molecular pathway activation derived from perturbation experiments in model systems as well as structural models of molecular interactions ('model signatures') constitute an important resource for estimating corresponding activation levels in tumours. However, relatively few strategies for estimating pathway activity from such model signatures exist and only few studies have used activation patterns of pathways to refine molecular classifications of cancer. Here we propose a novel network-based method for estimating pathway activation in tumours from model signatures. We find that although the pathway networks inferred from cancer expression data are highly consistent with the prior information contained in the model signatures, that they also exhibit a highly modular structure and that estimation of pathway activity is dependent on this modular structure. We apply our methodology to a panel of 438 estrogen receptor negative (ER-) and 785 estrogen receptor positive (ER+) breast cancers to infer activation patterns of important cancer related molecular pathways. We show that in ER negative basal and HER2+ breast cancer, gene expression modules reflecting T-cell helper-1 (Th1) and T-cell helper-2 (Th2) mediated immune responses play antagonistic roles as major risk factors for distant metastasis. Using Boolean interaction Cox-regression models to identify non-linear pathway combinations associated with clinical outcome, we show that simultaneous high activation of Th1 and low activation of a TGF-beta pathway module defines a subtype of particularly good prognosis and that this classification provides a better prognostic model than those based on the individual pathways. In ER+ breast cancer, we find that

  11. Improved prognostic classification of breast cancer defined by antagonistic activation patterns of immune response pathway modules

    Directory of Open Access Journals (Sweden)

    El-Ashry Dorraya

    2010-11-01

    Full Text Available Abstract Background Elucidating the activation pattern of molecular pathways across a given tumour type is a key challenge necessary for understanding the heterogeneity in clinical response and for developing novel more effective therapies. Gene expression signatures of molecular pathway activation derived from perturbation experiments in model systems as well as structural models of molecular interactions ("model signatures" constitute an important resource for estimating corresponding activation levels in tumours. However, relatively few strategies for estimating pathway activity from such model signatures exist and only few studies have used activation patterns of pathways to refine molecular classifications of cancer. Methods Here we propose a novel network-based method for estimating pathway activation in tumours from model signatures. We find that although the pathway networks inferred from cancer expression data are highly consistent with the prior information contained in the model signatures, that they also exhibit a highly modular structure and that estimation of pathway activity is dependent on this modular structure. We apply our methodology to a panel of 438 estrogen receptor negative (ER- and 785 estrogen receptor positive (ER+ breast cancers to infer activation patterns of important cancer related molecular pathways. Results We show that in ER negative basal and HER2+ breast cancer, gene expression modules reflecting T-cell helper-1 (Th1 and T-cell helper-2 (Th2 mediated immune responses play antagonistic roles as major risk factors for distant metastasis. Using Boolean interaction Cox-regression models to identify non-linear pathway combinations associated with clinical outcome, we show that simultaneous high activation of Th1 and low activation of a TGF-beta pathway module defines a subtype of particularly good prognosis and that this classification provides a better prognostic model than those based on the individual pathways

  12. Is Brain Activity during Action Observation Modulated by the Perceived Fairness of the Actor?

    Directory of Open Access Journals (Sweden)

    Joset A Etzel

    Full Text Available Perceiving other people's actions triggers activity in premotor and parietal areas, brain areas also involved in executing and sensing our own actions. Paralleling this phenomenon, observing emotional states (including pain in others is associated with activity in the same brain areas as activated when experiencing similar emotions directly. This emotion perception associated activity has been shown to be affected by the perceived fairness of the actor, and in-group membership more generally. Here, we examine whether action observation associated brain activity is also affected by the perceived social fairness of the actors. Perceived fairness was manipulated using an alternating iterated Prisoner's Dilemma game between the participant and two confederates, one of whom played fairly and the other unfairly. During fMRI scanning the participants watched movies of the confederates performing object-directed hand actions, and then performed hand actions themselves. Mass-univariate analysis showed that observing the actions triggered robust activation in regions associated with action execution, but failed to identify a strong modulation of this activation based on perceived fairness. Multivariate pattern analysis, however, identified clusters potentially carrying information about the perceived fairness of the actor in the middle temporal gyrus, left postcentral gyrus, right inferior parietal lobule, right middle cingulate cortex, right angular gyrus, and right superioroccipital gyrus. Despite being identified by a whole-brain searchlight analysis (and so without anatomical restriction, these clusters fall into areas frequently associated with action observation. We conclude that brain activity during action observation may be modulated by perceived fairness, but such modulation is subtle; robust activity is associated with observing the actions of both fair and unfair individuals.

  13. Is Brain Activity during Action Observation Modulated by the Perceived Fairness of the Actor?

    Science.gov (United States)

    Etzel, Joset A; Valchev, Nikola; Gazzola, Valeria; Keysers, Christian

    2016-01-01

    Perceiving other people's actions triggers activity in premotor and parietal areas, brain areas also involved in executing and sensing our own actions. Paralleling this phenomenon, observing emotional states (including pain) in others is associated with activity in the same brain areas as activated when experiencing similar emotions directly. This emotion perception associated activity has been shown to be affected by the perceived fairness of the actor, and in-group membership more generally. Here, we examine whether action observation associated brain activity is also affected by the perceived social fairness of the actors. Perceived fairness was manipulated using an alternating iterated Prisoner's Dilemma game between the participant and two confederates, one of whom played fairly and the other unfairly. During fMRI scanning the participants watched movies of the confederates performing object-directed hand actions, and then performed hand actions themselves. Mass-univariate analysis showed that observing the actions triggered robust activation in regions associated with action execution, but failed to identify a strong modulation of this activation based on perceived fairness. Multivariate pattern analysis, however, identified clusters potentially carrying information about the perceived fairness of the actor in the middle temporal gyrus, left postcentral gyrus, right inferior parietal lobule, right middle cingulate cortex, right angular gyrus, and right superioroccipital gyrus. Despite being identified by a whole-brain searchlight analysis (and so without anatomical restriction), these clusters fall into areas frequently associated with action observation. We conclude that brain activity during action observation may be modulated by perceived fairness, but such modulation is subtle; robust activity is associated with observing the actions of both fair and unfair individuals. PMID:26820995

  14. Projective Synchronization in Modulated Time-Delayed Chaotic Systems Using an Active Control Approach

    Institute of Scientific and Technical Information of China (English)

    冯存芳; 汪映海

    2011-01-01

    Projective synchronization in modulated time-delayed systems is studied by applying an active control method. Based on the Lyapunov asymptotical stability theorem, the controller and sufficient condition for projective synchronization are calculated analytically. We give a genera./ method with which we can achieve projective synchronization in modulated time-delayed chaotic systems. This method allows us to adjust the desired scaling factor arbitrarily. The effectiveness of our method is confirmed by using the famous delay-differential equations related to optical bistable or hybrid optical bistable devices. Numerical simulations fully support the analytical approach.%Projective synchronization in modulated time-delayed systems is studied by applying an active control method.Based on the Lyapunov asymptotical stability theorem,the controller and sufficient condition for projective synchronization are calculated analytically.We give a general method with which we can achieve projective synchronization in modulated time-delayed chaotic systems.This method allows us to adjust the desired scaling factor arbitrarily.The effectiveness of our method is confirmed by using the famous delay-differential equations related to optical bistable or hybrid optical bistable devices.Numerical simulations fully support the analytical approach.

  15. Activation Characteristics of Fuel Breeding Blanket Module in Fusion Driven Subcritical System

    Institute of Scientific and Technical Information of China (English)

    HUANG Qun-Ying; LI Jian-Gang; CHEN Yi-Xue

    2004-01-01

    @@ Shortage of energy resources and production of long-lived radioactivity wastes from fission reactors are among the main problems which will be faced in the world in the near future. The conceptual design of a fusion driven subcritical system (FDS) is underway in Institute of Plasma Physics, Chinese Academy of Sciences. There are alternative designs for multi-functional blanket modules of the FDS, such as fuel breeding blanket module (FBB)to produce fuels for fission reactors, tritium breeding blanket module to produce the fuel, i.e. tritium, for fusion reactor and waste transmutation blanket module to try to permanently dispose of long-lived radioactivity wastes from fission reactors, etc. Activation of the fuel breeding blanket of the fusion driven subcritical system (FDS-FBB) by D-T fusion neutrons from the plasma and fission neutrons from the hybrid blanket are calculated and analysed under the neutron wall loading 0.5 MW/m2 and neutron fluence 15 MW. yr/m2. The neutron spectrum is calculated with the worldwide-used transport code MCNP/4C and activation calculations are carried out with the well known European inventory code FISPACT/99 with the latest released IAEA Fusion Evaluated Nuclear Data Library FENDL-2.0 and the ENDF/B-V uranium evaluated data. Induced radioactivities, dose rates and afterheats, etc, for different components of the FDS-FBB are compared and analysed.

  16. Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins.

    Science.gov (United States)

    Singhuber, Judith; Baburin, Igor; Ecker, Gerhard F; Kopp, Brigitte; Hering, Steffen

    2011-10-01

    The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (I(GABA)) by a selection of 18 coumarin derivatives on recombinant α(1)β(2)γ(2S) GABA(A) receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC(50)=14 ± 1 μM) and oxypeucedanin (EC(50)=25 ± 8 μM) displayed the highest efficiency with I(GABA) potentiation of 116 ± 4 % and 547 ± 56 %, respectively. I(GABA) enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 μM) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish I(GABA) modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin - comprising three hydrophobic and one aromatic feature - identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABA(A) receptor modulators. PMID:21749864

  17. Screening and characterization of molecules that modulate the biological activity of IFNs-I.

    Science.gov (United States)

    Bürgi, Milagros; Zapol'skii, Viktor A; Hinkelmann, Bettina; Köster, Mario; Kaufmann, Dieter E; Sasse, Florenz; Hauser, Hansjörg; Etcheverrigaray, Marina; Kratje, Ricardo; Bollati-Fogolín, Mariela; Oggero, Marcos

    2016-09-10

    Type I Interferons (IFNs-I) are species-specific glycoproteins which play an important role as primary defence against viral infections and that can also modulate the adaptive immune system. In some autoimmune diseases, interferons (IFNs) are over-produced. IFNs are widely used as biopharmaceuticals for a variety of cancer indications, chronic viral diseases, and for their immuno-modulatory action in patients with multiple sclerosis; therefore, increasing their therapeutic efficiency and decreasing their side effects is of high clinical value. In this sense, it is interesting to find molecules that can modulate the activity of IFNs. In order to achieve that, it was necessary to establish a simple, fast and robust assay to analyze numerous compounds simultaneously. We developed four reporter gene assays (RGAs) to identify IFN activity modulator compounds by using WISH-Mx2/EGFP, HeLa-Mx2/EGFP, A549-Mx2/EGFP, and HEp2-Mx2/EGFP reporter cell lines (RCLs). All of them present a Z' factor higher than 0.7. By using these RGAs, natural and synthetic compounds were analyzed simultaneously. A total of 442 compounds were studied by the Low Throughput Screening (LTS) assay using the four RCLs to discriminate between their inhibitory or enhancing effects on IFN activity. Some of them were characterized and 15 leads were identified. Finally, one promising candidate with enhancing effect on IFN-α/-β activity and five compounds with inhibitory effect were described. PMID:27346232

  18. Patterns of synonymous codon usage bias in chloroplast genomes of seed plants

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Codon usage in chloroplast genome of six seed plants (Arabidopsis thaliana, Populus alba, Zea mays, Triticum aestivum,Pinus koraiensis and Cycas taitungensis) was analyzed to find general patterns of codon usage in chloroplast genomes of seed plants.The results show that chloroplast genomes of the six seed plants had similar codon usage patterns, with a strong bias towards a high representation of NNA and NNT codons. In chloroplast genomes of the six seed plants, the effective number of codons (ENC) for most genes was similar to that of the expected ENC based on the GC content at the third codon position, but several genes with low ENC values were laying below the expected curve. All of these data indicate that codon usage was dominated by a mutational bias in chloroplast genomes of seed plants and that selection appeared to be limited to a subset of genes and to only subtly affect codon us-age. Meantime, four, six, eight, nine, ten and 12 codons were defined as the optimal codons in chloroplast genomes of the six seed plants.

  19. A detailed comparative analysis of codon usage bias in Zika virus.

    Science.gov (United States)

    Cristina, Juan; Fajardo, Alvaro; Soñora, Martín; Moratorio, Gonzalo; Musto, Héctor

    2016-09-01

    Zika virus (ZIKV) is a member of the family Flaviviridae and its genome consists of a single-stranded positive sense RNA molecule with 10,794 nucleotides. Clinical manifestations of disease caused by ZIKV infection range from asymptomatic cases to an influenza-like syndrome. There is an increasing concern about the possible relation among microcephaly and ZIKV infection. To get insight into the relation of codon usage among viruses and their hosts is extremely important to understand virus survival, fitness, evasion from host's immune system and evolution. In this study, we performed a comprehensive analysis of codon usage and composition of ZIKV. The overall codon usage among ZIKV strains is similar and slightly biased. Different codon preferences in ZIKV genes in relation to codon usage of human, Aedes aegypti and Aedes albopictus genes were found. Most of the highly frequent codons are A-ending, which strongly suggests that mutational bias is the main force shaping codon usage in this virus. G+C compositional constraint as well as dinucleotide composition also influence the codon usage of ZIKV. The results of these studies suggest that the emergence of ZIKV outside Africa, in the Pacific and the Americas may also be reflected in ZIKV codon usage. No significant differences were found in codon usage among strains isolated from microcephaly cases and the rest of strains from the Asian cluster enrolled in these studies.

  20. Exploring Codon Usage Patterns of Alternatively Spliced Genes in Human Chromosome 1

    Institute of Scientific and Technical Information of China (English)

    马飞; 庄永龙; 黄颖; 李衍达

    2004-01-01

    In this study, 414 whole protein-coding sequences (238 004 codons) of alternatively spliced genes of human chromosome 1 have been employed to explore the patterns of codon usage bias among genes. Overall codon usage data analysis indicates that G- and C-ending codons are predominant in the genes. The base usage in all three codon positions suggests a selection-mutation balance. Multivariate statistical analysis reveals that the codon usage variation has a strong positive correlation with the expressivities of the genes (r=0.5790, P<0.0001). All 27 codons identified as optimal are G- and C-ending codons.Correlation analysis shows a strong negative correlation between the gene length and codon adaptation index value (r=-0.2252, P<0.0001), and a significantly positive correlation between the gene length and Nc values (r=0.1876, P<0.0001). These results suggest that the comparatively shorter genes in the genes have higher codon usage bias to maximize translational efficiency, and selection may also contribute to the reduction of highly expressed proteins.

  1. A detailed comparative analysis of codon usage bias in Zika virus.

    Science.gov (United States)

    Cristina, Juan; Fajardo, Alvaro; Soñora, Martín; Moratorio, Gonzalo; Musto, Héctor

    2016-09-01

    Zika virus (ZIKV) is a member of the family Flaviviridae and its genome consists of a single-stranded positive sense RNA molecule with 10,794 nucleotides. Clinical manifestations of disease caused by ZIKV infection range from asymptomatic cases to an influenza-like syndrome. There is an increasing concern about the possible relation among microcephaly and ZIKV infection. To get insight into the relation of codon usage among viruses and their hosts is extremely important to understand virus survival, fitness, evasion from host's immune system and evolution. In this study, we performed a comprehensive analysis of codon usage and composition of ZIKV. The overall codon usage among ZIKV strains is similar and slightly biased. Different codon preferences in ZIKV genes in relation to codon usage of human, Aedes aegypti and Aedes albopictus genes were found. Most of the highly frequent codons are A-ending, which strongly suggests that mutational bias is the main force shaping codon usage in this virus. G+C compositional constraint as well as dinucleotide composition also influence the codon usage of ZIKV. The results of these studies suggest that the emergence of ZIKV outside Africa, in the Pacific and the Americas may also be reflected in ZIKV codon usage. No significant differences were found in codon usage among strains isolated from microcephaly cases and the rest of strains from the Asian cluster enrolled in these studies. PMID:27449601

  2. Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia.

    Science.gov (United States)

    Jantzie, Lauren L; Winer, Jesse L; Corbett, Christopher J; Robinson, Shenandoah

    2016-01-01

    Preterm infants suffer central nervous system (CNS) injury from hypoxia-ischemia and inflammation - termed encephalopathy of prematurity. Mature CNS injury activates caspase and calpain proteases. Erythropoietin (EPO) limits apoptosis mediated by activated caspases, but its role in modulating calpain activation has not yet been investigated extensively following injury to the developing CNS. We hypothesized that excess calpain activation degrades developmentally regulated molecules essential for CNS circuit formation, myelination and axon integrity, including neuronal potassium-chloride co-transporter (KCC2), myelin basic protein (MBP) and phosphorylated neurofilament (pNF), respectively. Further, we predicted that post-injury EPO treatment could mitigate CNS calpain-mediated degradation. Using prenatal transient systemic hypoxia-ischemia (TSHI) in rats to mimic CNS injury from extreme preterm birth, and postnatal EPO treatment with a clinically relevant dosing regimen, we found sustained postnatal excess cortical calpain activation following prenatal TSHI, as shown by the cleavage of alpha II-spectrin (αII-spectrin) into 145-kDa αII-spectrin degradation products (αII-SDPs) and p35 into p25. Postnatal expression of the endogenous calpain inhibitor calpastatin was also reduced following prenatal TSHI. Calpain substrate expression following TSHI, including cortical KCC2, MBP and NF, was modulated by postnatal EPO treatment. Calpain activation was reflected in serum levels of αII-SDPs and KCC2 fragments, and notably, EPO treatment also modulated KCC2 fragment levels. Together, these data indicate that excess calpain activity contributes to the pathogenesis of encephalopathy of prematurity. Serum biomarkers of calpain activation may detect ongoing cerebral injury and responsiveness to EPO or similar neuroprotective strategies. PMID:26551007

  3. Comparative Analysis of Codon Usage Bias Patterns in Microsporidian Genomes.

    Directory of Open Access Journals (Sweden)

    Heng Xiang

    Full Text Available The sub-3 Mbp genomes from microsporidian species of the Encephalitozoon genus are the smallest known among eukaryotes and paragons of genomic reduction and compaction in parasites. However, their diminutive stature is not characteristic of all Microsporidia, whose genome sizes vary by an order of magnitude. This large variability suggests that different evolutionary forces are applied on the group as a whole. In this study, we have compared the codon usage bias (CUB between eight taxonomically distinct microsporidian genomes: Encephalitozoon intestinalis, Encephalitozoon cuniculi, Spraguea lophii, Trachipleistophora hominis, Enterocytozoon bieneusi, Nematocida parisii, Nosema bombycis and Nosema ceranae. While the CUB was found to be weak in all eight Microsporidia, nearly all (98% of the optimal codons in S. lophii, T. hominis, E. bieneusi, N. parisii, N. bombycis and N. ceranae are fond of A/U in third position whereas most (64.6% optimal codons in the Encephalitozoon species E. intestinalis and E. cuniculi are biased towards G/C. Although nucleotide composition biases are likely the main factor driving the CUB in Microsporidia according to correlation analyses, directed mutational pressure also likely affects the CUB as suggested by ENc-plots, correspondence and neutrality analyses. Overall, the Encephalitozoon genomes were found to be markedly different from the other microsporidians and, despite being the first sequenced representatives of this lineage, are uncharacteristic of the group as a whole. The disparities observed cannot be attributed solely to differences in host specificity and we hypothesize that other forces are at play in the lineage leading to Encephalitozoon species.

  4. Codon bias and gene ontology in holometabolous and hemimetabolous insects.

    Science.gov (United States)

    Carlini, David B; Makowski, Matthew

    2015-12-01

    The relationship between preferred codon use (PCU), developmental mode, and gene ontology (GO) was investigated in a sample of nine insect species with sequenced genomes. These species were selected to represent two distinct modes of insect development, holometabolism and hemimetabolism, with an aim toward determining whether the differences in developmental timing concomitant with developmental mode would be mirrored by differences in PCU in their developmental genes. We hypothesized that the developmental genes of holometabolous insects should be under greater selective pressure for efficient translation, manifest as increased PCU, than those of hemimetabolous insects because holometabolism requires abundant protein expression over shorter time intervals than hemimetabolism, where proteins are required more uniformly in time. Preferred codon sets were defined for each species, from which the frequency of PCU for each gene was obtained. Although there were substantial differences in the genomic base composition of holometabolous and hemimetabolous insects, both groups exhibited a general preference for GC-ending codons, with the former group having higher PCU averaged across all genes. For each species, the biological process GO term for each gene was assigned that of its Drosophila homolog(s), and PCU was calculated for each GO term category. The top two GO term categories for PCU enrichment in the holometabolous insects were anatomical structure development and cell differentiation. The increased PCU in the developmental genes of holometabolous insects may reflect a general strategy to maximize the protein production of genes expressed in bursts over short time periods, e.g., heat shock proteins. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 686-698, 2015. © 2015 Wiley Periodicals, Inc. PMID:26498580

  5. Tetracycline-Regulated Suppression of Amber Codons in Mammalian Cells

    OpenAIRE

    Park, Ho-Jin; RajBhandary, Uttam L.

    1998-01-01

    As an approach to inducible suppression of nonsense mutations in mammalian cells, we described recently an amber suppression system in mammalian cells dependent on coexpression of Escherichia coli glutaminyl-tRNA synthetase (GlnRS) along with the E. coli glutamine-inserting amber suppressor tRNA. Here, we report on tetracycline-regulated expression of the E. coli GlnRS gene and, thereby, tetracycline-regulated suppression of amber codons in mammalian HeLa and COS-1 cells. The E. coli GlnRS co...

  6. Positive affect modulates activity in the visual cortex to images of high calorie foods.

    Science.gov (United States)

    Killgore, William D S; Yurgelun-Todd, Deborah A

    2007-05-01

    Activity within the visual cortex can be influenced by the emotional salience of a stimulus, but it is not clear whether such cortical activity is modulated by the affective status of the individual. This study used functional magnetic resonance imaging (fMRI) to examine the relationship between affect ratings on the Positive and Negative Affect Schedule and activity within the occipital cortex of 13 normal-weight women while viewing images of high calorie and low calorie foods. Regression analyses revealed that when participants viewed high calorie foods, Positive Affect correlated significantly with activity within the lingual gyrus and calcarine cortex, whereas Negative Affect was unrelated to visual cortex activity. In contrast, during presentations of low calorie foods, affect ratings, regardless of valence, were unrelated to occipital cortex activity. These findings suggest a mechanism whereby positive affective state may affect the early stages of sensory processing, possibly influencing subsequent perceptual experience of a stimulus. PMID:17464782

  7. 3′ UTR Length and Messenger Ribonucleoprotein Composition Determine Endocleavage Efficiencies at Termination Codons

    Directory of Open Access Journals (Sweden)

    Volker Boehm

    2014-10-01

    Full Text Available Nonsense-mediated mRNA decay (NMD degrades different classes of mRNAs, including transcripts with premature termination codons (PTCs. The NMD factor SMG6 initiates degradation of substrate mRNAs by endonucleolytic cleavage. Here, we aim to delineate the cascade of NMD-activating events that culminate in endocleavage. We report that long 3′ UTRs elicit SMG6-mediated endonucleolytic degradation. The presence of an exon-junction complex (EJC within the 3′ UTR strongly stimulates endocleavage in a distance-independent manner. The interaction of SMG6 with EJCs is not required for endocleavage. Whereas the core NMD component UPF2 supports endonucleolytic decay of long 3′ UTR mRNAs, it is mostly dispensable during EJC-stimulated endocleavage. Using high-throughput sequencing, we map endocleavage positions of different PTC-containing reporter mRNAs and an endogenous NMD substrate to regions directly at and downstream of the termination codon. These results reveal how messenger ribonucleoprotein (mRNP parameters differentially influence SMG6-executed endonucleolysis and uncover central characteristics of this phenomenon associated with translation termination.

  8. Afferent-mediated modulation of the soleus muscle activity during the stance phase of human walking

    DEFF Research Database (Denmark)

    Nazarena, Mazzaro; Grey, Michael James; do Nascimento, Omar Feix;

    2006-01-01

    The aim of this study was to investigate the contribution of proprioceptive feedback to the amplitude modulation of the soleus muscle activity during human walking. We have previously shown that slow-velocity, small-amplitude ankle dorsiflexion enhancements and reductions applied during the stance......-mediated contribution from muscle group II afferents, cutaneous and proprioceptive afferents from the foot, and load-sensitive afferents to the soleus EMG. Slow-velocity, small-amplitude ankle trajectory modifications were combined with the pharmaceutical depression of group II polysynaptic pathways with tizanidine...... that the feedback from group II afferents, and possibly from load-sensitive afferents, contribute to the amplitude modulation of the soleus muscle activity during the stance phase of the step cycle. However, feedback from cutaneous afferents and instrinsic proprioceptive afferents from the foot does not seem...

  9. Development of active edge pixel sensors and four-side buttable modules using vertical integration technologies

    CERN Document Server

    Macchiolo, A; Moser, H-G; Nisius, R; Richter, R H; Terzo, S; Weigell, P

    2014-01-01

    We present an R&D activity focused on the development of novel modules for the upgrade of the ATLAS pixel system at the High Luminosity LHC (HL-LHC). The modules consist of n-in-p pixel sensors, 100 or 200 $\\mu$m thick, produced at VTT (Finland) with an active edge technology, which considerably reduces the dead area at the periphery of the device. The sensors are interconnected with solder bump-bonding to the ATLAS FE-I3 and FE-I4 read-out chips, and characterized with radioactive sources and beam tests at the CERN-SPS and DESY. The results of these measurements will be discussed for devices before and after irradiation up to a fluence of $5\\times 10^{15}$ \

  10. Aloe vera : Potential candidate in health management via modulation of biological activities

    Directory of Open Access Journals (Sweden)

    Arshad H Rahmani

    2015-01-01

    Full Text Available Treatment based on natural products is rapidly increasing worldwide due to the affordability and fewer side effects of such treatment. Various plants and the products derived from them are commonly used in primary health treatment, and they play a pivotal role in the treatment of diseases via modulation of biochemical and molecular pathways. Aloe vera, a succulent species, produces gel and latex, plays a therapeutic role in health management through antioxidant, antitumor, and anti-inflammatory activities, and also offers a suitable alternative approach for the treatment of various types of diseases. In this review, we summarize the possible mechanism of action and the therapeutic implications of Aloe vera in health maintenance based on its modulation of various biological activities.

  11. 维生素D受体基因起始密码子多态性与体力活动对青春期女童骨量增长的交互作用%Interaction of the polymorphism of vitamin D receptor gene start codon with physical activity on bone mass accrual in Chinese adolescent girls

    Institute of Scientific and Technical Information of China (English)

    李星; 何国鹏; 苏宜香

    2008-01-01

    Objective To investigate the association between the polymorphism of vitamin D receptor (VDR) gene start codon (Fok I) and bone mass accrual,and assessing if such an association could be modified bv physical activity in Chinese adolescent girls.Methods A total of 228 premenrche Chinese girls (9-11.5 years old) were recruited for 2-year study. Bone mineral densities (BMD) at the total body,total left hip (including femoral neck,trochanter,intertrochanter and Ward's triangle area) and lumbar spine (L1-L4)were measured by dual energy X-ray absorptiometry.The Fok I polymorphism of VDR gene was detected with PCR-RFLP.Results There remained 176 available subjects in our cohort when 2-year study was completed. No significant association was observed between Fok I polymorphism of VDR gene and percentage change in BMD at all sites. Girls with FF genotype had lower percentage change in total left hip BMD (THBMD) and femoral neck BMD (FNBMD) than girls with Ff+ff genotype only in low physical activity (<1 197 kJ/d),and physical activity was associated with percentage change in THBMD and FNBMD only in FF genotype group.Conclusion The Fok I polymorphism of VDR gene should have significant interaction effect with physical activity on bone mass accrual in Chinese adolescent girls.Girls with FF genotype in low physical activity would be the potential risk population for low bone mass accrual,and high physical activity would be of benefit to gain higher bone mass accrual for girls with FF genotype.%目的 探讨维生素D受体(VDR)基因起始密码子(Fok I位点)多态性与体力活动对青春期女童骨量增长的交互作用.方法 选择228名9~11.5岁未月经初潮的健康女童进行2年追踪,应用双能X线骨密度仪检测对象追踪前后全身、左侧近端股骨(包括股骨颈、大转子、粗隆间和华氏三角区)和L1~L4腰椎骨密度,应用PCR-RFLP技术检测VDR基因Fok I位点多态性.结果 本次研究的有效观察人数为176名.Fok I

  12. Respiratory activity in medulla oblongata and its modulation by adenosine and opioids

    OpenAIRE

    Herlenius, Eric

    1998-01-01

    From the moment of birth the complex neuronal networks generating breathing has to function continuously and adapt to the new postnatal environmental demands. This thesis aims at studying the perinatal development of respiratory control and its modulation by adenosine and opioids. Respiratory activity was studied in vitro using brainstem spinal cord preparations and in vivo with a barometric plethysmograph. In vitro whole-cell patch clamp recordings of respiratory related ne...

  13. Face gender modulates women’s brain activity during face encoding

    OpenAIRE

    Lovén, Johanna; Svärd, Joakim; Natalie C Ebner; Herlitz, Agneta; Fischer, Håkan

    2013-01-01

    Women typically remember more female than male faces, whereas men do not show a reliable own-gender bias. However, little is known about the neural correlates of this own-gender bias in face recognition memory. Using functional magnetic resonance imaging (fMRI), we investigated whether face gender modulated brain activity in fusiform and inferior occipital gyri during incidental encoding of faces. Fifteen women and 14 men underwent fMRI while passively viewing female and male faces, followed ...

  14. Multi-Senses Explication Activities Module for Dyslexic Children in Malaysia

    OpenAIRE

    Vijayaletchumy Subramaniam; Vijay Kumar Mallan; Noor Hayati Che Mat

    2013-01-01

    Dyslexic children are having abnormal difficulties in reading, spelling and writing. The awareness on these problems leads researcher to conduct a case study in the psycholinguistic field about the multi-senses explication activities in the words mastery among the dyslexic children in Sekolah Kebangsaan Padang Temu Melaka. Starting from the Information Processing Theory by Robert M. Gagne (1975) as the theoretical framework, this research aims to produce a module on the multi-senses explicati...

  15. A biased activation theory of the cognitive and attentional modulation of emotion

    OpenAIRE

    Edmund eRolls

    2013-01-01

    Cognition can influence emotion by biasing neural activity in the first cortical region in which the reward value and subjective pleasantness of stimuli is made explicit in the representation, the orbitofrontal cortex. The same effect occurs in a second cortical tier for emotion, the anterior cingulate cortex. Similar effects are found for selective attention, to for example the pleasantness vs the intensity of stimuli, which modulates representations of reward value and affect in the orbitof...

  16. A biased activation theory of the cognitive and attentional modulation of emotion

    OpenAIRE

    Rolls, Edmund T.

    2013-01-01

    Cognition can influence emotion by biasing neural activity in the first cortical region in which the reward value and subjective pleasantness of stimuli is made explicit in the representation, the orbitofrontal cortex (OFC). The same effect occurs in a second cortical tier for emotion, the anterior cingulate cortex (ACC). Similar effects are found for selective attention, to for example the pleasantness vs. the intensity of stimuli, which modulates representations of reward value and affect i...

  17. Modulation of the chaperone-like activity of bovine α-crystallin

    OpenAIRE

    Clark, John I.; Huang, Qing-ling

    1996-01-01

    The effects of pantethine, glutathione, and selected chemical reagents on the anti-aggregation activity of α-crystallin was evaluated. Protein aggregation was monitored by light scattering of solutions of denatured βL-crystallin or alcohol dehydrogenase (ADH). The ratios of βL-crystallin/α-crystallin and ADH/α-crystallin were adjusted so that partial inhibition of protein aggregation at 60°C or 37°C, respectively, was observed and modulation of the chaperone ac...

  18. Theta-modulated gamma-band synchronization among activated regions during a verb generation task

    Directory of Open Access Journals (Sweden)

    Sam McLeod Doesburg

    2012-06-01

    Full Text Available Expressive language is complex and involves processing within a distributed network of cortical regions. Functional MRI and magnetoencephalography (MEG have identified brain areas critical for expressive language, but how these regions communicate across the network remains poorly understood. It is thought that synchronization of oscillations between neural populations, particularly at a gamma rate (>30 Hz, underlies functional integration within cortical networks. Modulation of gamma rhythms by theta-band oscillations (4 – 8 Hz has been proposed as a mechanism for the integration of local cell coalitions into large-scale networks underlying cognition and perception. The present study tested the hypothesis that these oscillatory mechanisms of functional integration were present within the expressive language network. We recorded MEG while subjects performed a covert verb generation task. Using beamformer analysis, we localized activated cortical regions, calculated inter-regional phase locking between activated areas, and measured modulation of inter-regional gamma synchronization by theta phase. The results show task-dependent gamma-band synchronization among regions activated during the performance of the verb generation task, and we provide evidence that these transient and periodic instances of high-frequency connectivity were modulated by the phase of cortical theta oscillations. These findings suggest that oscillatory synchronization and cross-frequency interactions are mechanisms for functional integration among distributed brain areas supporting expressive language processing.

  19. Fast oscillatory activity in the anterior cingulate cortex: dopaminergic modulation and efect of perineuronal net loss

    Directory of Open Access Journals (Sweden)

    Pascal eSteullet

    2014-08-01

    Full Text Available Dopamine release in the prefrontal cortex plays a critical role in cognitive function such as working memory, attention and planning. Dopamine exerts complex modulation on excitability of pyramidal neurons and interneurons, and regulates excitatory and inhibitory synaptic transmission. Because of the complexity of this modulation, it is difficult to fully comprehend the effect of dopamine on neuronal network activity. In this study, we investigated the effect of dopamine on local high-frequency oscillatory neuronal activity (in  band in slices of the mouse anterior cingulate cortex (ACC. We found that dopamine enhanced the power of these oscillations induced by kainate and carbachol, but did not affect their peak frequency. Activation of D2R and in a lesser degree D1R increased the oscillation power, while activation of D4R had no effect. These high-frequency oscillations in the ACC relied on both phasic inhibitory and excitatory transmission and functional gap junctions. Thus, dopamine released in the ACC promotes high-frequency synchronized local cortical activity which is known to favor information transfer, fast selection and binding of distributed neuronal responses. Finally, the power of these oscillations was significantly enhanced after degradation of the perineuronal nets enwrapping most parvalbumin interneurons. This study provides new insights for a better understanding of the abnormal prefrontal gamma activity in schizophrenia patients who display prefrontal anomalies of both the dopaminergic system and the perineuronal nets.

  20. Yersinia enterocolitica differentially modulates RhoG activity in host cells.

    Science.gov (United States)

    Roppenser, Bernhard; Röder, Anja; Hentschke, Moritz; Ruckdeschel, Klaus; Aepfelbacher, Martin

    2009-03-01

    Pathogenic bacteria of the genus Yersinia (Y. pestis, Y. enterocolitica and Y. pseudotuberculosis) have evolved numerous virulence factors (termed a stratagem) to manipulate the activity of Rho GTPases. Here, we show that Y. enterocolitica modulates RhoG, an upstream regulator of other Rho GTPases. At the contact site of virulent Y. enterocolitica and host cells, we could visualise spatiotemporally organised activation and deactivation of RhoG. On the one hand, the beta1-integrin clustering protein Invasin on the bacterial surface was found to activate RhoG and this promoted cell invasion. On the other hand, active RhoG was downregulated by the type III secretion system effector YopE acting as a GTPase-activating protein (GAP). YopE localised to Golgi and endoplasmic reticulum, and this determined its specificity for RhoG and other selected Rho GTPases. RhoG and its downstream effector module Elmo/Dock180 controlled both Rac1 activation by Invasin and Rac1 deactivation by YopE. We propose that RhoG is a central target of the Yersinia stratagem and a major upstream regulator of Rac1 during different phases of the Yersinia infection cycle. PMID:19208761

  1. Perceptual demand modulates activation of human auditory cortex in response to task-irrelevant sounds.

    Science.gov (United States)

    Sabri, Merav; Humphries, Colin; Verber, Matthew; Mangalathu, Jain; Desai, Anjali; Binder, Jeffrey R; Liebenthal, Einat

    2013-09-01

    In the visual modality, perceptual demand on a goal-directed task has been shown to modulate the extent to which irrelevant information can be disregarded at a sensory-perceptual stage of processing. In the auditory modality, the effect of perceptual demand on neural representations of task-irrelevant sounds is unclear. We compared simultaneous ERPs and fMRI responses associated with task-irrelevant sounds across parametrically modulated perceptual task demands in a dichotic-listening paradigm. Participants performed a signal detection task in one ear (Attend ear) while ignoring task-irrelevant syllable sounds in the other ear (Ignore ear). Results revealed modulation of syllable processing by auditory perceptual demand in an ROI in middle left superior temporal gyrus and in negative ERP activity 130-230 msec post stimulus onset. Increasing the perceptual demand in the Attend ear was associated with a reduced neural response in both fMRI and ERP to task-irrelevant sounds. These findings are in support of a selection model whereby ongoing perceptual demands modulate task-irrelevant sound processing in auditory cortex.

  2. Cells in the monkey ponto-medullary reticular formation modulate their activity with slow finger movements.

    Science.gov (United States)

    Soteropoulos, Demetris S; Williams, Elizabeth R; Baker, Stuart N

    2012-08-15

    Recent work has shown that the primate reticulospinal tract can influence spinal interneurons and motoneurons involved in control of the hand. However, demonstrating connectivity does not reveal whether reticular outputs are modulated during the control of different types of hand movement. Here, we investigated how single unit discharge in the pontomedullary reticular formation (PMRF) modulated during performance of a slow finger movement task in macaque monkeys. Two animals performed an index finger flexion–extension task to track a target presented on a computer screen; single units were recorded both from ipsilateral PMRF (115 cells) and contralateral primary motor cortex (M1, 210 cells). Cells in both areas modulated their activity with the task (M1: 87%, PMRF: 86%). Some cells (18/115 in PMRF; 96/210 in M1) received sensory input from the hand, showing a short-latency modulation in their discharge following a rapid passive extension movement of the index finger. Effects in ipsilateral electromyogram to trains of stimuli were recorded at 45 sites in the PMRF. These responses involved muscles controlling the digits in 13/45 sites (including intrinsic hand muscles, 5/45 sites). We conclude that PMRF may contribute to the control of fine finger movements, in addition to its established role in control of more proximal limb and trunk movements. This finding may be especially important in understanding functional recovery after brain lesions such as stroke. PMID:22641776

  3. Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension*

    OpenAIRE

    Zhang, Lili; Xie, Peng; Wang, Jingzhou; Yang, Qingwu; Fang, Chuanqin; Zhou, Shuang; Li, Jingcheng

    2010-01-01

    The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-γ in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-γ expression and excessive VSMC phe...

  4. Prion protein gene analysis in three kindreds with fatal familial insomnia (FFI): codon 178 mutation and codon 129 polymorphism.

    OpenAIRE

    Medori, R; Tritschler, H J

    1993-01-01

    Fatal familial insomnia (FFI) is a disease linked to a GAC(Asp)-->AAC(Asn) mutation in codon 178 of the prion protein (PrP) gene. FFI is characterized clinically by untreatable progressive insomnia, dysautonomia, and motor dysfunctions and is characterized pathologically by selective thalamic atrophy. We confirmed the 178Asn mutation in the PrP gene of a third FFI family of French ancestry. Three family members who are under 40 years of age and who inherited the mutation showed only reduced p...

  5. TP53 codon 72 polymorphism in pigmentary phenotypes

    Indian Academy of Sciences (India)

    Kárita Antunes Costa; Lidia Andreu Guillo

    2012-03-01

    The p53 protein exerts different cellular functions, and recent findings have demonstrated its influence on the cascade of skin pigmentation during UV exposure. Among TP53 gene polymorphisms, the most studied is the G to C transversion in exon 4 at codon 72, which results in three distinct genotypes, Arg/Arg, Pro/Pro and Arg/Pro, each one encoding different p53 isoforms. Therefore, this study aimed to determine the relationship between TP53 codon 72 polymorphism and skin protection against sunburn. Genomic DNA was extracted from peripheral blood samples and genotyping was performed by PCR and confirmed by restriction enzyme digestion. The genotype frequency was 50% for Arg/Arg and 14.6% for Pro/Pro genotype. The frequency of heterozygous subjects was 35.4%. In our population, p53 genotypes were in Hardy–Weinberg (HW) equilibrium ($\\chi^{2}_{\\text{HM}}$ < 3.84), showing a predominance of arginine allele (total Arg allele frequency of 68%). No significant association between p53 genotype and skin colour, hair or eye colour and susceptibility to sun exposure was found. However, further analysis demonstrated a significant association between the genotype Pro/Pro and blue/green eyes among participants who presented redness (=0.016). Our findings indicate susceptibility to sun exposure when this phenotype (eye colour) occurs simultaneously with Pro/Pro genotype.

  6. Amplification of Frequency-Modulated Similariton Pulses in Length-Inhomogeneous Active Fibers

    Directory of Open Access Journals (Sweden)

    I. O. Zolotovskii

    2012-01-01

    Full Text Available The possibility of an effective gain of the self-similar frequency-modulated (FM wave packets is studied in the length-inhomogeneous active fibers. The dynamics of parabolic pulses with the constant chirp has been considered. The optimal profile for the change of the group-velocity dispersion corresponding to the optimal similariton pulse amplification has been obtained. It is shown that the use of FM pulses in the active (gain and length-inhomogeneous optical fibers with the normal group-velocity dispersion can provide subpicosecond optical pulse amplification up to the energies higher than 1 nJ.

  7. Synthesis, structure-activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators.

    Science.gov (United States)

    Schlienger, Nathalie; Lund, Birgitte W; Pawlas, Jan; Badalassi, Fabrizio; Bertozzi, Fabio; Lewinsky, Rasmus; Fejzic, Alma; Thygesen, Mikkel B; Tabatabaei, Ali; Bradley, Stefania Risso; Gardell, Luis R; Piu, Fabrice; Olsson, Roger

    2009-11-26

    Herein we describe the discovery of ACP-105 (1), a novel and potent nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity relative to the natural androgen testosterone. Compound 1 was developed from a series of compounds found in a HTS screen using the receptor selection and amplification technology (R-SAT). In vivo, 1 improved anabolic parameters in a 2-week chronic study in castrated male rats. In addition to compound 1, a number of potent antiandrogens were discovered from the same series of compounds whereof one compound, 13, had antagonist activity at the AR T877A mutant involved in prostate cancer.

  8. KATP channels modulate intrinsic firing activity of immature entorhinal cortex layer III neurons

    Directory of Open Access Journals (Sweden)

    Maria S. Lemak

    2014-08-01

    Full Text Available Medial temporal lobe structures are essential for memory formation which is associated with coherent network oscillations. During ontogenesis, these highly organized patterns develop from distinct, less synchronized forms of network activity. This maturation process goes along with marked changes in intrinsic firing patterns of individual neurons. One critical factor determining neuronal excitability is activity of ATP-sensitive K+ channels (KATP channels which coupled electrical activity to metabolic state. Here, we examined the role of KATP channels for intrinsic firing patterns and emerging network activity in the immature medial entorhinal cortex (mEC of rats. Western blot analysis of Kir6.2 (a subunit of the KATP channel confirmed expression of this protein in the immature entorhinal cortex. Neuronal activity was monitored by field potential (fp and whole-cell recordings from layer III of the mEC in horizontal brain slices obtained at postnatal day (P 6-13. Spontaneous fp-bursts were suppressed by the KATP channel opener diazoxide and prolonged after blockade of KATP channels by glibenclamide. Immature mEC LIII principal neurons displayed two dominant intrinsic firing patterns, prolonged bursts or regular firing activity, respectively. Burst discharges were suppressed by the KATP channel openers diazoxide and NN414, and enhanced by the KATP channel blockers tolbutamide and glibenclamide. Activity of regularly firing neurons was modulated in a frequency-dependent manner: the diazoxide-mediated reduction of firing correlated negatively with basal frequency, while the tolbutamide-mediated increase of firing showed a positive correlation. These data are in line with an activity-dependent regulation of KATP channel activity. Together, KATP channels exert powerful modulation of intrinsic firing patterns and network activity in the immature mEC.

  9. Versatile Dual Reporter Gene Systems for Investigating Stop Codon Readthrough in Plants

    OpenAIRE

    KAVANAGH, THOMAS; LAO, NGA THI

    2009-01-01

    PUBLISHED Background Translation is most often terminated when a ribosome encounters the first in-frame stop codon (UAA, UAG or UGA) in an mRNA. However, many viruses (and some cellular mRNAs) contain ?stop? codons that cause a proportion of ribosomes to terminate and others to incorporate an amino acid and continue to synthesize a ?readthrough?, or C-terminally extended, protein. This dynamic redefinition of codon meaning is dependent on specific sequence context. Methodology W...

  10. Eukaryotic evolutionary transitions are associated with extreme codon bias in functionally-related proteins.

    Directory of Open Access Journals (Sweden)

    Nicholas J Hudson

    Full Text Available Codon bias in the genome of an organism influences its phenome by changing the speed and efficiency of mRNA translation and hence protein abundance. We hypothesized that differences in codon bias, either between-species differences in orthologous genes, or within-species differences between genes, may play an evolutionary role. To explore this hypothesis, we compared the genome-wide codon bias in six species that occupy vital positions in the Eukaryotic Tree of Life. We acquired the entire protein coding sequences for these organisms, computed the codon bias for all genes in each organism and explored the output for relationships between codon bias and protein function, both within- and between-lineages. We discovered five notable coordinated patterns, with extreme codon bias most pronounced in traits considered highly characteristic of a given lineage. Firstly, the Homo sapiens genome had stronger codon bias for DNA-binding transcription factors than the Saccharomyces cerevisiae genome, whereas the opposite was true for ribosomal proteins--perhaps underscoring transcriptional regulation in the origin of complexity. Secondly, both mammalian species examined possessed extreme codon bias in genes relating to hair--a tissue unique to mammals. Thirdly, Arabidopsis thaliana showed extreme codon bias in genes implicated in cell wall formation and chloroplast function--which are unique to plants. Fourthly, Gallus gallus possessed strong codon bias in a subset of genes encoding mitochondrial proteins--perhaps reflecting the enhanced bioenergetic efficiency in birds that co-evolved with flight. And lastly, the G. gallus genome had extreme codon bias for the Ciliary Neurotrophic Factor--which may help to explain their spontaneous recovery from deafness. We propose that extreme codon bias in groups of genes that encode functionally related proteins has a pathway-level energetic explanation.

  11. Characterization of codon usage bias in the dUTPase gene of duck enteritis virus

    Institute of Scientific and Technical Information of China (English)

    Lichan Zhao; Anchun Cheng; Mingshu Wang; Guiping Yuan; Mingsheng Cai

    2008-01-01

    A comparative analysis of the codon usage bias in the newly discovered dUTPase gene(Assigned Accession No.:DQ4861491 of the duck enteritis virus(DEV)and the dUTPase gene of 32 reference herpesviruses was performed.The results indicated that the DEV dUT-Pase gene encodes a protein of 477 amino acids,which includes five conserved motifs with a 3-1-2-4-5 arrangement.The codon adap-tation index(CAI),effective number of codons(ENC),and GC3s values indicated synonymous codon usage bias in the dUTPase gene of herpesviruses,and this synonymous bias was correlated with host evolution.The codon usage pattens of the DEV dUTPase gene were phylogenetically conserved and similar to that of the dUTPase genes of the avian alphaherpesvirus.Although codon usage in each micro-orgamsm was different,there were no strain-specific differences among them.Sixty-one codons in the predicted polypeptide.with a strong bias towards A and T at the third codon position,were used.Comparison of the codon usage in the dUTPase gene of different organisms revealed that there were 19 codons showing distinct codon usage differences between the DEV and Escherichia coli dUTPase genes;16 between the DEV and yeast dUTPase genes;and 15 between the DEV and human dUTPase genes.Analysis of variance(ANOVA) showed significant differences between the DEV and yeast dUTPase genes(r=0.536,P<0.01).The extent of codon usage bias in the DEV dUTPase gene was highly correlated with the gene expression level,therefore the results may provide usefu information for gene classification and functional studies.

  12. Preferential binding of allosteric modulators to active and inactive conformational states of metabotropic glutamate receptors

    Directory of Open Access Journals (Sweden)

    Klein-Seetharaman Judith

    2008-02-01

    Full Text Available Abstract Metabotropic glutamate receptors (mGluRs are G protein coupled receptors that play important roles in synaptic plasticity and other neuro-physiological and pathological processes. Allosteric mGluR ligands are particularly promising drug targets because of their modulatory effects – enhancing or suppressing the response of mGluRs to glutamate. The mechanism by which this modulation occurs is not known. Here, we propose the hypothesis that positive and negative modulators will differentially stabilize the active and inactive conformations of the receptors, respectively. To test this hypothesis, we have generated computational models of the transmembrane regions of different mGluR subtypes in two different conformations. The inactive conformation was modeled using the crystal structure of the inactive, dark state of rhodopsin as template and the active conformation was created based on a recent model of the light-activated state of rhodopsin. Ligands for which the nature of their allosteric effects on mGluRs is experimentally known were docked to the modeled mGluR structures using ArgusLab and Autodock softwares. We find that the allosteric ligand binding pockets of mGluRs are overlapping with the retinal binding pocket of rhodopsin, and that ligands have strong preferences for the active and inactive states depending on their modulatory nature. In 8 out of 14 cases (57%, the negative modulators bound the inactive conformations with significant preference using both docking programs, and 6 out of 9 cases (67%, the positive modulators bound the active conformations. Considering results by the individual programs only, even higher correlations were observed: 12/14 (86% and 8/9 (89% for ArgusLab and 10/14 (71% and 7/9 (78% for AutoDock. These findings strongly support the hypothesis that mGluR allosteric modulation occurs via stabilization of different conformations analogous to those identified in rhodopsin where they are induced by

  13. Dark/light transition and vigilance states modulate jaw-closing muscle activity level in mice.

    Science.gov (United States)

    Katayama, Keisuke; Mochizuki, Ayako; Kato, Takafumi; Ikeda, Minako; Ikawa, Yasuha; Nakamura, Shiro; Nakayama, Kiyomi; Wakabayashi, Noriyuki; Baba, Kazuyoshi; Inoue, Tomio

    2015-12-01

    Bruxism is associated with an increase in the activity of the jaw-closing muscles during sleep and wakefulness. However, the changes in jaw-closing muscle activity across states of vigilance over a 24-h period are unclear. In this study, we investigated the effects of dark/light transition and sleep/wake state on EMG activity of the masseter (jaw-closing) muscle in comparison with the activity of the upper trapezius muscle (a neck muscle) over a 24-h period in mice. The activities of the masseter and neck muscles during wakefulness were much greater than during non-REM and REM sleep. In contrast, the activities of both muscles slightly, but significantly, decreased during the transition period from dark to light. Histograms of masseter activity during wakefulness and non-REM sleep showed bimodal distributions, whereas the neck muscle showed unimodal activation in all states. These results suggest that the activities of jaw-closing and neck muscles are modulated by both sleep/wake state and dark/light transition, with the latter being to a lesser degree. Furthermore, even during non-REM sleep, jaw-closing muscles display bimodal activation, which may contribute to the occurrence of exaggerated aberrant muscle activity, such as sleep bruxism. PMID:26188127

  14. Different Brain Network Activations Induced by Modulation and Nonmodulation Laser Acupuncture

    Directory of Open Access Journals (Sweden)

    Chang-Wei Hsieh

    2011-01-01

    Full Text Available The aim of this study is to compare the distinct cerebral activation with continued wave (CW and 10 Hz-modulated wave (MW stimulation during low-level laser acupuncture. Functional magnetic resonance imaging (fMRI studies were performed to investigate the possible mechanism during laser acupuncture stimulation at the left foot's yongquan (K1 acupoint. There are 12 healthy right-handed volunteers for each type of laser stimulation (10-Hz-Modulated wave: 8 males and 4 females; continued wave: 9 males and 3 females. The analysis of multisubjects in this experiment was applied by random-effect (RFX analysis. In CW groups, significant activations were found within the inferior parietal lobule, the primary somatosensory cortex, and the precuneus of left parietal lobe. Medial and superior frontal gyrus of left frontal lobe were also aroused. In MW groups, significant activations were found within the primary motor cortex and middle temporal gyrus of left hemisphere and bilateral cuneus. Placebo stimulation did not show any activation. Most activation areas were involved in the functions of memory, attention, and self-consciousness. The results showed the cerebral hemodynamic responses of two laser acupuncture stimulation modes and implied that its mechanism was not only based upon afferent sensory information processing, but that it also had the hemodynamic property altered during external stimulation.

  15. Plant carbohydrate binding module enhances activity of hybrid microbial cellulase enzyme

    Directory of Open Access Journals (Sweden)

    Caitlin Siobhan Byrt

    2012-11-01

    Full Text Available A synthetic, highly active cellulase enzyme suitable for in planta production may be a valuable tool for biotechnological approaches to develop transgenic biofuel crops with improved digestibility. Here, we demonstrate that the addition of a plant derived carbohydrate binding module (CBM to a synthetic glycosyl hydrolase (GH improved the activity of the hydrolase in releasing sugar from plant biomass. A CEL-HYB1-CBM enzyme was generated by fusing a hybrid microbial cellulase, CEL-HYB1, with the carbohydrate-binding module (CBM of the tomato (Solanum lycopersicum SlCel9C1 cellulase. CEL-HYB1 and CEL-HYB1-CBM enzymes were produced in vitro using Pichia pastoris and the activity of these enzymes was tested using CMC, MUC and native crystalline cellulose assays. The presence of the CBM substantially improved the endo-glucanase activity of CEL-HYB1, especially against the native crystalline cellulose encountered in Sorghum plant cell walls. These results indicate that addition of an endogenous plant derived CBM to cellulase enzymes may enhance hydrolytic activity.

  16. Modulation of Banana Polyphenol Oxidase (Ppo Activity by Naturally Occurring Bioactive Compounds From Plant Extracts

    Directory of Open Access Journals (Sweden)

    Alamelumangai. M

    2015-01-01

    Full Text Available Polyphenol Oxidase (PPO (E.C number 1.14.18.1 was extracted from banana (Musa paradisiaca and partially purified by acetone precipitation. The enzyme was found to have high affinity towards its substrate, catechol. In this study, various plant extracts like Glycyrrhiza glabra, Rubia cordifolia, Hesperethusa crenulata and oil from the seeds of Hydnocarpus laurifolia were observed to modulate the activity of banana PPO. Method In this study, various plant extracts were observed to modulate the activity of banana PPO at two different concentrations (0.4 and 40 μg/ml concentrations Result Among these 4 plant extracts, Glycyrrhiza glabra and Rubia cordifolia were found to increase the activity of PPO up to 1.35- 2.7 fold at two different concentrations (4 and 40 μg/ml. Few other two samples like Chaulmogra oil (2 and 4 μl/ml and the Hesperethusa crenulata plant extract (0.4 and 40 μg/ml concentrations, when used at low concentrations decreased the enzyme activity (38 %. Conclusion The novelty of this study is to screen their naturally occurring bioactive compounds from the plant extracts and their inhibitory activity against PPO.

  17. Complex Mutation and Weak Selection together Determined the Codon Usage Bias in Bryophyte Mitochondrial Genomes

    Institute of Scientific and Technical Information of China (English)

    Bin Wang; Jing Liu; Liang Jin; Xue-Ying Feng; Jian-Qun Chen

    2010-01-01

    Mutation and selection are two major forces causing codon usage biases. How these two forces influence the codon usages in green plant mitochondrial genomes has not been well investigated. In the present study, we surveyed five bryophyte mitochondrial genomes to reveal their codon usagepatterns as well as the determining forces. Three interesting findings were made. First, comparing to Chara vulgaris, an algal species sister to all extant land plants, bryophytes have more G, C-ending codon usages in their mitochondrial genes. This is consistent with the generally higher genomic GC content in bryophyte mitochondria, suggesting an increased mutational pressure toward GC. Second, as indicated by Wright's Nc-GC3s plot, mutation, not selection, is the major force affecting codon usages of bryophyte mitochondrial genes. However, the real mutational dynamics seem very complex. Context-dependent analysis indicated that nucleotide at the 2nd codon position would slightly affect synonymous codon choices. Finally, in bryophyte mitochondria, tRNA genes would apply a weak selection force to finetune the synonymous codon frequencies, as revealed by data of Ser4-Pro-Thr-Val families. In summary,complex mutation and weak selection together determined the codon usages in bryophyte mitochondrial genomes.

  18. P53 codon 11, 72, and 248 gene polymorphisms in endometriosis

    OpenAIRE

    Hsieh, Yao-Yuan; Lin, Chich-Sheng

    2006-01-01

    Objective: Mutated p53 gene is related to the instability of cell growth and cell cycle progression. We aimed to evaluate the association between endometriosis and p53 codon 11, 72 and 248 gene polymorphisms. Patients and methods: Women were divided into two groups: (1) moderate/severe endometriosis (n=148), and (2) non-endometriosis groups (n=150). P53 gene polymorphisms include codon11 Glu/Gln or Lys (GAG->CAG or AAG), codon 72 Arg/Pro (CGC->CCC), and codon 248 Arg/Thr (CGG->TCG). These gen...

  19. The soybean retroelement SIRE1 uses stop codon suppression to express its envelope-like protein

    OpenAIRE

    Havecker, Ericka R.; Voytas, Daniel F

    2003-01-01

    The soybean SIRE1 family of Ty1/copia retrotransposons encodes an envelope-like gene (env-like). We analysed the DNA sequences of nine SIRE1 insertions and observed that the gag/pol and env-like genes are in the same reading frame and separated by a single UAG stop codon. The six nucleotides immediately downstream of the stop codon conform to a degenerate nucleotide motif, CARYYA, which is sufficient to facilitate stop codon suppression in tobacco mosaic virus. In vivo stop codon suppression ...

  20. Codon 219 polymorphism of PRNP in healthy caucasians and Creutzfeldt-Jakob disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Petraroli, R.; Pocchiari, M. [Instituto Superiore di Sanita, Rome (Italy)

    1996-04-01

    A number of point and insert mutations of the PrP gene (PRNP) have been linked to familial Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker disease (GSS). Moreover, the methionine/valine homozygosity at the polymorphic codon 129 of PRNP may cause a predisposition to sporadic and iatrogenic CJD or may control the age at onset of familial cases carrying either the 144-bp insertion or codon 178, codon 198, and codon 210 pathogenic mutations in PRNP. In addition, the association of methionine or valine at codon 129 and the point mutation at codon 178 on the same allele seem to play an important role in determining either fatal familial insomnia or CJD. However, it is noteworthy that a relationship between codon 129 polymorphism and accelerated pathogenesis (early age at onset or shorter duration of the disease) has not been seen in familial CJD patients with codon 200 mutation or in GSS patients with codon 102 mutation, arguing that other, as yet unidentified, gene products or environmental factors, or both, may influence the clinical expression of these diseases. 17 refs.

  1. Mapping codon usage of the translation initiation region in porcine reproductive and respiratory syndrome virus genome

    Directory of Open Access Journals (Sweden)

    Dou Yong-xi

    2011-10-01

    Full Text Available Abstract Background Porcine reproductive and respitatory syndrome virus (PRRSV is a recently emerged pathogen and severely affects swine populations worldwide. The replication of PRRSV is tightly controlled by viral gene expression and the codon usage of translation initiation region within each gene could potentially regulate the translation rate. Therefore, a better understanding of the codon usage pattern of the initiation translation region would shed light on the regulation of PRRSV gene expression. Results In this study, the codon usage in the translation initiation region and in the whole coding sequence was compared in PRRSV ORF1a and ORFs2-7. To investigate the potential role of codon usage in affecting the translation initiation rate, we established a codon usage model for PRRSV translation initiation region. We observed that some non-preferential codons are preferentially used in the translation initiation region in particular ORFs. Although some positions vary with codons, they intend to use codons with negative CUB. Furthermore, our model of codon usage showed that the conserved pattern of CUB is not directly consensus with the conserved sequence, but shaped under the translation selection. Conclusions The non-variation pattern with negative CUB in the PRRSV translation initiation region scanned by ribosomes is considered the rate-limiting step in the translation process.

  2. Experimental Test of L- and D-Amino Acid Binding to L- and D-Codons Suggests that Homochirality and Codon Directionality Emerged with the Genetic Code

    OpenAIRE

    Robert Root-Bernstein

    2010-01-01

    L-amino acids bind preferentially to their D-codons, but almost nothing is known about whether D-amino acids correspondingly prefer L-codons, or how codon directionality affects amino acid binding. To investigate these issues, two D-RNA-oligonucleotides having inverse base sequences (D-CGUA and D-AUGC) and their corresponding L-RNA-oligonucleotides (L-CGUA and L-AUGC) were synthesized and their affinity determined for Gly and eleven pairs of L- and D-amino acids. The data support the hypothes...

  3. Pre-irradiation testing of actively cooled Be-Cu divertor modules

    Energy Technology Data Exchange (ETDEWEB)

    Linke, J.; Duwe, R.; Kuehnlein, W. [Forschungszentrum Juelich GmbH (Germany)] [and others

    1995-09-01

    A set of neutron irradiation tests is prepared on different plasma facing materials (PFM) candidates and miniaturized components for ITER. Beside beryllium the irradiation program which will be performed in the High Flux Reactor (HFR) in Petten, includes different carbon fiber composites (CFQ) and tungsten alloys. The target values for the neutron irradiation will be 0.5 dpa at temperatures of 350{degrees}C and 700{degrees}C, resp.. The post irradiation examination (PIE) will cover a wide range of mechanical tests; in addition the degradation of thermal conductivity will be investigated. To determine the high heat flux (HHF) performance of actively cooled divertor modules, electron beam tests which simulate the expected heat loads during the operation of ITER, are scheduled in the hot cell electron beam facility JUDITH. These tests on a selection of different actively cooled beryllium-copper and CFC-copper divertor modules are performed before and after neutron irradiation; the pre-irradiation testing is an essential part of the program to quantify the zero-fluence high heat flux performance and to detect defects in the modules, in particular in the brazed joints.

  4. Bicarbonate and Ca2+ sensing modulators activate photoreceptor ROS-GC1 synergistically

    Directory of Open Access Journals (Sweden)

    Teresa eDuda

    2016-01-01

    Full Text Available Photoreceptor ROS-GC1, a prototype subfamily member of the membrane guanylate cyclase family, is a central component of phototransduction. It is a single transmembrane-spanning protein, composed of modular blocks. In rods, guanylate cyclase activating proteins (GCAPs 1 and 2 bind to its juxtamembrane domain and the C-terminal extension, respectively, to accelerate cyclic GMP synthesis when Ca2+ levels are low. In cones, the additional expression of the Ca2+-dependent guanylate cyclase activating protein (CD-GCAP S100B which binds to its C-terminal extension, supports acceleration of cyclic GMP synthesis at high Ca2+ levels. Independent of Ca2+, ROS-GC1 activity is also stimulated directly by bicarbonate binding to the core catalytic domain. Several enticing molecular features of this transduction system are revealed in the present study. In combination, bicarbonate and Ca2+-dependent modulators raised maximal ROS-GC activity to levels that exceeded the sum of their individual effects. The F514S mutation in ROS-GC1 that causes blindness in type 1 Leber’s congenital amaurosis severely reduced basal ROS-GC1 activity. GCAP2 and S100B Ca2+ signaling modes remained functional, while the GCAP1-modulated mode was diminished. Bicarbonate nearly restored basal activity as well as GCAP2- and S100B-stimulated activities of the F514S mutant to normal levels but could not resurrect GCAP1 stimulation. We conclude that GCAP1 and GCAP2 forge distinct pathways through domain-specific modules of ROS-GC1 whereas the S100B and GCAP2 pathways may overlap. The synergistic interlinking of bicarbonate to GCAPs- and S100B-modulated pathways intensifies and tunes the dependence of cyclic GMP synthesis on intracellular Ca2+. Our study challenges the recently proposed GCAP1 and GCAP2 overlapping phototransduction model (Peshenko, I.V., Olshevskaya, and Dizhoor, A. M. (2015 J Biol. Chem 290, 6913-6924.

  5. Cucurbitacin IIb exhibits anti-inflammatory activity through modulating multiple cellular behaviors of mouse lymphocytes.

    Directory of Open Access Journals (Sweden)

    Yao Wang

    Full Text Available Cucurbitacin IIb (CuIIb is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27(Kip1 and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3(+ T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65, it blocked the nuclear translocation of NF-κB (p65. In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response.

  6. Mangroves Build Land. "Mangroves are a Valuable Resource." Grades 7 and 8. A Two Lesson Unit. Student Learning Activity Module.

    Science.gov (United States)

    Frank, James

    This module is an activity and film-oriented unit focusing on the importance of mangroves in the South Florida ecosystem. The module is part of a series designed to be used by teachers, students, and community members to help them utilize community resources in developing and teaching environmental concepts and responsibility, and in seeking ways…

  7. Activation of murine invariant NKT cells promotes susceptibility to candidiasis by IL-10 induced modulation of phagocyte antifungal activity.

    Science.gov (United States)

    Haraguchi, Norihiro; Kikuchi, Norihiro; Morishima, Yuko; Matsuyama, Masashi; Sakurai, Hirofumi; Shibuya, Akira; Shibuya, Kazuko; Taniguchi, Masaru; Ishii, Yukio

    2016-07-01

    Invariant NKT (iNKT) cells play an important role in a variety of antimicrobial immune responses due to their ability to produce high levels of immune-modulating cytokines. Here, we investigated the role of iNKT cells in host defense against candidiasis using Jα18-deficient mice (Jα18(-/-) ), which lack iNKT cells. Jα18(-/-) mice were more resistant to the development of lethal candidiasis than wild-type (WT) mice. In contrast, treatment of WT mice with the iNKT cell activating ligand α-galactosylceramide markedly enhanced their mortality after infection with Candida albicans. Serum IL-10 levels were significantly elevated in WT mice in response to infection with C. albicans. Futhermore, IL-10 production increased after in vitro coculture of peritoneal macrophages with iNKT cells and C. albicans. The numbers of peritoneal macrophages, the production of IL-1β and IL-18, and caspase-1 activity were also significantly elevated in Jα18(-/-) mice after infection with C. albicans. The adoptive transfer of iNKT cells or exogenous administration of IL-10 into Jα18(-/-) reversed susceptibility to candidiasis to the level of WT mice. These results suggest that activation of iNKT cells increases the initial severity of C. albicans infection, most likely mediated by IL-10 induced modulation of macrophage antifungal activity. PMID:27151377

  8. Model documentation report: Macroeconomic Activity Module (MAM) of the National Energy Modeling System

    Energy Technology Data Exchange (ETDEWEB)

    1994-02-07

    This report documents the objectives, analytical approach, and development of the National Energy Modeling System (NEMS) Macroeconomic Activity Module (MAM) used to develop the Annual Energy Outlook for 1994 (AEO94). The report catalogues and describes the module assumptions, computations, methodology, parameter estimation techniques, and mainframe source code. This document serves three purposes. First, it is a reference document providing a detailed description of the NEMS MAM used for the AEO 1994 production runs for model analysts, users, and the public. Second, this report meets the legal requirement of the Energy Information Administration (EIA) to provide adequate documentation in support of its models (Public Law 94-385, section 57.b.2). Third, it facilitates continuity in model development by providing documentation from which energy analysts can undertake model enhancements, data updates, and parameter refinements as future projects.

  9. Different pulse pattern generation by frequency detuning in pulse modulated actively mode-locked ytterbium doped fiber laser

    Science.gov (United States)

    Chen, He; Chen, Sheng-Ping; Si, Lei; Zhang, Bin; Jiang, Zong-Fu

    2015-10-01

    We report the results of our recent experimental investigation of the modulation frequency detuning effect on the output pulse dynamics in a pulse modulated actively mode-locked ytterbium doped fiber laser. The experimental study shows the existence of five different mode-locking states that mainly depend on the modulation frequency detuning, which are: (a) amplitude-even harmonic/fundamental mode-locking, (b) Q-switched harmonic/fundamental mode-locking, (c) sinusoidal wave modulation mode, (d) pulses bundle state, and (e) noise-like state. A detailed experimental characterization of the output pulses dynamics in each operating mode is presented.

  10. Modulation of HMG-CoA reductase activity by pantetheine/pantethine.

    Science.gov (United States)

    Cighetti, G; Del Puppo, M; Paroni, R; Galli Kienle, M

    1988-11-25

    The ability of pantetheine/pantethine to modulate the activity of HMG-CoA reductase (EC 1.1.1.34) was determined in vitro with rat liver microsomes. The decay of the activity was obtained with pantethine in the 10(-5)-10(-4) M range, whereas stimulation by pantetheine occurred at 10(-3)-10(-2) M, as previously reported for GSSG and GSH, respectively. Inhibition of HMG-CoA by pantethine in isolated liver cells was also investigated by measuring the enzyme activity in microsomes isolated from hepatocytes incubated without or with 1 mM pantethine under conditions previously shown by us to induce inhibition of cholesterol synthesis from acetate. The enzyme amount was not modified by pantethine, but in cells treated with the disulphide, the relative amounts of the thiolic active forms of the enzyme, both phosphorylated and dephosphorylated, were decreased to about half compared to controls. PMID:3196742

  11. Somatostatin modulates insulin-degrading-enzyme metabolism: implications for the regulation of microglia activity in AD.

    Directory of Open Access Journals (Sweden)

    Grazia Tundo

    Full Text Available The deposition of β-amyloid (Aβ into senile plaques and the impairment of somatostatin-mediated neurotransmission are key pathological events in the onset of Alzheimer's disease (AD. Insulin-degrading-enzyme (IDE is one of the main extracellular protease targeting Aβ, and thus it represents an interesting pharmacological target for AD therapy. We show that the active form of somatostatin-14 regulates IDE activity by affecting its expression and secretion in microglia cells. A similar effect can also be observed when adding octreotide. Following a previous observation where somatostatin directly interacts with IDE, here we demonstrate that somatostatin regulates Aβ catabolism by modulating IDE proteolytic activity in IDE gene-silencing experiments. As a whole, these data indicate the relevant role played by somatostatin and, potentially, by analogue octreotide, in preventing Aβ accumulation by partially restoring IDE activity.

  12. Biological activities of the homologous loop regions in the laminin α chain LG modules.

    Science.gov (United States)

    Katagiri, Fumihiko; Hara, Toshihiro; Yamada, Yuji; Urushibata, Shunsuke; Hozumi, Kentaro; Kikkawa, Yamato; Nomizu, Motoyoshi

    2014-06-10

    Each laminin α chain (α1-α5 chains) has chain-specific diverse biological functions. The C-terminal globular domain of the α chain consists of five laminin-like globular (LG1-5) modules and plays a critical role in biological activities. The LG modules consist of a 14-stranded β-sheet (A-N) sandwich structure. Previously, we described the chain-specific biological activities of the loop regions between the E and F strands in the LG4 modules using five homologous peptides (G4EF1-G4EF5). Here, we further analyze the biological activities of the E-F strands loop regions in the rest of LG modules. We designed 20 homologous peptides (approximately 20 amino acid length), and 17 soluble peptides were used for the cell attachment assay. Thirteen peptides promoted cell attachment activity with different cell morphologies. Cell attachment to peptides G1EF1, G1EF2, G2EF1, G3EF4, and G5EF4 was inhibited by heparin, and peptides G1EF1, G1EF2, and G2EF1 specifically bound to syndecan-overexpressing cells. Cell attachment to peptides G2EF3, G3EF1, G3EF3, G5EF1, G5EF3, and G5EF5 was inhibited EDTA. Further, cell attachment to peptides G3EF3, G5EF1, and G5EF5 was inhibited by both anti-integrin α2 and β1 antibodies, whereas cell attachment to peptide G5EF3 was inhibited by only anti-integrin β1 antibody. Cell attachment to peptides G1EF4, G3EF4, and G5EF4 was inhibited by both heparin and EDTA and was not inhibited by anti-integrin antibodies. The active peptide sequence alignments suggest that the syndecan-binding peptides contain a "basic amino acid (BAA)-Gly-BAA" motif in the middle of the molecule and that the integrin-binding peptides contain an "acidic amino acid (AAA)"-Gly-BAA motif. Core-switched peptide analyses suggested that the "BAA-Gly-BAA" motif is critical for binding to syndecans and that the "AAA-Gly-BAA" motif has potential to recognize integrins. These findings are useful for understanding chain-specific biological activities of laminins and to evaluate

  13. Modulation of the Activity of Secretory Phospholipase A2 by Antimicrobial Peptides

    Science.gov (United States)

    Zhao, Hongxia; Kinnunen, Paavo K. J.

    2003-01-01

    The antimicrobial peptides magainin 2, indolicidin, and temporins B and L were found to modulate the hydrolytic activity of secretory phospholipase A2 (sPLA2) from bee venom and in human lacrimal fluid. More specifically, hydrolysis of phosphatidylcholine (PC) liposomes by bee venom sPLA2 at 10 μM Ca2+ was attenuated by these peptides while augmented product formation was observed in the presence of 5 mM Ca2+. The activity of sPLA2 towards anionic liposomes was significantly enhanced by the antimicrobial peptides at low [Ca2+] and was further enhanced in the presence of 5 mM Ca2+. Similarly, with 5 mM Ca2+ the hydrolysis of anionic liposomes was enhanced significantly by human lacrimal fluid sPLA2, while that of PC liposomes was attenuated. These results indicate that concerted action of antimicrobial peptides and sPLA2 could improve the efficiency of the innate response to infections. Interestingly, inclusion of a cationic gemini surfactant in the vesicles showed an essentially similar pattern on sPLA2 activity, suggesting that the modulation of the enzyme activity by the antimicrobial peptides may involve also charge properties of the substrate surface. PMID:12604528

  14. Oscillatory phase modulates the timing of neuronal activations and resulting behavior.

    Science.gov (United States)

    Coon, W G; Gunduz, A; Brunner, P; Ritaccio, A L; Pesaran, B; Schalk, G

    2016-06-01

    Human behavioral response timing is highly variable from trial to trial. While it is generally understood that behavioral variability must be due to trial-by-trial variations in brain function, it is still largely unknown which physiological mechanisms govern the timing of neural activity as it travels through networks of neuronal populations, and how variations in the timing of neural activity relate to variations in the timing of behavior. In our study, we submitted recordings from the cortical surface to novel analytic techniques to chart the trajectory of neuronal population activity across the human cortex in single trials, and found joint modulation of the timing of this activity and of consequent behavior by neuronal oscillations in the alpha band (8-12Hz). Specifically, we established that the onset of population activity tends to occur during the trough of oscillatory activity, and that deviations from this preferred relationship are related to changes in the timing of population activity and the speed of the resulting behavioral response. These results indicate that neuronal activity incurs variable delays as it propagates across neuronal populations, and that the duration of each delay is a function of the instantaneous phase of oscillatory activity. We conclude that the results presented in this paper are supportive of a general model for variability in the effective speed of information transmission in the human brain and for variability in the timing of human behavior. PMID:26975551

  15. A Comprehensive Analysis of Codon Usage Patterns in Blunt Snout Bream (Megalobrama amblycephala Based on RNA-Seq Data

    Directory of Open Access Journals (Sweden)

    Xiaoke Duan

    2015-05-01

    Full Text Available Blunt snout bream (Megalobrama amblycephala is an important fish species for its delicacy and high economic value in China. Codon usage analysis could be helpful to understand its codon biology, mRNA translation and vertebrate evolution. Based on RNA-Seq data for M. amblycephala, high-frequency codons (CUG, AGA, GUG, CAG and GAG, as well as low-frequency ones (NUA and NCG codons were identified. A total of 724 high-frequency codon pairs were observed. Meanwhile, 14 preferred and 199 avoided neighboring codon pairs were also identified, but bias was almost not shown with one or more intervening codons inserted between the same pairs. Codon usage bias in the regions close to start and stop codons indicated apparent heterogeneity, which even occurs in the flanking nucleotide sequence. Codon usage bias (RSCU and SCUO was related to GC3 (GC content of 3rd nucleotide in codon bias. Six GO (Gene ontology categories and the number of methylation targets were influenced by GC3. Codon usage patterns comparison among 23 vertebrates showed species specificities by using GC contents, codon usage and codon context analysis. This work provided new insights into fish biology and new information for breeding projects.

  16. Nucleotide composition bias and codon usage trends of gene populations in Mycoplasma capricolum subsp. capricolum and M. agalactiae

    Indian Academy of Sciences (India)

    Xiao-Xia Ma; Yu-Ping Feng; Jia-Ling Bai; De-Rong Zhang; Xin-Shi Lin; Zhong-Ren Ma

    2015-06-01

    Because of the low GC content of the gene population, amino acids of the two mycoplasmas tend to be encoded by synonymous codons with an A or T end. Compared with the codon usage of ovine, Mycoplasma capricolum and M. agalactiae tend to select optimal codons, which are rare codons in ovine. Due to codon usage pattern caused by genes with key biological functions, the overall codon usage trends represent a certain evolutionary direction in the life cycle of the two mycoplasmas. The overall codon usage trends of a gene population of M. capricolum subsp. capricolum can be obviously separated from other mycoplasmas, and the overall codon usage trends of M. agalactiae are highly similar to those of M. bovis. These results partly indicate the independent evolution of the two mycoplasmas without the limits of the host cell’s environment. The GC and AT skews estimate nucleotide composition bias at different positions of nucleotide triplets and the protein consideration caused by the nucleotide composition bias at codon positions 1 and 2 largely take part in synonymous codon usage patterns of the two mycoplasmas. The correlation between the codon adaptation index and codon usage variation indicates that the effect of codon usage on gene expression in M. capricolum subsp. capricolum is opposite to that of M. agalactiae, further suggesting independence of the evolutionary process influencing the overall codon usage trends of gene populations of mycoplasmas.

  17. Codon Optimization to Enhance Expression Yields Insights into Chloroplast Translation1[OPEN

    Science.gov (United States)

    Chan, Hui-Ting; Williams-Carrier, Rosalind; Barkan, Alice

    2016-01-01

    Codon optimization based on psbA genes from 133 plant species eliminated 105 (human clotting factor VIII heavy chain [FVIII HC]) and 59 (polio VIRAL CAPSID PROTEIN1 [VP1]) rare codons; replacement with only the most highly preferred codons decreased transgene expression (77- to 111-fold) when compared with the codon usage hierarchy of the psbA genes. Targeted proteomic quantification by parallel reaction monitoring analysis showed 4.9- to 7.1-fold or 22.5- to 28.1-fold increase in FVIII or VP1 codon-optimized genes when normalized with stable isotope-labeled standard peptides (or housekeeping protein peptides), but quantitation using western blots showed 6.3- to 8-fold or 91- to 125-fold increase of transgene expression from the same batch of materials, due to limitations in quantitative protein transfer, denaturation, solubility, or stability. Parallel reaction monitoring, to our knowledge validated here for the first time for in planta quantitation of biopharmaceuticals, is especially useful for insoluble or multimeric proteins required for oral drug delivery. Northern blots confirmed that the increase of codon-optimized protein synthesis is at the translational level rather than any impact on transcript abundance. Ribosome footprints did not increase proportionately with VP1 translation or even decreased after FVIII codon optimization but is useful in diagnosing additional rate-limiting steps. A major ribosome pause at CTC leucine codons in the native gene of FVIII HC was eliminated upon codon optimization. Ribosome stalls observed at clusters of serine codons in the codon-optimized VP1 gene provide an opportunity for further optimization. In addition to increasing our understanding of chloroplast translation, these new tools should help to advance this concept toward human clinical studies. PMID:27465114

  18. Modulation of cocaine-induced activity by intracerebral administration of CXCL12.

    Science.gov (United States)

    Trecki, J; Unterwald, E M

    2009-06-16

    The role of chemokines in immune function is clearly established. Recent evidence suggests that these molecules also play an important role in the central nervous system as modulators of neuronal activity. The chemokine CXCL12 has been identified in several regions of the adult rat brain including the substantia nigra, ventral tegmental area and caudate putamen. CXCR4, a receptor activated by CXCL12, is expressed by dopaminergic neurons in the substantia nigra. The present study tested the effects of intracranial injections of CXCL12 on cocaine-induced locomotion and stereotypic activity in adult male Sprague-Dawley rats. Results demonstrate that intracerebral ventricular administration of CXCL12 (25 ng/4 microl) 15 min prior to cocaine (20 mg/kg intraperitoneal (i.p.)) produced a significant potentiation of both ambulatory and stereotypic activity as compared to cocaine alone. The effects of CXCL12 were blocked by administration of the selective CXCR4 antagonist, AMD 3100. Administration of CXCL12 into specific brain regions was performed to further understand the site of action of CXCL12. Bilateral administration of CXCL12 (25 ng/0.5 microl) into the ventral tegmental area 15 min prior to cocaine (20 mg/kg i.p.) significantly potentiated cocaine-induced ambulatory activity, whereas microinjections of CXCL12 into the caudate putamen selectively increased stereotypy. Conversely, administration of CXCL12 into the lateral shell of the nucleus accumbens resulted in an inhibition of cocaine-stimulated ambulatory activity. No alterations in ambulatory or stereotypic activity were observed following CXCL12 administration into the core of the nucleus accumbens. These results demonstrate that CXCL12 can modulate the behavioral effects produced by cocaine in a brain region-specific manner. PMID:19303923

  19. Effect of low-level laser therapy on the modulation of the mitochondrial activity of macrophages

    Directory of Open Access Journals (Sweden)

    Nadhia H. C. Souza

    2014-08-01

    Full Text Available BACKGROUND: Macrophages play a major role among the inflammatory cells that invade muscle tissue following an injury. Low-level laser therapy (LLLT has long been used in clinical practice to accelerate the muscle repair process. However, little is known regarding its effect on macrophages. OBJECTIVE: This study evaluated the effect of LLLT on the mitochondrial activity (MA of macrophages. METHOD: J774 macrophages were treated with lipopolysaccharide (LPS and interferon - gamma (IFN-γ (activation for 24 h to simulate an inflammatory process, then irradiated with LLLT using two sets of parameters (780 nm; 70 mW; 3 J/cm2 and 660 nm; 15 mW; 7.5 J/cm2. Non-activated/non-irradiated cells composed the control group. MA was evaluated by the cell mitochondrial activity (MTT assay (after 1, 3 and 5 days in three independent experiments. The data were analyzed statistically. RESULTS: After 1 day of culture, activated and 780 nm irradiated macrophages showed lower MA than activated macrophages, but activated and 660 nm irradiated macrophages showed MA similar to activated cells. After 3 days, activated and irradiated (660 nm and 780 nm macrophages showed greater MA than activated macrophages, and after 5 days, the activated and irradiated (660 nm and 780 nm macrophages showed similar MA to the activated macrophages. CONCLUSIONS: These results show that 660 nm and 780 nm LLLT can modulate the cellular activation status of macrophages in inflammation, highlighting the importance of this resource and of the correct determination of its parameters in the repair process of skeletal muscle.

  20. Effect of low-level laser therapy on the modulation of the mitochondrial activity of macrophages

    Science.gov (United States)

    Souza, Nadhia H. C.; Ferrari, Raquel A. M.; Silva, Daniela F. T.; Nunes, Fabio D.; Bussadori, Sandra K.; Fernandes, Kristianne P. S.

    2014-01-01

    BACKGROUND: Macrophages play a major role among the inflammatory cells that invade muscle tissue following an injury. Low-level laser therapy (LLLT) has long been used in clinical practice to accelerate the muscle repair process. However, little is known regarding its effect on macrophages. OBJECTIVE: This study evaluated the effect of LLLT on the mitochondrial activity (MA) of macrophages. METHOD: J774 macrophages were treated with lipopolysaccharide (LPS) and interferon - gamma (IFN-γ) (activation) for 24 h to simulate an inflammatory process, then irradiated with LLLT using two sets of parameters (780 nm; 70 mW; 3 J/cm2 and 660 nm; 15 mW; 7.5 J/cm2). Non-activated/non-irradiated cells composed the control group. MA was evaluated by the cell mitochondrial activity (MTT) assay (after 1, 3 and 5 days) in three independent experiments. The data were analyzed statistically. RESULTS: After 1 day of culture, activated and 780 nm irradiated macrophages showed lower MA than activated macrophages, but activated and 660 nm irradiated macrophages showed MA similar to activated cells. After 3 days, activated and irradiated (660 nm and 780 nm) macrophages showed greater MA than activated macrophages, and after 5 days, the activated and irradiated (660 nm and 780 nm) macrophages showed similar MA to the activated macrophages. CONCLUSIONS: These results show that 660 nm and 780 nm LLLT can modulate the cellular activation status of macrophages in inflammation, highlighting the importance of this resource and of the correct determination of its parameters in the repair process of skeletal muscle. PMID:25076002

  1. GPCODON ALIGNMENT: A GLOBAL PAIRWISE CODON BASED SEQUENCE ALIGNMENT APPROACH

    Directory of Open Access Journals (Sweden)

    Zeinab A. Fareed

    2016-02-01

    Full Text Available The alignment of two DNA sequences is a basic step in the analysis of biological data. Sequencing a long DNA sequence is one of the most interesting problems in bioinformatics. Several techniques have been developed to solve this sequence alignment problem like dynamic programming and heuristic algorithms. In this paper, we introduce (GPCodon alignment a pairwise DNA-DNA method for global sequence alignment that improves the accuracy of pairwise sequence alignment. We use a new scoring matrix to produce the final alignment called the empirical codon substitution matrix. Using this matrix in our technique enabled the discovery of new relationships between sequences that could not be discovered using traditional matrices. In addition, we present experimental results that show the performance of the proposed technique over eleven datasets of average length of 2967 bps. We compared the efficiency and accuracy of our techniques against a comparable tool called “Pairwise Align Codons” [1].

  2. Liver Fatty acid binding protein (L-Fabp) modulates murine stellate cell activation and diet induced nonalcoholic fatty liver disease

    OpenAIRE

    Chen, Anping; Tang, Youcai; Davis, Victoria; Hsu, Fong-Fu; Kennedy, Susan M; Song, Haowei; Turk, John; Brunt, Elizabeth M.; Newberry, Elizabeth P.; Davidson, Nicholas O.

    2013-01-01

    Activation of hepatic stellate cells (HSCs) is crucial to the development of fibrosis in nonalcoholic fatty liver disease. Quiescent HSCs contain lipid droplets (LDs), whose depletion upon activation induces a fibrogenic gene program. Here we show that liver fatty acid-binding protein (L-Fabp), an abundant cytosolic protein that modulates fatty acid (FA) metabolism in enterocytes and hepatocytes also modulates HSC FA utilization and in turn regulates the fibrogenic program. L-Fabp expression ...

  3. The relationship between third-codon position nucleotide content, codon bias, mRNA secondary structure and gene expression in the drosophilid alcohol dehydrogenase genes Adh and Adhr.

    Science.gov (United States)

    Carlini, D B; Chen, Y; Stephan, W

    2001-01-01

    To gain insights into the relationship between codon bias, mRNA secondary structure, third-codon position nucleotide distribution, and gene expression, we predicted secondary structures in two related drosophilid genes, Adh and Adhr, which differ in degree of codon bias and level of gene expression. Individual structural elements (helices) were inferred using the comparative method. For each gene, four types of randomization simulations were performed to maintain/remove codon bias and/or to maintain or alter third-codon position nucleotide composition (N3). In the weakly expressed, weakly biased gene Adhr, the potential for secondary structure formation was found to be much stronger than in the highly expressed, highly biased gene Adh. This is consistent with the observation of approximately equal G and C percentages in Adhr ( approximately 31% across species), whereas in Adh the N3 distribution is shifted toward C (42% across species). Perturbing the N3 distribution to approximately equal amounts of A, G, C, and T increases the potential for secondary structure formation in Adh, but decreases it in Adhr. On the other hand, simulations that reduce codon bias without changing N3 content indicate that codon bias per se has only a weak effect on the formation of secondary structures. These results suggest that, for these two drosophilid genes, secondary structure is a relatively independent, negative regulator of gene expression. Whereas the degree of codon bias is positively correlated with level of gene expression, strong individual secondary structural elements may be selected for to retard mRNA translation and to decrease gene expression. PMID:11606539

  4. RET codon 609 mutations: a contribution for better clinical managing

    Directory of Open Access Journals (Sweden)

    Caterina Mian

    2012-01-01

    Full Text Available Medullary thyroid carcinoma currently accounts for 5-8% of all thyroid cancers. The clinical course of this disease varies from extremely indolent tumors that can go unchanged for years to an extremely aggressive variant that is associated with a high mortality rate. As many as 75% of all medullary thyroid carcinomas are sporadic, with an average age at presentation reported as 60 years, and the remaining 25% are hereditary with an earlier age of presentation, ranging from 20 to 40 years. Germline RET proto-oncogene mutations are the genetic causes of multiple endocrine neoplasia type 2 and a strong genotype-phenotype correlation exists, particularly between a specific RET codon mutation and the (a age-related onset and (b thyroid tumor progression, from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, to nodal metastases. RET mutations predispose an individual to the development of medullary thyroid carcinomas and can also influence the individual response to RET protein receptor-targeted therapies. RET codon 609point mutations are rare genetic events belonging to the intermediate risk category for the onset of medullary thyroid carcinoma. A large genealogy resulting in a less aggressive form of medullary thyroid carcinoma is associated with the high penetrance of pheochromocytoma and has been reported in the literature. In this short review article, we comment on our previous report of a large multiple endocrine neoplasia type 2A kindred with the same Cys609Ser germline RET mutation in which, conversely, the syndrome was characterized by a slightly aggressive, highly penetrant form of medullary thyroid carcinoma that was associated with low penetrance of pheochromocytoma and primary hyperparathyroidism.

  5. Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine.

    Science.gov (United States)

    Gaspari, Sevasti; Papachatzaki, Maria M; Koo, Ja Wook; Carr, Fiona B; Tsimpanouli, Maria-Efstratia; Stergiou, Eugenia; Bagot, Rosemary C; Ferguson, Deveroux; Mouzon, Ezekiell; Chakravarty, Sumana; Deisseroth, Karl; Lobo, Mary Kay; Zachariou, Venetia

    2014-07-01

    Regulator of G protein signalling 9-2 (Rgs9-2) modulates the actions of a wide range of CNS-acting drugs by controlling signal transduction of several GPCRs in the striatum. RGS9-2 acts via a complex mechanism that involves interactions with Gα subunits, the Gβ5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposures to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools that allow manipulations of Rgs9-2 activity in particular brain regions of adult mice in order to better understand the mechanism via which this protein modulates opiate addiction and analgesia. We used adeno-associated viruses (AAVs) to express forms of Rgs9-2 in the dorsal and ventral striatum (nucleus accumbens, NAc) in order to examine the influence of this protein in morphine actions. Consistent with earlier behavioural findings from constitutive Rgs9 knockout mice, we show that Rgs9-2 actions in the NAc modulate morphine reward and dependence. Notably, Rgs9-2 in the NAc affects the analgesic actions of morphine as well as the development of analgesic tolerance. Using optogenetics we demonstrate that activation of Channelrhodopsin2 in Rgs9-2-expressing neurons, or in D1 dopamine receptor (Drd1)-enriched medium spiny neurons, accelerates the development of morphine tolerance, whereas activation of D2 dopamine receptor (Drd2)-enriched neurons does not significantly affect the development of tolerance. Together, these data provide new information on the signal transduction mechanisms underlying opiate actions in the NAc.

  6. Modulation of Backbone Flexibility for Effective Dissociation of Antibacterial and Hemolytic Activity in Cyclic Peptides.

    Science.gov (United States)

    Oddo, Alberto; Thomsen, Thomas T; Britt, Hannah M; Løbner-Olesen, Anders; Thulstrup, Peter W; Sanderson, John M; Hansen, Paul R

    2016-08-11

    Bacterial resistance to antibiotic therapy is on the rise and threatens to evolve into a worldwide emergency: alternative solutions to current therapies are urgently needed. Cationic amphipathic peptides are potent membrane-active agents that hold promise as the next-generation therapy for multidrug-resistant infections. The peptides' behavior upon encountering the bacterial cell wall is crucial, and much effort has been dedicated to the investigation and optimization of this amphipathicity-driven interaction. In this study we examined the interaction of a novel series of nine-membered flexible cyclic AMPs with liposomes mimicking the characteristics of bacterial membranes. Employed techniques included circular dichroism and marker release assays, as well as microbiological experiments. Our analysis was aimed at correlating ring flexibility with their antimicrobial, hemolytic, and membrane activity. By doing so, we obtained useful insights to guide the optimization of cyclic antimicrobial peptides via modulation of their backbone flexibility without loss of activity. PMID:27563396

  7. Antitumor properties and modulation of antioxidant enzymes' activity by Aloe vera leaf active principles isolated via supercritical carbon dioxide extraction.

    Science.gov (United States)

    El-Shemy, H A; Aboul-Soud, M A M; Nassr-Allah, A A; Aboul-Enein, K M; Kabash, A; Yagi, A

    2010-01-01

    The aim of this study was to evaluate the potential anticancer properties and modulatory effect of selected Aloe vera (A. vera) active principles on antioxidant enzyme activities. Thus, three anthraquinones (Namely: aloesin, aloe-emodin and barbaloin) were extracted from A. vera leaves by supercritical fluid extraction and subsequently purified by high performance liquid chromatography. Additionally, the N-terminal octapeptide derived from verectin, a biologically active 14 kDa glycoprotein present in A. vera, was also tested. In vivo, active principles exhibited significant prolongation of the life span of tumor-transplanted animals in the following order: barbaloin> octapeptide> aloesin > aloe-emodin. A. vera active principles exhibited significant inhibition on Ehrlich ascite carcinoma cell (EACC) number, when compared to positive control group, in the following order: barbaloin> aloe-emodin > octapeptide > aloesin. Moreover, in trypan blue cell viability assay, active principles showed a significant concentration-dependent cytotoxicity against acute myeloid leukemia (AML) and acute lymphocytes leukemia (ALL) cancerous cells. Furthermore, in MTT cell viability test, aloe-emodin was found to be active against two human colon cancer cell lines (i.e. DLD-1 and HT2), with IC(50) values of 8.94 and 10.78 microM, respectively. Treatments of human AML leukemic cells with active principles (100 microg ml(-1)) resulted in varying intensities of internucleosomal DNA fragmentation, hallmark of cells undergoing apoptosis, in the following order: aloe-emodin> aloesin> barbaloin> octapeptide. Intererstingly, treatment of EACC tumors with active principles resulted in a significant elevation activity of key antioxidant enzymes (SOD, GST, tGPx, and LDH). Our data suggest that the tested A. vera compounds may exert their chemo-preventive effect through modulating antioxidant and detoxification enzyme activity levels, as they are one of the indicators of tumorigenesis. These

  8. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

    Directory of Open Access Journals (Sweden)

    J. Abraham Domínguez-Avila

    2016-06-01

    Full Text Available Peroxisome proliferator-activated receptors (PPAR are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity.

  9. Modulation of electroencephalograph activity by manual acupuncture stimulation in healthy subjects: An autoregressive spectral analysis

    Institute of Scientific and Technical Information of China (English)

    Yi Guo-Sheng; Wang Jiang; Deng Bin; Wei Xi-Le; Han Chun-Xiao

    2013-01-01

    To investigate whether and how manual acupuncture (MA) modulates brain activities,we design an experiment where acupuncture at acupoint ST36 of the right leg is used to obtain electroencephalograph (EEG) signals in healthy subjects.We adopt the autoregressive (AR) Burg method to estimate the power spectrum of EEG signals and analyze the relative powers in delta (0 Hz-4 Hz),theta (4 Hz-8 Hz),alpha (8 Hz-13 Hz),and beta (13 Hz-30 Hz) bands.Our results show that MA at ST36 can significantly increase the EEG slow wave relative power (delta band) and reduce the fast wave relative powers (alpha and beta bands),while there are no statistical differences in theta band relative power between different acupuncture states.In order to quantify the ratio of slow to fast wave EEG activity,we compute the power ratio index.It is found that the MA can significantly increase the power ratio index,especially in frontal and central lobes.All the results highlight the modulation of brain activities with MA and may provide potential help for the clinical use of acupuncture.The proposed quantitative method of acupuncture signals may be further used to make MA more standardized.

  10. Development of active edge pixel sensors and four-side buttable modules using vertical integration technologies

    Energy Technology Data Exchange (ETDEWEB)

    Macchiolo, A., E-mail: Anna.Macchiolo@mpp.mpg.de [Max-Planck-Institut for Physics, Föhringer Ring 6, D-80805 Munich (Germany); Andricek, L. [Semiconductor Laboratory of the Max-Planck-Society, Otto Hahn Ring 6, D-81739 Munich (Germany); Moser, H.-G.; Nisius, R. [Max-Planck-Institut for Physics, Föhringer Ring 6, D-80805 Munich (Germany); Richter, R.H. [Semiconductor Laboratory of the Max-Planck-Society, Otto Hahn Ring 6, D-81739 Munich (Germany); Terzo, S.; Weigell, P. [Max-Planck-Institut for Physics, Föhringer Ring 6, D-80805 Munich (Germany)

    2014-11-21

    We present an R and D activity focused on the development of novel modules for the upgrade of the ATLAS pixel system at the High Luminosity LHC (HL-LHC). The modules consist of n-in-p pixel sensors, 100 or 200 μm thick, produced at VTT (Finland) with an active edge technology, which considerably reduces the dead area at the periphery of the device. The sensors are interconnected with solder bump-bonding to the ATLAS FE-I3 and FE-I4 read-out chips, and characterised with radioactive sources and beam tests at the CERN-SPS and DESY. The results of these measurements will be discussed for devices before and after irradiation up to a fluence of 5×10{sub 15}n{sub eq}/cm{sup 2}. We will also report on the R and D activity to obtain Inter Chip Vias (ICVs) on the ATLAS read-out chip in collaboration with the Fraunhofer Institute EMFT. This step is meant to prove the feasibility of the signal transport to the newly created readout pads on the backside of the chips allowing for four side buttable devices without the presently used cantilever for wire bonding. The read-out chips with ICVs will be interconnected to thin pixel sensors, 75 μm and 150 μm thick, with the Solid Liquid Interdiffusion (SLID) technology, which is an alternative to the standard solder bump-bonding.

  11. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets.

    Science.gov (United States)

    Domínguez-Avila, J Abraham; González-Aguilar, Gustavo A; Alvarez-Parrilla, Emilio; de la Rosa, Laura A

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. PMID:27367676

  12. Modulation of electroencephalograph activity by manual acupuncture stimulation in healthy subjects: An autoregressive spectral analysis

    International Nuclear Information System (INIS)

    To investigate whether and how manual acupuncture (MA) modulates brain activities, we design an experiment where acupuncture at acupoint ST36 of the right leg is used to obtain electroencephalograph (EEG) signals in healthy subjects. We adopt the autoregressive (AR) Burg method to estimate the power spectrum of EEG signals and analyze the relative powers in delta (0 Hz–4 Hz), theta (4 Hz–8 Hz), alpha (8 Hz–13 Hz), and beta (13 Hz–30 Hz) bands. Our results show that MA at ST36 can significantly increase the EEG slow wave relative power (delta band) and reduce the fast wave relative powers (alpha and beta bands), while there are no statistical differences in theta band relative power between different acupuncture states. In order to quantify the ratio of slow to fast wave EEG activity, we compute the power ratio index. It is found that the MA can significantly increase the power ratio index, especially in frontal and central lobes. All the results highlight the modulation of brain activities with MA and may provide potential help for the clinical use of acupuncture. The proposed quantitative method of acupuncture signals may be further used to make MA more standardized. (interdisciplinary physics and related areas of science and technology)

  13. Synthesis and Biological Activity of 6-Selenocaffeine: Potential Modulator of Chemotherapeutic Drugs in Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Inês L. Martins

    2013-05-01

    Full Text Available We report the development of a new microwave-based synthetic methodology mediated by Woollins’ reagent that allowed an efficient conversion of caffeine into 6-selenocaffeine. A preliminary evaluation on the modulation of antioxidant activity upon selenation of caffeine, using the DPPH assay, indicated a mild antioxidant activity for 6-selenocaffeine, contrasting with caffeine, that exhibited no antioxidant activity under the same experimental conditions. Interestingly, whereas 6-selenocaffeine has revealed to have a low cytotoxic potential in both MCF10A and MCF-7 breast cells (24 h, up to 100 µM, MTT assay, a differential effect was observed when used in combination with the anticancer agents doxorubicin and oxaliplatin in MCF-7 breast cancer cells. The co-treatment of doxorubicin (1 µM and 6-selenocaffeine (100 µM resulted in a slight decrease in cellular viability when compared to doxorubicin (1 µM alone. Conversely, the seleno-caffeine derivative at the same concentration markedly increased the viability of oxaliplatin (100 µM-treated cells (p < 0.01. Overall, this work highlights an emerging methodology to synthesize organoselenium compounds and points out the differential roles of 6-selenocaffeine in the modulation of the cytotoxicity of anticancer agents.

  14. Development of active edge pixel sensors and four-side buttable modules using vertical integration technologies

    Science.gov (United States)

    Macchiolo, A.; Andricek, L.; Moser, H.-G.; Nisius, R.; Richter, R. H.; Terzo, S.; Weigell, P.

    2014-11-01

    We present an R&D activity focused on the development of novel modules for the upgrade of the ATLAS pixel system at the High Luminosity LHC (HL-LHC). The modules consist of n-in-p pixel sensors, 100 or 200 μm thick, produced at VTT (Finland) with an active edge technology, which considerably reduces the dead area at the periphery of the device. The sensors are interconnected with solder bump-bonding to the ATLAS FE-I3 and FE-I4 read-out chips, and characterised with radioactive sources and beam tests at the CERN-SPS and DESY. The results of these measurements will be discussed for devices before and after irradiation up to a fluence of 5 ×1015neq /cm2. We will also report on the R&D activity to obtain Inter Chip Vias (ICVs) on the ATLAS read-out chip in collaboration with the Fraunhofer Institute EMFT. This step is meant to prove the feasibility of the signal transport to the newly created readout pads on the backside of the chips allowing for four side buttable devices without the presently used cantilever for wire bonding. The read-out chips with ICVs will be interconnected to thin pixel sensors, 75 μm and 150 μm thick, with the Solid Liquid Interdiffusion (SLID) technology, which is an alternative to the standard solder bump-bonding.

  15. Modulation of the chaperone-like activity of bovine alpha-crystallin.

    Science.gov (United States)

    Clark, J I; Huang, Q L

    1996-12-24

    The effects of pantethine, glutathione, and selected chemical reagents on the anti-aggregation activity of alpha-crystallin was evaluated. Protein aggregation was monitored by light scattering of solutions of denatured beta L-crystallin or alcohol dehydrogenase (ADH). The ratios of beta L-crystallin/alpha-crystallin and ADH/alpha-crystallin were adjusted so that partial inhibition of protein aggregation at 60 degrees C or 37 degrees C, respectively, was observed and modulation of the chaperone action of alpha-crystallin could be evaluated easily with selected endogenous metabolites. Enhancement of the anti-aggregation activity in the beta L-crystallin assay was strongest with pantethine, which appeared to interact with alpha-crystallin. Enhancement of the anti-aggregation activity in the ADH assay was strongest with glutathione which appeared to interact with ADH. The results indicated that the products of common metabolic pathways can modulate the chaperone-like effects of alpha-crystallin on protein aggregation. PMID:8986785

  16. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

    Science.gov (United States)

    Domínguez-Avila, J. Abraham; González-Aguilar, Gustavo A.; Alvarez-Parrilla, Emilio; de la Rosa, Laura A.

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. PMID:27367676

  17. Significant Modules and Biological Processes between Active Components of Salvia miltiorrhiza Depside Salt and Aspirin

    Directory of Open Access Journals (Sweden)

    Yuan Li

    2016-01-01

    Full Text Available The aim of this study is to examine and compare the similarities and differences between active components of S. miltiorrhiza depside salt and aspirin using perspective of pharmacological molecular networks. Active components of S. miltiorrhiza depside salt and aspirin’s related genes were identified via the STITCH4.0 and GeneCards Database. A text search engine (Agilent Literature Search 2.71 and MCODE software were applied to construct network and divide modules, respectively. Finally, 32, 2, and 28 overlapping genes, modules, and pathways were identified between active components of S. miltiorrhiza depside salt and aspirin. A multidimensional framework of drug network showed that two networks reflected commonly in human aortic endothelial cells and atherosclerosis process. Aspirin plays a more important role in metabolism, such as the well-known AA metabolism pathway and other lipid or carbohydrate metabolism pathways. S. miltiorrhiza depside salt still plays a regulatory role in type II diabetes mellitus, insulin resistance, and adipocytokine signaling pathway. Therefore, this study suggests that aspirin combined with S. miltiorrhiza depside salt may be more efficient in treatment of CHD patients, especially those with diabetes mellitus or hyperlipidemia. Further clinical trials to confirm this hypothesis are still needed.

  18. Optogenetic micro-electrocorticography for modulating and localizing cerebral cortex activity

    Science.gov (United States)

    Richner, Thomas J.; Thongpang, Sanitta; Brodnick, Sarah K.; Schendel, Amelia A.; Falk, Ryan W.; Krugner-Higby, Lisa A.; Pashaie, Ramin; Williams, Justin C.

    2014-02-01

    Objective. Spatial localization of neural activity from within the brain with electrocorticography (ECoG) and electroencephalography remains a challenge in clinical and research settings, and while microfabricated ECoG (micro-ECoG) array technology continues to improve, complementary methods to simultaneously modulate cortical activity while recording are needed. Approach. We developed a neural interface utilizing optogenetics, cranial windowing, and micro-ECoG arrays fabricated on a transparent polymer. This approach enabled us to directly modulate neural activity at known locations around micro-ECoG arrays in mice expressing Channelrhodopsin-2. We applied photostimuli varying in time, space and frequency to the cortical surface, and we targeted multiple depths within the cortex using an optical fiber while recording micro-ECoG signals. Main results. Negative potentials of up to 1.5 mV were evoked by photostimuli applied to the entire cortical window, while focally applied photostimuli evoked spatially localized micro-ECoG potentials. Two simultaneously applied focal stimuli could be separated, depending on the distance between them. Photostimuli applied within the cortex with an optical fiber evoked more complex micro-ECoG potentials with multiple positive and negative peaks whose relative amplitudes depended on the depth of the fiber. Significance. Optogenetic ECoG has potential applications in the study of epilepsy, cortical dynamics, and neuroprostheses.

  19. Matrix stiffness modulates formation and activity of neuronal networks of controlled architectures.

    Science.gov (United States)

    Lantoine, Joséphine; Grevesse, Thomas; Villers, Agnès; Delhaye, Geoffrey; Mestdagh, Camille; Versaevel, Marie; Mohammed, Danahe; Bruyère, Céline; Alaimo, Laura; Lacour, Stéphanie P; Ris, Laurence; Gabriele, Sylvain

    2016-05-01

    The ability to construct easily in vitro networks of primary neurons organized with imposed topologies is required for neural tissue engineering as well as for the development of neuronal interfaces with desirable characteristics. However, accumulating evidence suggests that the mechanical properties of the culture matrix can modulate important neuronal functions such as growth, extension, branching and activity. Here we designed robust and reproducible laminin-polylysine grid micropatterns on cell culture substrates that have similar biochemical properties but a 100-fold difference in Young's modulus to investigate the role of the matrix rigidity on the formation and activity of cortical neuronal networks. We found that cell bodies of primary cortical neurons gradually accumulate in circular islands, whereas axonal extensions spread on linear tracks to connect circular islands. Our findings indicate that migration of cortical neurons is enhanced on soft substrates, leading to a faster formation of neuronal networks. Furthermore, the pre-synaptic density was two times higher on stiff substrates and consistently the number of action potentials and miniature synaptic currents was enhanced on stiff substrates. Taken together, our results provide compelling evidence to indicate that matrix stiffness is a key parameter to modulate the growth dynamics, synaptic density and electrophysiological activity of cortical neuronal networks, thus providing useful information on scaffold design for neural tissue engineering.

  20. Modulation of Subgenual Anterior Cingulate Cortex Activity With Real-Time Neurofeedback

    OpenAIRE

    Hamilton, J. Paul; Glover, Gary H.; Hsu, Jung-Jiin; Johnson, Rebecca F.; Gotlib, Ian H.

    2011-01-01

    The advent of real-time neurofeedback techniques has allowed us to begin to map the controllability of sensory and cognitive and, more recently, affective centers in the brain. The subgenual anterior cingulate cortex (sACC) is thought to be involved in generation of affective states and has been implicated in psychopathology. In this study, we examined whether individuals could use realtime fMRI neurofeedback to modulate sACC activity. Following a localizer task used to identify an sACC regio...

  1. Integration of Optical Manipulation and Electrophysiological Tools to Modulate and Record Activity in Neural Networks

    Science.gov (United States)

    Difato, F.; Schibalsky, L.; Benfenati, F.; Blau, A.

    2011-07-01

    We present an optical system that combines IR (1064 nm) holographic optical tweezers with a sub-nanosecond-pulsed UV (355 nm) laser microdissector for the optical manipulation of single neurons and entire networks both on transparent and non-transparent substrates in vitro. The phase-modulated laser beam can illuminate the sample concurrently or independently from above or below assuring compatibility with different types of microelectrode array and patch-clamp electrophysiology. By combining electrophysiological and optical tools, neural activity in response to localized stimuli or injury can be studied and quantified at sub-cellular, cellular, and network level.

  2. Advanced glycation end products induce fibrogenic activity in NASH by modulating the TNFα converting enzyme activity

    OpenAIRE

    Joy, Jiang X; Chen, Xiangling; Fukada, Hiroo; Serizawa, Nobuko; Devaraj, Sridevi; Török, Natalie J.

    2013-01-01

    Advanced glycation end products (AGEs) accumulate in patients with diabetes, yet the link between AGEs and the inflammatory and fibrogenic activity in non-alcoholic steatohepatitis (NASH) has not been explored. TNFα converting enzyme (TACE) is at the center of inflammatory processes. As the main natural regulator of TACE activity is the tissue inhibitor of metalloproteinase 3 (Timp3), we hypothesized that AGEs induce TACE through NADPH oxidase 2 (NOX2); and the downregulation of Sirtuin 1 (Si...

  3. Modulation of hepatocarcinoma cell morphology and activity by parylene-C coating on PDMS.

    Directory of Open Access Journals (Sweden)

    Nazaré Pereira-Rodrigues

    Full Text Available BACKGROUND: The ability to understand and locally control the morphogenesis of mammalian cells is a fundamental objective of cell and developmental biology as well as tissue engineering research. We present parylene-C (ParC deposited on polydimethylsiloxane (PDMS as a new substratum for in vitro advanced cell culture in the case of Human Hepatocarcinoma (HepG2 cells. PRINCIPAL FINDINGS: Our findings establish that the intrinsic properties of ParC-coated PDMS (ParC/PDMS influence and modulate initial extracellular matrix (ECM; here, type-I collagen surface architecture, as compared to non-coated PDMS substratum. Morphological changes induced by the presence of ParC on PDMS were shown to directly affect liver cell metabolic activity and the expression of transmembrane receptors implicated in cell adhesion and cell-cell interaction. These changes were characterized by atomic force microscopy (AFM, which elucidated differences in HepG2 cell adhesion, spreading, and reorganization into two- or three-dimensional structures by neosynthesis of ECM components. Local modulation of cell aggregation was successfully performed using ParC/PDMS micropatterns constructed by simple microfabrication. CONCLUSION/SIGNIFICANCE: We demonstrated for the first time the modulation of HepG2 cells' behavior in relation to the intrinsic physical properties of PDMS and ParC, enabling the local modulation of cell spreading in a 2D or 3D manner by simple microfabrication techniques. This work will provide promising insights into the development of cell-based platforms that have many applications in the field of in vitro liver tissue engineering, pharmacology and therapeutics.

  4. Histones Differentially Modulate the Anticoagulant and Profibrinolytic Activities of Heparin, Heparin Derivatives, and Dabigatran.

    Science.gov (United States)

    Ammollo, Concetta Tiziana; Semeraro, Nicola; Carratù, Maria Rosaria; Colucci, Mario; Semeraro, Fabrizio

    2016-02-01

    The antithrombin activity of unfractionated heparin (UFH) is offset by extracellular histones, which, along with DNA, represent a novel mediator of thrombosis and a structural component of thrombi. Here, we systematically evaluated the effect of histones, DNA, and histone-DNA complexes on the anticoagulant and profibrinolytic activities of UFH, its derivatives enoxaparin and fondaparinux, and the direct thrombin inhibitor dabigatran. Thrombin generation was assessed by calibrated automated thrombinography, inhibition of factor Xa and thrombin by synthetic substrates, tissue plasminogen activator-mediated clot lysis by turbidimetry, and thrombin-activatable fibrinolysis inhibitor (TAFI) activation by a functional assay. Histones alone delayed coagulation and slightly stimulated fibrinolysis. The anticoagulant activity of UFH and enoxaparin was markedly inhibited by histones, whereas that of fondaparinux was enhanced. Histones neutralized both the anti-Xa and anti-IIa activities of UFH and preferentially blocked the anti-IIa activity of enoxaparin. The anti-Xa activity of fondaparinux was not influenced by histones when analyzed by chromogenic substrates, but was potentiated in a plasma prothrombinase assay. Histones inhibited the profibrinolytic activity of UFH and enoxaparin and enhanced that of fondaparinux by acting on the modulation of TAFI activation by anticoagulants. Histone H1 was mainly responsible for these effects. Histone-DNA complexes, as well as intact neutrophil extracellular traps, impaired the activities of UFH, enoxaparin, and fondaparinux. Dabigatran was not noticeably affected by histones and/or DNA, whatever the assay performed. In conclusion, histones and DNA present in the forming clot may variably influence the antithrombotic activities of anticoagulants, suggesting a potential therapeutic advantage of dabigatran and fondaparinux over heparins.

  5. Dopaminergic modulation of the spectral characteristics in the rat brain oscillatory activity

    International Nuclear Information System (INIS)

    Highlights: ► The oscillatory activity recorded at different locations of the rat brain present a power law characteristic (PLC). ► Dopaminergic drugs are able to modify the power law spectral characteristic of the oscillatory activity. ► Drugs with opposite effects over the dopaminergic system (agonists/antagonists), induce opposite changes in the PLC. ► There is a fulcrum point for the modulation of the PLC around 20 Hz. ► The brain operates in a state of self-organized criticality (SOC) sensitive to dopaminergic modulation. - Abstract: Oscillatory activity can be widely recorded in the brain. It has been demonstrated to play an important role not only in the physiology of movement, perception and cognition, but also in the pathophysiology of a variety of diseases. In frequency domain, neurophysiological recordings show a power spectrum (PSD) following a log (PSD) ∝ log (f)−β, that reveals an intrinsic feature of many complex systems in nature: the presence of a scale-free dynamics characterized by a power-law component (PLC). Here we analyzed the influence of dopaminergic drugs over the PLC of the oscillatory activity recorded from different locations of the rat brain. Dopamine (DA) is a neurotransmitter that is required for a number of physiological functions like normal feeding, locomotion, posturing, grooming and reaction time. Alterations in the dopaminergic system cause vast effects in the dynamics of the brain activity, that may be crucial in the pathophysiology of neurological (like Parkinson’s disease) or psychiatric (like schizophrenia) diseases. Our results show that drugs with opposite effects over the dopaminergic system, induce opposite changes in the characteristics of the PLC: DA agonists/antagonists cause the PLC to swing around a fulcrum point in the range of 20 Hz. Changes in the harmonic component of the spectrum were also detected. However, differences between recordings are better explained by the modulation of the PLC than

  6. Comparative analysis of codon usage bias in Crenarchaea and Euryarchaea genome reveals differential preference of synonymous codons to encode highly expressed ribosomal and RNA polymerase proteins

    Indian Academy of Sciences (India)

    VISHWA JYOTI BARUAH; SIDDHARTHA SANKAR SATAPATHY; BHESH RAJ POWDEL; ROCKTOTPAL KONWARH; ALAK KUMAR BURAGOHAIN; SUVENDRA KUMAR RAY

    2016-09-01

    The present study was undertaken to investigate the pattern of optimal codon usage in Archaea. Comparative analysis was executed to understand the pattern of codon usage bias between the high expression genes (HEG) and the whole genomes in two Archaeal phyla, Crenarchaea and Euryarchaea. The G+C% of the HEG was found to be less in comparison to the genome G+ C% in Crenarchaea, whereas reverse was the case in Euryarchaea. The preponderance of U/A ending codons that code for HEG in Crenarchaea was in sharp contrast to the C/G ended ones in Euryarchaea. The analysis revealed prevalence of U-ending codons even within the WWY (nucleotide ambiguity code) families in Crenarchaea vis-à-vis Euryarchaea, bacteria and Eukarya. No plausible interpretation of the observed disparity could be made either in the context of tRNA gene composition or genome G +C%. The results in this study attested that the preferential biasness for codons in HEG of Crenarchaea might be different from Euryarchaea. The main highlights are (i) varied CUB in the HEG and in the whole genomes in Euryarchaea and Crenarchaea. (ii) Crenarchaea was found to have some unusual optimal codons (OCs) compared to other organisms. (iii) G+ C% (and GC 3) of the HEG were different from the genome G + C% in the two phyla. (iv) Genome G + C% and tRNAgene number failed to explain CUB in Crenarchaea. (v) Translational selection is possibly responsible for A + T rich OCs in Crenarchaea.

  7. Characterization of codon usage pattern and influencing factors in Japanese encephalitis virus.

    Science.gov (United States)

    Singh, Niraj K; Tyagi, Anuj; Kaur, Rajinder; Verma, Ramneek; Gupta, Praveen K

    2016-08-01

    Recently, several outbreaks of Japanese encephalitis (JE), caused by Japanese encephalitis virus (JEV), have been reported and it has become cause of concern across the world. In this study, detailed analysis of JEV codon usage pattern was performed. The relative synonymous codon usage (RSCU) values along with mean effective number of codons (ENC) value of 55.30 indicated the presence of low codon usages bias in JEV. The effect of mutational pressure on codon usage bias was confirmed by significant correlations of A3s, U3s, G3s, C3s, GC3s, ENC values, with overall nucleotide contents (A%, U%, G%, C%, and GC%). The correlation analysis of A3s, U3s, G3s, C3s, GC3s, with axis values of correspondence analysis (CoA) further confirmed the role of mutational pressure. However, the correlation analysis of Gravy values and Aroma values with A3s, U3s, G3s, C3s, and GC3s, indicated the presence of natural selection on codon usage bias in addition to mutational pressure. The natural selection was further confirmed by codon adaptation index (CAI) analysis. Additionally, relative dinucleotide frequencies, geographical distribution, and evolutionary processes also influenced the codon usage pattern to some extent. PMID:27189042

  8. Selective Factors Associated with the Evolution of Codon Usage in Natural Populations of Arboviruses.

    Science.gov (United States)

    Velazquez-Salinas, Lauro; Zarate, Selene; Eschbaumer, Michael; Pereira Lobo, Francisco; Gladue, Douglas P; Arzt, Jonathan; Novella, Isabel S; Rodriguez, Luis L

    2016-01-01

    Arboviruses (arthropod borne viruses) have life cycles that include both vertebrate and invertebrate hosts with substantial differences in vector and host specificity between different viruses. Most arboviruses utilize RNA for their genetic material and are completely dependent on host tRNAs for their translation, suggesting that virus codon usage could be a target for selection. In the current study we analyzed the relative synonymous codon usage (RSCU) patterns of 26 arboviruses together with 25 vectors and hosts, including 8 vertebrates and 17 invertebrates. We used hierarchical cluster analysis (HCA) and principal component analysis (PCA) to identify trends in codon usage. HCA demonstrated that the RSCU of arboviruses reflects that of their natural hosts, but not that of dead-end hosts. Of the two major components identified by PCA, the first accounted for 62.1% of the total variance, and among the 59 codons analyzed in this study, the leucine codon CTG had the highest correlation with the first principal component, however isoleucine had the highest correlation during amino acid analysis. Nucleotide and dinucleotide composition were the variables that explained most of the total codon usage variance. The results suggest that the main factors driving the evolution of codon usage in arboviruses is based on the nucleotide and dinucleotide composition present in the host. Comparing codon usage of arboviruses and potential vector hosts can help identifying potential vectors for emerging arboviruses.

  9. Comparative Analysis of Codon Usage Patterns Among Mitochondrion, Chloroplast and Nuclear Genes in Triticum aestivum L.

    Institute of Scientific and Technical Information of China (English)

    Wen-Juan Zhang; Jie Zhou; Zuo-Feng Li; Li Wang; Xun Gu; Yang Zhong

    2007-01-01

    In many organisms, the difference in codon usage patterns among genes reflects variation in local base compositional biases and the intensity of natural selection. In this study, a comparative analysis was performed to investigate the characteristics of codon bias and factors in shaping the codon usage patterns among mitochondrion,chloroplast and nuclear genes in common wheat (Triticum aestivum L.). GC contents in nuclear genes were higher than that in mitochondrion and chloroplast genes. The neutrality and correspondence analyses indicated that the codon usage in nuclear genes would be a result of relative strong mutational bias, while the codon usage patterns of rnitochondrion and chloroplast genes were more conserved in GC content and influenced by translation level.The Parity Rule 2 (PR2) plot analysis showed that pyrimidines were used more frequently than purines at the third codon position in the three genomes. In addition, using a new alterative strategy, 11, 12, and 24 triplets were defined as preferred codons in the mitochondrion, chloroplast and nuclear genes, respectively. These findings suggested that the mitochondrion, chloroplast and nuclear genes shared particularly different features of codon usage and evolutionary constraints.

  10. Selective Factors Associated with the Evolution of Codon Usage in Natural Populations of Arboviruses

    Science.gov (United States)

    Velazquez-Salinas, Lauro; Zarate, Selene; Eschbaumer, Michael; Pereira Lobo, Francisco; Gladue, Douglas P.; Arzt, Jonathan; Novella, Isabel S.; Rodriguez, Luis L.

    2016-01-01

    Arboviruses (arthropod borne viruses) have life cycles that include both vertebrate and invertebrate hosts with substantial differences in vector and host specificity between different viruses. Most arboviruses utilize RNA for their genetic material and are completely dependent on host tRNAs for their translation, suggesting that virus codon usage could be a target for selection. In the current study we analyzed the relative synonymous codon usage (RSCU) patterns of 26 arboviruses together with 25 vectors and hosts, including 8 vertebrates and 17 invertebrates. We used hierarchical cluster analysis (HCA) and principal component analysis (PCA) to identify trends in codon usage. HCA demonstrated that the RSCU of arboviruses reflects that of their natural hosts, but not that of dead-end hosts. Of the two major components identified by PCA, the first accounted for 62.1% of the total variance, and among the 59 codons analyzed in this study, the leucine codon CTG had the highest correlation with the first principal component, however isoleucine had the highest correlation during amino acid analysis. Nucleotide and dinucleotide composition were the variables that explained most of the total codon usage variance. The results suggest that the main factors driving the evolution of codon usage in arboviruses is based on the nucleotide and dinucleotide composition present in the host. Comparing codon usage of arboviruses and potential vector hosts can help identifying potential vectors for emerging arboviruses. PMID:27455096

  11. Analysis of the synonymous codon usage bias in recently emerged enterovirus D68 strains.

    Science.gov (United States)

    Karniychuk, Uladzimir U

    2016-09-01

    Understanding the codon usage pattern of a pathogen and relationship between pathogen and host's codon usage patterns has fundamental and applied interests. Enterovirus D68 (EV-D68) is an emerging pathogen with a potentially high public health significance. In the present study, the synonymous codon usage bias of 27 recently emerged, and historical EV-D68 strains was analyzed. In contrast to previously studied enteroviruses (enterovirus 71 and poliovirus), EV-D68 and human host have a high discrepancy between favored codons. Analysis of viral synonymous codon usage bias metrics, viral nucleotide/dinucleotide compositional parameters, and viral protein properties showed that mutational pressure is more involved in shaping the synonymous codon usage bias of EV-D68 than translation selection. Computation of codon adaptation indices allowed to estimate expression potential of the EV-D68 genome in several commonly used laboratory animals. This approach requires experimental validation and may provide an auxiliary tool for the rational selection of laboratory animals to model emerging viral diseases. Enterovirus D68 genome compositional and codon usage data can be useful for further pathogenesis, animal model, and vaccine design studies. PMID:27364082

  12. Codon optimization of the adenoviral fiber negatively impacts structural protein expression and viral fitness

    Science.gov (United States)

    Villanueva, Eneko; Martí-Solano, Maria; Fillat, Cristina

    2016-06-01

    Codon usage adaptation of lytic viruses to their hosts is determinant for viral fitness. In this work, we analyzed the codon usage of adenoviral proteins by principal component analysis and assessed their codon adaptation to the host. We observed a general clustering of adenoviral proteins according to their function. However, there was a significant variation in the codon preference between the host-interacting fiber protein and the rest of structural late phase proteins, with a non-optimal codon usage of the fiber. To understand the impact of codon bias in the fiber, we optimized the Adenovirus-5 fiber to the codon usage of the hexon structural protein. The optimized fiber displayed increased expression in a non-viral context. However, infection with adenoviruses containing the optimized fiber resulted in decreased expression of the fiber and of wild-type structural proteins. Consequently, this led to a drastic reduction in viral release. The insertion of an exogenous optimized protein as a late gene in the adenovirus with the optimized fiber further interfered with viral fitness. These results highlight the importance of balancing codon usage in viral proteins to adequately exploit cellular resources for efficient infection and open new opportunities to regulate viral fitness for virotherapy and vaccine development.

  13. On the Modulation of Brain Activation During Simulated Weight Bearing in Supine Gait-Like Stepping.

    Science.gov (United States)

    Jaeger, Lukas; Marchal-Crespo, Laura; Wolf, Peter; Luft, Andreas R; Riener, Robert; Michels, Lars; Kollias, Spyros

    2016-01-01

    To date, the neurophysiological correlates of muscle activation required for weight bearing during walking are poorly understood although, a supraspinal involvement has been discussed in the literature for many years. The present study investigates the effect of simulated ground reaction forces (0, 20, and 40% of individual body weight) on brain activation in sixteen healthy participants. A magnetic resonance compatible robot was applied to render three different levels of load against the feet of the participants during active and passive gait-like stepping movements. Brain activation was analyzed by the means of voxel-wise whole brain analysis as well as by a region-of-interest analysis. A significant modulation of brain activation in sensorimotor areas by the load level could neither be demonstrated during active nor during passive stepping. These observations suggest that the regulation of muscle activation under different weight-bearing conditions during stepping occurs at the level of spinal circuitry or the brainstem rather than at the supraspinal level.

  14. cAMP Modulates Macrophage Development by Suppressing M-CSF-Induced MAPKs Activation

    Institute of Scientific and Technical Information of China (English)

    Ning Zhu; Jian Cui; Chunxia Qiao; Yan Li; Yuanfang Ma; Jiyan Zhang; Beifen Shen

    2008-01-01

    M-CSF is a key cytokine in macrophage development by inducing MAPKs activation, and cAMP can inhibit MAPKs activation induced by inflammatory stimuli. To explore the effects of cAMP on M-CSF-induced MAPKs activation and on macrophage development, the model of bone marrow-derived murine macrophages (BMMs) was used. The effects of cAMP on M-CSF-induced MAPKs activation were analyzed by Western blotting assay, and the effects of cAMP on CD14 and F4/80 expression during macrophage development were examined by FACS analysis.Macrophage morphology showed the successful establishment of the model of macrophage development. Western blotting assay revealed that M-CSF activated ERK, JNK and p38 in both mature and immature macrophages, and cAMP inhibited M-CSF-induced ERK, JNK and p38 activation in a time-dependent manner. FACS analysis revealed that macrophage development was impaired with cAMP pretreatment. In conclusion, cAMP modulates macrophage development by suppressing M-CSF-induced MAPKs activation.

  15. The role of metals in modulating metalloprotease activity in the AD brain.

    Science.gov (United States)

    Filiz, Gulay; Price, Katherine A; Caragounis, Aphrodite; Du, Tai; Crouch, Peter J; White, Anthony R

    2008-03-01

    Biometals such as copper and zinc have an important role in Alzheimer's disease (AD). Accumulating evidence indicates that copper homeostasis is altered in AD brain with elevated extracellular and low intracellular copper levels. Studies in animals and cell cultures have suggested that increasing intracellular copper can ameliorate AD-like pathology including amyloid deposition and tau phosphorylation. Modulating copper homeostasis can also improve cognitive function in animal models of AD. Treatments are now being developed that may result in redistribution of copper within the brain. Metal ligands such as clioquinol (CQ), DP-109 or pyrrolidine dithiocarbamate (PDTC) have shown promising results in animal models of AD, however, the actual mode of action in vivo has not been fully determined. We previously reported that CQ-metal complexes were able to increase intracellular copper levels in vitro. This resulted in stimulation of phosphoinositol-3-kinase activity and mitogen activated protein kinases (MAPK). Increased kinase activity resulted in up-regulated matrix metalloprotease (MMP2 and MMP3) activity resulting in enhanced degradation of secreted A beta. These findings are consistent with previous studies reporting metal-mediated activation of MAPKs and MMPs. How this activation occurs is unknown but evidence suggests that copper may be able to activate membrane receptors such as the epidermal growth factor receptor (EGFR) and result in downstream activation of MAPK pathways. This has been supported by studies showing metal-mediated activation of EGFR through ligand-independent processes in a number of cell-types. Our initial studies reveal that copper complexes can in fact activate EGFR. However, further studies are necessary to determine if metal complexes such as CQ-copper induce up-regulation of A beta-degrading MMP activity through this mechanism. Elucidation of this pathway may have important implications for the development of metal ligand based

  16. Differences in codon bias cannot explain differences in translational power among microbes

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    Dethlefsen Les

    2005-01-01

    Full Text Available Abstract Background Translational power is the cellular rate of protein synthesis normalized to the biomass invested in translational machinery. Published data suggest a previously unrecognized pattern: translational power is higher among rapidly growing microbes, and lower among slowly growing microbes. One factor known to affect translational power is biased use of synonymous codons. The correlation within an organism between expression level and degree of codon bias among genes of Escherichia coli and other bacteria capable of rapid growth is commonly attributed to selection for high translational power. Conversely, the absence of such a correlation in some slowly growing microbes has been interpreted as the absence of selection for translational power. Because codon bias caused by translational selection varies between rapidly growing and slowly growing microbes, we investigated whether observed differences in translational power among microbes could be explained entirely by differences in the degree of codon bias. Although the data are not available to estimate the effect of codon bias in other species, we developed an empirically-based mathematical model to compare the translation rate of E. coli to the translation rate of a hypothetical strain which differs from E. coli only by lacking codon bias. Results Our reanalysis of data from the scientific literature suggests that translational power can differ by a factor of 5 or more between E. coli and slowly growing microbial species. Using empirical codon-specific in vivo translation rates for 29 codons, and several scenarios for extrapolating from these data to estimates over all codons, we find that codon bias cannot account for more than a doubling of the translation rate in E. coli, even with unrealistic simplifying assumptions that exaggerate the effect of codon bias. With more realistic assumptions, our best estimate is that codon bias accelerates translation in E. coli by no more than

  17. Cytochrome P450 genes in coronary artery diseases: Codon usage analysis reveals genomic GC adaptation.

    Science.gov (United States)

    Malakar, Arup Kumar; Halder, Binata; Paul, Prosenjit; Chakraborty, Supriyo

    2016-09-15

    Establishing codon usage biases are imperative for understanding the etiology of coronary artery diseases (CAD) as well as the genetic factors associated with these diseases. The aim of this study was to evaluate the contribution of 18 responsible cytochrome P450 (CYP) genes for the risk of CAD. Effective number of codon (Nc) showed a negative correlation with both GC3 and synonymous codon usage order (SCUO) suggesting an antagonistic relationship between codon usage and Nc of genes. The dinucleotide analysis revealed that CG and TA dinucleotides have the lowest odds ratio in these genes. Principal component analysis showed that GC composition has a profound effect in separating the genes along the first major axis. Our findings revealed that mutational pressure and natural selection could possibly be the major factors responsible for codon bias in these genes. The study not only offers an insight into the mechanisms of genomic GC adaptation, but also illustrates the complexity of CYP genes in CAD. PMID:27275533

  18. Surfactant protein A integrates activation signal strength to differentially modulate T cell proliferation.

    Science.gov (United States)

    Mukherjee, Sambuddho; Giamberardino, Charles; Thomas, Joseph; Evans, Kathy; Goto, Hisatsugu; Ledford, Julie G; Hsia, Bethany; Pastva, Amy M; Wright, Jo Rae

    2012-02-01

    Pulmonary surfactant lipoproteins lower the surface tension at the alveolar-airway interface of the lung and participate in host defense. Previous studies reported that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that SP-A-mediated modulation of T cell activation depends upon the strength, duration, and type of lymphocyte activating signals. Modulation of T cell signal strength imparted by different activating agents ex vivo and in vivo in different mouse models and in vitro with human T cells shows a strong correlation between strength of signal (SoS) and functional effects of SP-A interactions. T cell proliferation is enhanced in the presence of SP-A at low SoS imparted by exogenous mitogens, specific Abs, APCs, or in homeostatic proliferation. Proliferation is inhibited at higher SoS imparted by different doses of the same T cell mitogens or indirect stimuli such as LPS. Importantly, reconstitution with exogenous SP-A into the lungs of SP-A(-/-) mice stimulated with a strong signal also resulted in suppression of T cell proliferation while elevating baseline proliferation in unstimulated T cells. These signal strength and SP-A-dependent effects are mediated by changes in intracellular Ca(2+) levels over time, involving extrinsic Ca(2+)-activated channels late during activation. These effects are intrinsic to the global T cell population and are manifested in vivo in naive as well as memory phenotype T cells. Thus, SP-A appears to integrate signal thresholds to control T cell proliferation. PMID:22219327

  19. Factors affecting mito-nuclear codon usage interactions in the OXPHOS system of Drosophila melanogaster

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Codon usage bias varies considerably among genomes and even within the genes of the same genome.In eukaryotic organisms,energy production in the form of oxidative phosphorylation(OXPHOS)is the only process under control of both nuclear and mitochondrial genomes.Although factors affecting codon usage in a single genome have been studied,this has not occurred when both interactional genomes are involved.Consequently, we investigated whether or not other factors influence codon usage of coevolved genes.We used Drosophila melanogaster as a model organism.Our χ2 test on the number of codons of nuclear and mitochondrial genes involved in the OXPHOS system was significantly different (χ2=7945.16,P<0.01).A plot of effective number of codons against GC3s content of nuclear genes showed that few genes lie on the expected curve,indicating that codon usage was random.Correspondence analysis indicated a significant correlation between axis 1 and codon adaptation index(R=0.947,P<0.01)in every nuclear gene sequence.Thus,codon usage bias of nuclear genes appeared to be affected by translational selection.Correlation between axis 1 coordinates and GC content(R=0.814.P<0.01)indicated that the codon usage of nuclear genes was also affected by GC composition.Analysis of mitochondrial genes did not reveal a significant correlation between axis 1 and any parameter.Statistical analyses indicated that codon usages of both nDNA and mtDNA were subjected to context-dependent mutations.

  20. Restoring wtp53 activity in HIPK2 depleted MCF7 cells by modulating metallothionein and zinc.

    Science.gov (United States)

    Puca, Rosa; Nardinocchi, Lavinia; Bossi, Gianluca; Sacchi, Ada; Rechavi, Gideon; Givol, David; D'Orazi, Gabriella

    2009-01-01

    The maintenance of p53 transactivation activity is important for p53 apoptotic function. We have shown that stable knockdown of HIPK2 induces p53 misfolding with inhibition of p53 target gene transcription. In this study we established a lentiviral-based system for doxycyclin (Dox)-induced conditional interference of HIPK2 expression to evaluate the molecular mechanisms involved in p53 deregulation. We found that HIPK2 knockdown induced metallothionein 2A (MT2A) upregulation as assessed by RT-PCR analysis, increased promoter acetylation, and increased promoter luciferase activity. The MT2A upregulation correlated with resistance to Adriamycin (ADR)-driven apoptosis and with p53 inhibition. Thus, acute knockdown of HIPK2 (HIPK2i) induced misfolded p53 protein in MCF7 breast cancer cells and inhibited p53 DNA-binding and transcription activities in response to ADR treatment. Previous works show that MT may modulate p53 activity through zinc exchange. Here, we found that inhibition of MT2A expression by siRNA in the HIPK2i cells restored p53 transcription activity. Similarly zinc supplementation to HIPK2i cells restored p53 transcription activity and drug-induced apoptosis. These data support the notion that MT2A is involved in p53 deregulation and strengthen the possibility that combination of chemotherapy and zinc might be useful to treat tumors with inactive wtp53. PMID:18996371

  1. Neural correlates of executive dysfunction in schizophrenia: failure to modulate brain activity with task demands.

    Science.gov (United States)

    Dirnberger, Georg; Fuller, Rebecca; Frith, Chris; Jahanshahi, Marjan

    2014-11-12

    In schizophrenia, executive functions are impaired and are associated with altered activation of prefrontal areas. We used H2[15]O PET to examine patients with schizophrenia and matched controls on a random number generation (RNG) task and a control counting (COUNT) task. To assess the effects of increasing task demand, both tasks were performed at three different rates (intervals 1, 2 or 3 s). Both groups showed a significant increase in the nonrandomness of responses at faster rates of RNG. Despite similar performances, patients but not controls showed higher activation of the right dorsolateral prefrontal cortex (DLPFC) and atypically reduced activation of the right anterior cingulate gyrus and the right medial frontal gyrus in RNG compared with COUNT, whereas only for controls, activation of the left DLPFC was increased and activation of the right superior temporal gyrus and the right superior frontal gyrus was reduced in the same comparison. Whereas for the controls several cortical areas including the bilateral superior temporal gyrus and the bilateral DLPFC, together with the right cerebellum, showed significant changes in regional cerebral blood flow with faster or slower rates, patients with schizophrenia showed rate-dependent changes only in the left cerebellum. In conclusion, the patients' failure to modulate cortical activation with changing demands of rate, particularly in prefrontal areas and in the cerebellum, and even when performance is similar to that in healthy controls, is a characteristic of their abnormal pattern of executive processing. PMID:25275638

  2. SUMOylation modulates the transcriptional activity of androgen receptor in a target gene and pathway selective manner.

    Science.gov (United States)

    Sutinen, Päivi; Malinen, Marjo; Heikkinen, Sami; Palvimo, Jorma J

    2014-07-01

    Androgen receptor (AR) plays an important regulatory role in prostate cancer. AR's transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications, such as SUMOylation. To study the role of AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer cell lines stably expressing wild-type (wt) or doubly SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene expression analyses reveal that the SUMOylation modulates the AR function in a target gene and pathway selective manner. The transcripts that are differentially regulated by androgen and SUMOylation are linked to cellular movement, cell death, cellular proliferation, cellular development and cell cycle. Fittingly, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation can modulate the chromatin occupancy of AR on many loci in a fashion that parallels their differential androgen-regulated expression. De novo motif analyses reveal that FOXA1, C/EBP and AP-1 motifs are differentially enriched at the wtAR- and the AR-K386R,K520R-preferred genomic binding positions. Taken together, our data indicate that SUMOylation does not simply repress the AR activity, but it regulates AR's interaction with the chromatin and the receptor's target gene selection.

  3. Phasic and Tonic mGlu7 Receptor Activity Modulates the Thalamocortical Network.

    Science.gov (United States)

    Tassin, Valériane; Girard, Benoît; Chotte, Apolline; Fontanaud, Pierre; Rigault, Delphine; Kalinichev, Mikhail; Perroy, Julie; Acher, Francine; Fagni, Laurent; Bertaso, Federica

    2016-01-01

    Mutation of the metabotropic glutamate receptor type 7 (mGlu7) induces absence-like epileptic seizures, but its precise role in the somatosensory thalamocortical network remains unknown. By combining electrophysiological recordings, optogenetics, and pharmacology, we dissected the contribution of the mGlu7 receptor at mouse thalamic synapses. We found that mGlu7 is functionally expressed at both glutamatergic and GABAergic synapses, where it can inhibit neurotransmission and regulate short-term plasticity. These effects depend on the PDZ-ligand of the receptor, as they are lost in mutant mice. Interestingly, the very low affinity of mGlu7 receptors for glutamate raises the question of how it can be activated, namely at GABAergic synapses and in basal conditions. Inactivation of the receptor activity with the mGlu7 negative allosteric modulator (NAM), ADX71743, enhances thalamic synaptic transmission. In vivo administration of the NAM induces a lethargic state with spindle and/or spike-and-wave discharges accompanied by a behavioral arrest typical of absence epileptic seizures. This provides evidence for mGlu7 receptor-mediated tonic modulation of a physiological function in vivo preventing synchronous and potentially pathological oscillations. PMID:27199672

  4. A 5'-region polymorphism modulates promoter activity of the tumor suppressor gene MFSD2A

    Directory of Open Access Journals (Sweden)

    Kunitoh Hideo

    2011-07-01

    Full Text Available Abstract Background The MFSD2A gene maps within a linkage disequilibrium block containing the MYCL1-EcoRI polymorphism associated with prognosis and survival in lung cancer patients. Survival discrepancies between Asians and Caucasians point to ethnic differences in allelic frequencies of the functional genetic variations. Results Analysis of three single-nucleotide polymorphisms (SNPs mapping in the MFSD2A 5'-regulatory region using a luciferase reporter system showed that SNP rs12072037, in linkage disequilibrium with the MYCL1-EcoRI polymorphism and polymorphic in Asians but not in Caucasians, modulated transcriptional activity of the MFSD2A promoter in cell lines expressing AHR and ARNT transcription factors, which potentially bind to the SNP site. Conclusion SNP rs12072037 modulates MFSD2A promoter activity and thus might affect MFSD2A levels in normal lung and in lung tumors, representing a candidate ethnically specific genetic factor underlying the association between the MYCL1 locus and lung cancer patients' survival.

  5. Modulation of yeast telomerase activity by Cdc13 and Est1 in vitro

    Science.gov (United States)

    Chen, Yu-Fan; Lu, Chia-Ying; Lin, Yi-Chien; Yu, Tai-Yuan; Chang, Chun-Ping; Li, Jing-Ru; Li, Hung-Wen; Lin, Jing-Jer

    2016-01-01

    Telomerase is the enzyme involved in extending telomeric DNA. Control of telomerase activity by modulating its access to chromosome ends is one of the most important fundamental mechanisms. This study established an in vitro yeast telomerase reconstitution system that resembles telomere replication in vivo. In this system, a tailed-duplex DNA formed by telomeric DNA was employed to mimic the structure of telomeres. The core catalytic components of telomerase Est2/Tlc1 RNA were used as the telomeric DNA extension machinery. Using the reconstituted systems, this study found that binding of Cdc13 to telomeric DNA inhibited the access of telomerase to its substrate. The result was further confirmed by a single-molecule approach using the tethered-particle motion (TPM)-based telomerase assay. The findings also showed that the inhibitory effect can be relieved by telomerase-associated protein Est1, consistent with the role of Cdc13 and Est1 in regulating telomere extension in vivo. Significantly, this study found that the DNA binding property of Cdc13 was altered by Est1, providing the first mechanistic evidence of Est1 regulating the access of telomerase to its substrate. Thus, the roles of Cdc13 and Est1 in modulating telomerase activity were clearly defined using the in vitro reconstituted system. PMID:27659693

  6. Lung protease/anti-protease network and modulation of mucus production and surfactant activity.

    Science.gov (United States)

    Garcia-Verdugo, Ignacio; Descamps, Delphyne; Chignard, Michel; Touqui, Lhousseine; Sallenave, Jean-Michel

    2010-11-01

    Lung epithelium guarantees gas-exchange (performed in the alveoli) and protects from external insults (pathogens, pollutants…) present within inhaled air. Both functions are facilitated by secretions lining airway surface liquid, mucus (in the upper airways) and pulmonary surfactant (in the alveoli). Mucins, the main glycoproteins present within the mucus, are responsible for its rheologic properties and participate in lung defense mechanisms. In parallel, lung collectins are pattern recognition molecules present in pulmonary surfactant that also modulate lung defense. During chronic airways diseases, excessive protease activity can promote mucus hypersecretion and degradation of lung collectins and therefore contribute to the pathophysiology of these diseases. Importantly, secretion of local and systemic anti-proteases might be crucial to equilibrate the protease/anti-protease unbalance and therefore preserve the function of lung host defense compounds and airway surface liquid homeostasis. In this review we will present information relative to proteases able to modulate mucin production and lung collectin integrity, two important compounds of innate immune defense. One strategy to preserve physiological mucus production and collectin integrity during chronic airways diseases might be the over-expression of local 'alarm' anti-proteases such as SLPI and elafin. Interestingly, a cross-talk between lung collectins and anti-protease activity has recently been described, implicating the presence within the lung of a complex network between proteases, anti-proteases and pattern recognition molecules, which aims to keep or restore homeostasis in resting or inflamed lungs. PMID:20493919

  7. Phasic and tonic mGlu7 receptor activity modulates the thalamocortical network

    Directory of Open Access Journals (Sweden)

    Valériane eTassin

    2016-04-01

    Full Text Available Mutation of the metabotropic glutamate receptor type 7 (mGlu7 induces absence-like epileptic seizures, but its precise role in the somatosensory thalamocortical network remains unknown. By combining electrophysiological recordings, optogenetics and pharmacology we dissected the contribution of the mGlu7 receptor at mouse thalamic synapses. We found that mGlu7 is functionally expressed at both glutamatergic and GABAergic synapses, where it can inhibit neurotransmission and regulate short-term plasticity. These effects depend on the PDZ-ligand of the receptor, as they are lost in mutant mice. Interestingly, the very low affinity of mGlu7 receptors for glutamate raises the question of how it can be activated, namely at GABAergic synapses and in basal conditions. Inactivation of the receptor activity with the mGlu7 negative allosteric modulator (NAM, ADX71743, enhances thalamic synaptic transmission. In vivo administration of the NAM induces a lethargic state with spindle and/or spike-and-wave discharges accompanied by a behavioral arrest typical of absence epileptic seizures. This provides evidence for mGlu7 receptor-mediated tonic modulation of a physiological function in vivo preventing synchronous and potentially pathological oscillations.

  8. Epigenetic modulations in activated cells early after HIV-1 infection and their possible functional consequences.

    Directory of Open Access Journals (Sweden)

    Juliana T Maricato

    Full Text Available Epigenetic modifications refer to a number of biological processes which alter the structure of chromatin and its transcriptional activity such as DNA methylation and histone post-translational processing. Studies have tried to elucidate how the viral genome and its products are affected by epigenetic modifications imposed by cell machinery and how it affects the ability of the virus to either, replicate and produce a viable progeny or be driven to latency. The purpose of this study was to evaluate epigenetic modifications in PBMCs and CD4+ cells after HIV-1 infection analyzing three approaches: (i global DNA- methylation; (ii qPCR array and (iii western blot. HIV-1 infection led to methylation increases in the cellular DNA regardless the activation status of PBMCs. The analysis of H3K9me3 and H3K27me3 suggested a trend towards transcriptional repression in activated cells after HIV-1 infection. Using a qPCR array, we detected genes related to epigenetic processes highly modulated in activated HIV-1 infected cells. SETDB2 and RSK2 transcripts showed highest up-regulation levels. SETDB2 signaling is related to transcriptional silencing while RSK2 is related to either silencing or activation of gene expression depending on the signaling pathway triggered down-stream. In addition, activated cells infected by HIV-1 showed lower CD69 expression and a decrease of IL-2, IFN-γ and metabolism-related factors transcripts indicating a possible functional consequence towards global transcriptional repression found in HIV-1 infected cells. Conversely, based on epigenetic markers studied here, non-stimulated cells infected by HIV-1, showed signs of global transcriptional activation. Our results suggest that HIV-1 infection exerts epigenetic modulations in activated cells that may lead these cells to transcriptional repression with important functional consequences. Moreover, non-stimulated cells seem to increase gene transcription after HIV-1 infection

  9. Amygdala activity can be modulated by unexpected chord functions during music listening.

    Science.gov (United States)

    Koelsch, Stefan; Fritz, Thomas; Schlaug, Gottfried

    2008-12-01

    Numerous earlier studies have investigated the cognitive processing of musical syntax with regular and irregular chord sequences. However, irregular sequences may also be perceived as unexpected, and therefore have a different emotional valence than regular sequences. We provide behavioral data showing that irregular chord functions presented in chord sequence paradigms are perceived as less pleasant than regular sequences. A reanalysis of functional MRI data showed increased blood oxygen level-dependent signal changes bilaterally in the amygdala in response to music-syntactically irregular (compared with regular) chord functions. The combined data indicate that music-syntactically irregular events elicit brain activity related to emotional processes, and that, in addition to intensely pleasurable music or highly unpleasant music, single chord functions can also modulate amygdala activity. PMID:19050462

  10. Metabolic pathways and activity-dependent modulation of glutamate concentration in the human brain.

    Science.gov (United States)

    Mangia, Silvia; Giove, Federico; Dinuzzo, Mauro

    2012-11-01

    Glutamate is one of the most versatile molecules present in the human brain, involved in protein synthesis, energy production, ammonia detoxification, and transport of reducing equivalents. Aside from these critical metabolic roles, glutamate plays a major part in brain function, being not only the most abundant excitatory neurotransmitter, but also the precursor for γ-aminobutyric acid, the predominant inhibitory neurotransmitter. Regulation of glutamate levels is pivotal for normal brain function, as abnormal extracellular concentration of glutamate can lead to impaired neurotransmission, neurodegeneration and even neuronal death. Understanding how the neuron-astrocyte functional and metabolic interactions modulate glutamate concentration during different activation status and under physiological and pathological conditions is a challenging task, and can only be tentatively estimated from current literature. In this paper, we focus on describing the various metabolic pathways which potentially affect glutamate concentration in the brain, and emphasize which ones are likely to produce the variations in glutamate concentration observed during enhanced neuronal activity in human studies.

  11. Behavioral activation system modulation on brain activation during appetitive and aversive stimulus processing

    OpenAIRE

    Barrós-Loscertales, Alfonso; Ventura-Campos, Noelia; Sanjuán-Tomás, Ana; Belloch, Vicente; Parcet, Maria-Antònia; Ávila, César

    2010-01-01

    The reinforcement sensitivity theory (RST) proposed the behavioral activation system (BAS) as a neurobehavioral system that is dependent on dopamine-irrigated structures and that mediates the individual differences in sensitivity and reactivity to appetitive stimuli associated with BAS-related personality traits. Theoretical developments propose that high BAS sensitivity is associated with both enhanced appetitive stimuli processing and the diminished processing of aversive stimuli. The objec...

  12. Peptides complementary to the active loop of porin P2 from Haemophilus influenzae modulate its activity

    Directory of Open Access Journals (Sweden)

    Galdiero S

    2012-05-01

    Full Text Available Marco Cantisani,1 Mariateresa Vitiello,2 Annarita Falanga,1 Emiliana Finamore,2 Marilena Galdiero,2 Stefania Galdiero11Department of Biological Sciences, CIRPeB and IBB CNR, University of Naples "Federico II," Napoli, Italy; 2Department of Experimental Medicine, II University of Naples, Napoli, ItalyAbstract: Haemophilus influenzae type b (Hib is one of the leading causes of invasive bacterial infection in young children. It is characterized by inflammation that is mainly mediated by cytokines and chemokines. One of the most abundant components of the Hib outer membrane is the P2 porin, which has been shown to induce the release of several inflammatory cytokines. A synthetic peptide corresponding to loop L7 of the porin activates JNK and p38 mitogen-activated protein kinase (MAPK pathways. We report a novel use of the complementary peptide approach to design a peptide that is able to bind selectively to the protein P2, thereby reducing its activity. This work provides insights into essential molecular details of P2 that may affect the pathogenesis of Hib infections where interruption of the signaling cascade could represent an attractive therapeutic strategy.Keywords: complementary-peptide, rational design, porin

  13. Association of P53 codon 72 polymorphism and lung cancer in an ethnic Iranian population.

    Science.gov (United States)

    Eydian, Z; Asna'ashari, A M H; Behravan, J; Sharifi-Rad, J; Entezari Heravi, R

    2016-01-01

    Lung cancer is one of the most common causes of cancer death worldwide. Molecular genetic studies indicated that activation of dominant oncogenes or inactivation of tumor suppressor genes and the presence of polymorphism in these genes correlated with prevalence of new lung cancers. P53 as a tumor suppressor gene located at 17p13 chromosome and it is one of the most well-known mutant genes in all cancer types. Mutation in P53 can disturb the transcriptional function and suppression of cell cycle control and increase in cell division and amplification. We can predict the susceptibility of people inside a society to lung cancer with evaluation of P53 gene polymorphism. A total of 200 patients with lung cancer and 200 healthy controls participated in this case-control study. Genomic DNA was extracted from blood samples and PCR-RFLP analyses were used to genotype the P53 gene polymorphism in codon 72 of exon 4, chromosome 17. Among 200 lung cancer patients and 200 controls, there was no significant correlation between sexuality and cigarette smoking status. We did not find any relationship between cigarette smoking status and genotypes or pack-years but there was a significant correlation between cigarette smoking status and adenocarcinoma patients (P=0.03). The results of the present study revealed that there is no association between P53 codon 72 polymorphism and increased risk of lung cancer in patients and controls but according to results of adenocarcinoma in never-smoker patients, it seems that environmental factors may have more important role than genetic susceptibility in our ethnic Iranian population. PMID:27585259

  14. Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation.

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    Ilse M Beck

    Full Text Available Compound A possesses glucocorticoid receptor (GR-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-κB-mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates heat shock factor 1 (HSF1, upregulates Hsp70, a known GR chaperone, and also modulates various aspects of inflammation. We found that the selective GR modulator Compound A and heat shock trigger similar cellular effects in A549 lung epithelial cells. With regard to their anti-inflammatory mechanism, heat shock and Compound A are both able to reduce TNF-stimulated IκBα degradation and NF-κB p65 nuclear translocation. We established an interaction between Compound A-activated GR and Hsp70, but remarkably, although the presence of the Hsp70 chaperone as such appears pivotal for the Compound A-mediated inflammatory gene repression, subsequent novel Hsp70 protein synthesis is uncoupled from an observed CpdA-induced Hsp70 mRNA upregulation and hence obsolete in mediating CpdA's anti-inflammatory effect. The lack of a Compound A-induced increase in Hsp70 protein levels in A549 cells is not mediated by a rapid proteasomal degradation of Hsp70 or by a Compound A-induced general block on translation. Similar to heat shock, Compound A can upregulate transcription of Hsp70 genes in various cell lines and BALB/c mice. Interestingly, whereas Compound A-dependent Hsp70 promoter activation is GR-dependent but HSF1-independent, heat shock-induced Hsp70 expression alternatively occurs in a GR-independent and HSF1-dependent manner in A549 lung epithelial cells.

  15. Enhanced exo-inulinase activity and stability by fusion of an inulin-binding module.

    Science.gov (United States)

    Zhou, Shun-Hua; Liu, Yuan; Zhao, Yu-Juan; Chi, Zhe; Chi, Zhen-Ming; Liu, Guang-Lei

    2016-09-01

    In this study, an inulin-binding module from Bacillus macerans was successfully fused to an exo-inulinase from Kluyveromyces marxianus, creating a hybrid functional enzyme. The recombinant exo-inulinase (rINU), the hybrid enzyme (rINUIBM), and the recombinant inulin-binding module (rIBM) were, respectively, heterologously expressed and biochemically characterized. It was found that both the inulinase activity and the catalytic efficiency (k cat/K m(app)) of the rINUIBM were considerably higher than those of rINU. Though the rINU and the rINUIBM shared the same optimum pH of 4.5, the optimum temperature of the rINUIBM (60 °C) was 5 °C higher than that of the rINU. Notably, the fused IBM significantly enhanced both the pH stability and the thermostability of the rINUIBM, suggesting that the rINUIBM obtained would have more extensive potential applications. Furthermore, the fusion of the IBM could substantially improve the inulin-binding capability of the rINUIBM, which was consistent with the determination of the K m(app). This meant that the fused IBM could play a critical role in the recognition of polysaccharides and enhanced the hydrolase activity of the associated inulinase by increasing enzyme-substrate proximity. Besides, the extra supplement of the independent non-catalytic rIBM could also improve the inulinase activity of the rINU. However, this improvement was much better in case of the fusion. Consequently, the IBM could be designated as a multifunctional domain that was responsible for the activity enhancement, the stabilization, and the substrate binding of the rINUIBM. All these features obtained in this study make the rINUIBM become an attractive candidate for an efficient inulin hydrolysis.

  16. Multiple monoaminergic modulation of posturo-locomotor network activity in the newborn rat spinal cord

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    Lauriane eBeliez

    2014-08-01

    Full Text Available Studies devoted to understanding locomotor control have mainly addressed the functioning of the neural circuits controlling leg movements and relatively little is known of the operation of networks that activate trunk muscles in coordination with limb movements. The aim of the present work was (1 to identify the exogenous neurotransmitter cocktail that most strongly activates postural thoracic circuitry; (2 to investigate how the biogenic amines serotonin (5-HT, dopamine (DA and noradrenaline (NA modulate the coordination between limb and axial motor networks. Experiments were carried out on in vitro isolated spinal cord preparations from newborn rats. We recorded from ventral roots to monitor hindlimb locomotor and axial postural network activity. Each combination of the three amines with excitatory amino acids (EAAs elicited coordinated rhythmic motor activity at all segmental levels with specific characteristics. The variability in cycle period was similar with 5-HT and DA while it was significantly higher with NA. DA elicited motor bursts of smaller amplitude in thoracic segments compared to 5-HT and NA, while both DA and NA elicited motor bursts of higher amplitude than 5-HT in the lumbar and sacral segments. The amines modulated the phase relationships of bursts in various segments with respect to the reference lumbar segment. At the thoracic level there was a phase lag between all recorded segments in the presence of 5-HT, while DA and NA elicited synchronous bursting. At the sacral level, 5-HT and DA induced an intersegmental phase shift while relationships became phase-locked with NA. Various combinations of EAAs with two or even all three amines elicited rhythmic motor output that was more variable than with one amine alone. Our results provide new data on the coordinating processes between spinal cord networks, demonstrating that each amine has a characteristic signature regarding its specific effect on intersegmental phase

  17. Vagal modulation of pre-inspiratory activity in hypoglossal discharge in the decerebrate rat.

    Science.gov (United States)

    Ghali, Michael George Zaki

    2015-08-15

    Respiration consists of three phases--inspiration (I), post-inspiration (post-I), and late expiration (E2). Pre-I is a subphase occurring at the end of E2. Hypoglossal (XII) discharge contains I and occasionally pre-I activity. Functionally, XII pre-I underlies tongue muscle contraction and expansion of the upper airway, causing a decrease in airway resistance in anticipation of the succeeding inspiratory effort. It has been shown that vagotomy causes an increase in pre-I activity in XII in anesthetized animals. Also, in anesthetized artificially-ventilated animals, XII onset is synchronized with that of inspiratory phrenic nerve (PhN) activity. Therefore, we sought to systematically test the hypothesis that XII pre-I is present in vagus-intact unanesthetized decerebrate animals and vagal afferents negatively modulate XII pre-I discharge in decerebrate rats, in the absence of confounding anesthesia. Experiments were performed on seven Sprague-Dawley unanesthetized decerebrate adult male rats and bilateral PhN and XII recordings performed. In three animals, vagotomy was performed during PhN recordings and one animal was vagotomized during initial surgical preparation prior to recordings. In vagus-intact animals, XII pre-I duration averaged 12.4 ms. Vagotomy was associated with greater XII pre-I duration, expressed in absolute time (89.5 vs. 12.4 ms; p<0.01) as well as relative to the XII bursting period (18.9 vs. 3.4%; p<0.01). Vagal deafferentation was also associated with a larger relative amplitude of the pre-I XII activity relative to total XII discharge (12.4 vs. 2.1%; p<0.01). We conclude that pre-I discharge is present in vagus-intact artificially-ventilated unanesthetized decerebrate animals and is negatively modulated by vagal afferents. PMID:25979456

  18. Rho signaling in Entamoeba histolytica modulates actomyosin-dependent activities stimulated during invasive behavior.

    Science.gov (United States)

    Franco-Barraza, Janusz; Zamudio-Meza, Horacio; Franco, Elizabeth; del Carmen Domínguez-Robles, M; Villegas-Sepúlveda, Nicolás; Meza, Isaura

    2006-03-01

    Interaction of Entamoeba histolytica trophozoites with target cells and substrates activates signaling pathways in the parasite. Phosphorylation cascades triggered by phospho-inositide and adenyl-cyclase-dependent pathways modulate reorganization of the actin cytoskeleton to form structures that facilitate adhesion. In contrast, little is known about participation of Rho proteins and Rho signaling in actin rearrangements. We report here the in vivo expression of at least one Rho protein in trophozoites, whose activation induced actin reorganization and actin-myosin interaction. Antibodies to EhRhoA1 recombinant protein mainly localized Rho in the cytosol of nonactivated amoebae, but it was translocated to vesicular membranes and to some extent to the plasma membrane after treatment with lysophosphatidic acid (LPA), a specific agonist of Rho activation. Activated Rho was identified in LPA-treated trophozoites. LPA induced striking polymerization of actin into distinct dynamic structures. Disorganization of these structures by inhibition of Rho effector, Rho-kinase (ROCK), and by ML-7, an inhibitor of myosin light chain kinase dependent phosphorylation of myosin light chain, suggested that the actin structures also contained myosin. LPA stimulated concanavalin-A-mediated formation of caps, chemotaxis, invasion of extracellular matrix substrates, and erythrophagocytosis, but not binding to fibronectin. ROCK inhibition impaired LPA-stimulated functions and to some extent adhesion to fibronectin. Similar results were obtained with ML-7. These data suggest the presence and operation of Rho-signaling pathways in E. histolytica, that together with other, already described, signaling routes modulate actomyosin-dependent motile processes, particularly stimulated during invasive behavior.

  19. Generic phosphatase activity detection using zinc mediated aggregation modulation of polypeptide-modified gold nanoparticles

    Science.gov (United States)

    Selegård, Robert; Enander, Karin; Aili, Daniel

    2014-11-01

    A challenge in the design of plasmonic nanoparticle-based colorimetric assays is that the change in colloidal stability, which generates the colorimetric response, is often directly linked to the biomolecular recognition event. New assay strategies are hence required for every type of substrate and enzyme of interest. Here, a generic strategy for monitoring of phosphatase activity is presented where substrate recognition is completely decoupled from the nanoparticle stability modulation mechanism, which enables detection of a wide range of enzymes using different natural substrates with a single simple detection scheme. Phosphatase activity generates inorganic phosphate that forms an insoluble complex with Zn2+. In a sample containing a preset concentration of Zn2+, phosphatase activity will markedly reduce the concentration of dissolved Zn2+ from the original value, which in turn affects the aggregation of gold nanoparticles functionalized with a designed Zn2+ responsive polypeptide. The change in nanoparticle stability thus provides a rapid and sensitive readout of the phosphatase activity. The assay is not limited to a particular enzyme or enzyme substrate, which is demonstrated using three completely different phosphatases and five different substrates, and thus constitutes a highly interesting system for drug screening and diagnostics.A challenge in the design of plasmonic nanoparticle-based colorimetric assays is that the change in colloidal stability, which generates the colorimetric response, is often directly linked to the biomolecular recognition event. New assay strategies are hence required for every type of substrate and enzyme of interest. Here, a generic strategy for monitoring of phosphatase activity is presented where substrate recognition is completely decoupled from the nanoparticle stability modulation mechanism, which enables detection of a wide range of enzymes using different natural substrates with a single simple detection scheme

  20. Bile Salts Modulate the Mucin-Activated Type VI Secretion System of Pandemic Vibrio cholerae.

    Science.gov (United States)

    Bachmann, Verena; Kostiuk, Benjamin; Unterweger, Daniel; Diaz-Satizabal, Laura; Ogg, Stephen; Pukatzki, Stefan

    2015-01-01

    The causative agent of cholera, Vibrio cholerae, regulates its diverse virulence factors to thrive in the human small intestine and environmental reservoirs. Among this pathogen's arsenal of virulence factors is the tightly regulated type VI secretion system (T6SS). This system acts as an inverted bacteriophage to inject toxins into competing bacteria and eukaryotic phagocytes. V. cholerae strains responsible for the current 7th pandemic activate their T6SS within the host. We established that T6SS-mediated competition occurs upon T6SS activation in the infant mouse, and that this system is functional under anaerobic conditions. When investigating the intestinal host factors mucins (a glycoprotein component of mucus) and bile for potential regulatory roles in controlling the T6SS, we discovered that once mucins activate the T6SS, bile acids can further modulate T6SS activity. Microbiota modify bile acids to inhibit T6SS-mediated killing of commensal bacteria. This interplay is a novel interaction between commensal bacteria, host factors, and the V. cholerae T6SS, showing an active host role in infection.

  1. Modulation of phase-II enzyme activities in benzene treated ovariectomized rats.

    Science.gov (United States)

    Verma, Yeshvandra; Rana, S V S

    2011-05-01

    The aim of the study was to determine the influence of ovariectomy on phase II enzymes viz. glutathione-S-transferase (GST), glutathione peroxidase (GPX) and catalase (CAT) in liver and kidney of female rats treated with benzene. The results showed the significant decrease of the GST and GPX activity in benzene treated rats after ovariectomy. However progesterone supplementation stimulated the activity of GST and GPX in liver and kidney of benzene treated non ovariectomized and ovariectomized rats. Progesterone supplementation to benzene treated ovariectomized rats helps to gain in CAT activity. Our results on DNA damage using single cell gel electrophoresis also confirmed our findings on antioxidant enzymes. The results showed that lack of protective progesterone against benzene toxicity is reflected in alterations in antioxidant enzyme activities. However progesterone therapy to benzene treated ovariectomized rats results in activating the antioxidant defence system. Since female workers are engaged in industrial sector, these results are important from occupational health point of view. Benzene exposure affects their reproductive health. Nevertheless, it could be modulated by suitable hormonal therapy. PMID:21787707

  2. Bile Salts Modulate the Mucin-Activated Type VI Secretion System of Pandemic Vibrio cholerae.

    Directory of Open Access Journals (Sweden)

    Verena Bachmann

    Full Text Available The causative agent of cholera, Vibrio cholerae, regulates its diverse virulence factors to thrive in the human small intestine and environmental reservoirs. Among this pathogen's arsenal of virulence factors is the tightly regulated type VI secretion system (T6SS. This system acts as an inverted bacteriophage to inject toxins into competing bacteria and eukaryotic phagocytes. V. cholerae strains responsible for the current 7th pandemic activate their T6SS within the host. We established that T6SS-mediated competition occurs upon T6SS activation in the infant mouse, and that this system is functional under anaerobic conditions. When investigating the intestinal host factors mucins (a glycoprotein component of mucus and bile for potential regulatory roles in controlling the T6SS, we discovered that once mucins activate the T6SS, bile acids can further modulate T6SS activity. Microbiota modify bile acids to inhibit T6SS-mediated killing of commensal bacteria. This interplay is a novel interaction between commensal bacteria, host factors, and the V. cholerae T6SS, showing an active host role in infection.

  3. BAS-drive trait modulates dorsomedial striatum activity during reward response-outcome associations.

    Science.gov (United States)

    Costumero, Víctor; Barrós-Loscertales, Alfonso; Fuentes, Paola; Rosell-Negre, Patricia; Bustamante, Juan Carlos; Ávila, César

    2016-09-01

    According to the Reinforcement Sensitivity Theory, behavioral studies have found that individuals with stronger reward sensitivity easily detect cues of reward and establish faster associations between instrumental responses and reward. Neuroimaging studies have shown that processing anticipatory cues of reward is accompanied by stronger ventral striatum activity in individuals with stronger reward sensitivity. Even though establishing response-outcome contingencies has been consistently associated with dorsal striatum, individual differences in this process are poorly understood. Here, we aimed to study the relation between reward sensitivity and brain activity while processing response-reward contingencies. Forty-five participants completed the BIS/BAS questionnaire and performed a gambling task paradigm in which they received monetary rewards or punishments. Overall, our task replicated previous results that have related processing high reward outcomes with activation of striatum and medial frontal areas, whereas processing high punishment outcomes was associated with stronger activity in insula and middle cingulate. As expected, the individual differences in the activity of dorsomedial striatum correlated positively with BAS-Drive. Our results agree with previous studies that have related the dorsomedial striatum with instrumental performance, and suggest that the individual differences in this area may form part of the neural substrate responsible for modulating instrumental conditioning by reward sensitivity. PMID:26489979

  4. Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate γ-Secretase Activities.

    Science.gov (United States)

    Futai, Eugene; Osawa, Satoko; Cai, Tetsuo; Fujisawa, Tomoya; Ishiura, Shoichi; Tomita, Taisuke

    2016-01-01

    γ-Secretase is a multisubunit membrane protein complex containing presenilin (PS1) as a catalytic subunit. Familial Alzheimer disease (FAD) mutations within PS1 were analyzed in yeast cells artificially expressing membrane-bound substrate, amyloid precursor protein, or Notch fused to Gal4 transcriptional activator. The FAD mutations, L166P and G384A (Leu-166 to Pro and Gly-384 to Ala substitution, respectively), were loss-of-function in yeast. We identified five amino acid substitutions that suppress the FAD mutations. The cleavage of amyloid precursor protein or Notch was recovered by the secondary mutations. We also found that secondary mutations alone activated the γ-secretase activity. FAD mutants with suppressor mutations, L432M or S438P within TMD9 together with a missense mutation in the second or sixth loops, regained γ-secretase activity when introduced into presenilin null mouse fibroblasts. Notably, the cells with suppressor mutants produced a decreased amount of Aβ42, which is responsible for Alzheimer disease. These results indicate that the yeast system is useful to screen for mutations and chemicals that modulate γ-secretase activity.

  5. The modulation of platelet adhesion and activation by chitosan through plasma and extracellular matrix proteins.

    Science.gov (United States)

    Lord, Megan S; Cheng, Bill; McCarthy, Simon J; Jung, MoonSun; Whitelock, John M

    2011-10-01

    Chitosan has been shown to promote initial wound closure events to prevent blood loss. Platelet adhesion and activation are crucial early events in these processes after traumatic bleeding leading to thrombus formation. Platelet adhesion to chitosan was found to be enhanced in the presence of adsorbed plasma and extracellular matrix proteins and was found to be primarily mediated by α(IIb)β(3) integrins, while α(2)β(1) integrins were found to be involved in platelet adhesion to collagen and perlecan. Platelets were found to be activated by chitosan, as shown by an increase in the expression of α(IIb)β(3) integrins and P-selectin, while the extent of activation was modulated by the presence of proteins including perlecan and fibrinogen. Collagen-coated chitosan was found to activate platelets to the same extent as either chitosan or collagen alone. These data support the role of plasma and extracellular matrix proteins in promoting chitosan mediated platelet adhesion and activation supporting the hypothesis that chitosan promotes wound healing via these interactions.

  6. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network.

    Directory of Open Access Journals (Sweden)

    Fernanda Palhano-Fontes

    Full Text Available The experiences induced by psychedelics share a wide variety of subjective features, related to the complex changes in perception and cognition induced by this class of drugs. A remarkable increase in introspection is at the core of these altered states of consciousness. Self-oriented mental activity has been consistently linked to the Default Mode Network (DMN, a set of brain regions more active during rest than during the execution of a goal-directed task. Here we used fMRI technique to inspect the DMN during the psychedelic state induced by Ayahuasca in ten experienced subjects. Ayahuasca is a potion traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. In particular, we examined whether Ayahuasca changes the activity and connectivity of the DMN and the connection between the DMN and the task-positive network (TPN. Ayahuasca caused a significant decrease in activity through most parts of the DMN, including its most consistent hubs: the Posterior Cingulate Cortex (PCC/Precuneus and the medial Prefrontal Cortex (mPFC. Functional connectivity within the PCC/Precuneus decreased after Ayahuasca intake. No significant change was observed in the DMN-TPN orthogonality. Altogether, our results support the notion that the altered state of consciousness induced by Ayahuasca, like those induced by psilocybin (another serotonergic psychedelic, meditation and sleep, is linked to the modulation of the activity and the connectivity of the DMN.

  7. BAS-drive trait modulates dorsomedial striatum activity during reward response-outcome associations.

    Science.gov (United States)

    Costumero, Víctor; Barrós-Loscertales, Alfonso; Fuentes, Paola; Rosell-Negre, Patricia; Bustamante, Juan Carlos; Ávila, César

    2016-09-01

    According to the Reinforcement Sensitivity Theory, behavioral studies have found that individuals with stronger reward sensitivity easily detect cues of reward and establish faster associations between instrumental responses and reward. Neuroimaging studies have shown that processing anticipatory cues of reward is accompanied by stronger ventral striatum activity in individuals with stronger reward sensitivity. Even though establishing response-outcome contingencies has been consistently associated with dorsal striatum, individual differences in this process are poorly understood. Here, we aimed to study the relation between reward sensitivity and brain activity while processing response-reward contingencies. Forty-five participants completed the BIS/BAS questionnaire and performed a gambling task paradigm in which they received monetary rewards or punishments. Overall, our task replicated previous results that have related processing high reward outcomes with activation of striatum and medial frontal areas, whereas processing high punishment outcomes was associated with stronger activity in insula and middle cingulate. As expected, the individual differences in the activity of dorsomedial striatum correlated positively with BAS-Drive. Our results agree with previous studies that have related the dorsomedial striatum with instrumental performance, and suggest that the individual differences in this area may form part of the neural substrate responsible for modulating instrumental conditioning by reward sensitivity.

  8. Plasminogen activator inhibitor type 1 interacts with alpha3 subunit of proteasome and modulates its activity.

    Science.gov (United States)

    Boncela, Joanna; Przygodzka, Patrycja; Papiewska-Pajak, Izabela; Wyroba, Elzbieta; Osinska, Magdalena; Cierniewski, Czeslaw S

    2011-02-25

    Plasminogen activator inhibitor type-1 (PAI-1), a multifunctional protein, is an important physiological regulator of fibrinolysis, extracellular matrix homeostasis, and cell motility. Recent observations show that PAI-1 may also be implicated in maintaining integrity of cells, especially with respect to cellular proliferation or apoptosis. In the present study we provide evidence that PAI-1 interacts with proteasome and affects its activity. First, by using the yeast two-hybrid system, we found that the α3 subunit of proteasome directly interacts with PAI-1. Then, to ensure that the PAI-1-proteasome complex is formed in vivo, both proteins were coimmunoprecipitated from endothelial cells and identified with specific antibodies. The specificity of this interaction was evidenced after transfection of HeLa cells with pCMV-PAI-1 and coimmunoprecipitation of both proteins with anti-PAI-1 antibodies. Subsequently, cellular distribution of the PAI-1-proteasome complexes was established by immunogold staining and electron microscopy analyses. Both proteins appeared in a diffuse cytosolic pattern but also could be found in a dense perinuclear and nuclear location. Furthermore, PAI-1 induced formation of aggresomes freely located in endothelial cytoplasm. Increased PAI-1 expression abrogated degradation of degron analyzed after cotransfection of HeLa cells with pCMV-PAI-1 and pd2EGFP-N1 and prevented degradation of p53 as well as IκBα, as evidenced both by confocal microscopy and Western immunoblotting.

  9. Plasminogen Activator Inhibitor Type 1 Interacts with α3 Subunit of Proteasome and Modulates Its Activity*

    Science.gov (United States)

    Boncela, Joanna; Przygodzka, Patrycja; Papiewska-Pajak, Izabela; Wyroba, Elzbieta; Osinska, Magdalena; Cierniewski, Czeslaw S.

    2011-01-01

    Plasminogen activator inhibitor type-1 (PAI-1), a multifunctional protein, is an important physiological regulator of fibrinolysis, extracellular matrix homeostasis, and cell motility. Recent observations show that PAI-1 may also be implicated in maintaining integrity of cells, especially with respect to cellular proliferation or apoptosis. In the present study we provide evidence that PAI-1 interacts with proteasome and affects its activity. First, by using the yeast two-hybrid system, we found that the α3 subunit of proteasome directly interacts with PAI-1. Then, to ensure that the PAI-1-proteasome complex is formed in vivo, both proteins were coimmunoprecipitated from endothelial cells and identified with specific antibodies. The specificity of this interaction was evidenced after transfection of HeLa cells with pCMV-PAI-1 and coimmunoprecipitation of both proteins with anti-PAI-1 antibodies. Subsequently, cellular distribution of the PAI-1-proteasome complexes was established by immunogold staining and electron microscopy analyses. Both proteins appeared in a diffuse cytosolic pattern but also could be found in a dense perinuclear and nuclear location. Furthermore, PAI-1 induced formation of aggresomes freely located in endothelial cytoplasm. Increased PAI-1 expression abrogated degradation of degron analyzed after cotransfection of HeLa cells with pCMV-PAI-1 and pd2EGFP-N1 and prevented degradation of p53 as well as IκBα, as evidenced both by confocal microscopy and Western immunoblotting. PMID:21135093

  10. The availability of attentional resources modulates the inhibitory strength related to weakly activated priming.

    Science.gov (United States)

    Wang, Yongchun; Wang, Yonghui; Liu, Peng; Dai, Dongyang; Di, Meilin; Chen, Qiang

    2016-08-01

    The current study investigated the role of attention in inhibitory processes (the inhibitory processes described in the current study refer only to those associated with masked or flanked priming) using a mixed paradigm involving the negative compatibility effect (NCE) and object-based attention. Accumulating evidence suggests that attention can be spread more easily within the same object, which increases the availability of attentional resources, than across different objects. Accordingly, we manipulated distractor location (with primes presented in the same object versus presented in different objects) together with prime/target compatibility (compatible versus incompatible) and prime-distractor stimulus onset asynchrony (SOA, 23 ms vs 70 ms). The aim was to investigate whether inhibitory processes related to weakly activated priming, which have been previously assumed to be automatic, depend on the availability of attentional resources. The results of Experiment 1 showed a significant NCE for the 70-ms SOA when the prime and distractor were presented in the same object (greater attentional resource availability); however, reversed NCEs were obtained for all other conditions. Experiment 2 was designed to disentangle whether the results of Experiment 1 were affected by the prime position, and the results indicated that the prime position did not modulate the NCE in Experiment 1. Together, these results are consistent with the claim that the availability of attentional resources modulates the inhibitory strength related to weakly activated priming. Specifically, if attentional resources are assigned to the distractor when it is presented in the same object as the prime, the strength of the inhibition elicited by the distractor may increase and reverse the activation elicited by the prime, which could lead to a significant NCE. PMID:27198916

  11. Coumestrol, Bisphenol-A, DDT, and TCDD Modulation of Interleukin-2 Expression in Activated CD+4 Jurkat T Cells

    OpenAIRE

    McMurray, Robert W.; Tchounwou, Paul B.; Kenneth Ndebele

    2004-01-01

    Endogenous estrogens are known to modulate several components of immune response, including interleukin-2 (IL-2) production. IL-2 is a cytokine that plays an important role in adaptive immune responses. These responses may be modulated by xenoestrogens such as coumestrol, bisphenol A (BPA), DDT, and TCDD. In this research, we examined the effects and potential mechanisms of action of these estrogenic compounds on IL-2 production in activated CD4+ Jurkat T cells. IL-2 production was analyzed b...

  12. Versatile dual reporter gene systems for investigating stop codon readthrough in plants.

    Directory of Open Access Journals (Sweden)

    Nga T Lao

    Full Text Available BACKGROUND: Translation is most often terminated when a ribosome encounters the first in-frame stop codon (UAA, UAG or UGA in an mRNA. However, many viruses (and some cellular mRNAs contain "stop" codons that cause a proportion of ribosomes to terminate and others to incorporate an amino acid and continue to synthesize a "readthrough", or C-terminally extended, protein. This dynamic redefinition of codon meaning is dependent on specific sequence context. METHODOLOGY: We describe two versatile dual reporter systems which facilitate investigation of stop codon readthrough in vivo in intact plants, and identification of the amino acid incorporated at the decoded stop codon. The first is based on the reporter enzymes NAN and GUS for which sensitive fluorogenic and histochemical substrates are available; the second on GST and GFP. CONCLUSIONS: We show that the NAN-GUS system can be used for direct in planta measurements of readthrough efficiency following transient expression of reporter constructs in leaves, and moreover, that the system is sufficiently sensitive to permit measurement of readthrough in stably transformed plants. We further show that the GST-GFP system can be used to affinity purify readthrough products for mass spectrometric analysis and provide the first definitive evidence that tyrosine alone is specified in vivo by a 'leaky' UAG codon, and tyrosine and tryptophan, respectively, at decoded UAA, and UGA codons in the Tobacco mosaic virus (TMV readthrough context.

  13. Expanding the amino acid repertoire of ribosomal polypeptide synthesis via the artificial division of codon boxes

    Science.gov (United States)

    Iwane, Yoshihiko; Hitomi, Azusa; Murakami, Hiroshi; Katoh, Takayuki; Goto, Yuki; Suga, Hiroaki

    2016-04-01

    In ribosomal polypeptide synthesis the library of amino acid building blocks is limited by the manner in which codons are used. Of the proteinogenic amino acids, 18 are coded for by multiple codons and therefore many of the 61 sense codons can be considered redundant. Here we report a method to reduce the redundancy of codons by artificially dividing codon boxes to create vacant codons that can then be reassigned to non-proteinogenic amino acids and thereby expand the library of genetically encoded amino acids. To achieve this, we reconstituted a cell-free translation system with 32 in vitro transcripts of transfer RNASNN (tRNASNN) (S = G or C), assigning the initiator and 20 elongator amino acids. Reassignment of three redundant codons was achieved by replacing redundant tRNASNNs with tRNASNNs pre-charged with non-proteinogenic amino acids. As a demonstration, we expressed a 32-mer linear peptide that consists of 20 proteinogenic and three non-proteinogenic amino acids, and a 14-mer macrocyclic peptide that contains more than four non-proteinogenic amino acids.

  14. Genome-Wide Analysis of the Synonymous Codon Usage Patterns in Riemerella anatipestifer

    Science.gov (United States)

    Liu, Jibin; Zhu, Dekang; Ma, Guangpeng; Liu, Mafeng; Wang, Mingshu; Jia, Renyong; Chen, Shun; Sun, Kunfeng; Yang, Qiao; Wu, Ying; Chen, Xiaoyue; Cheng, Anchun

    2016-01-01

    Riemerella anatipestifer (RA) belongs to the Flavobacteriaceae family and can cause a septicemia disease in poultry. The synonymous codon usage patterns of bacteria reflect a series of evolutionary changes that enable bacteria to improve tolerance of the various environments. We detailed the codon usage patterns of RA isolates from the available 12 sequenced genomes by multiple codon and statistical analysis. Nucleotide compositions and relative synonymous codon usage (RSCU) analysis revealed that A or U ending codons are predominant in RA. Neutrality analysis found no significant correlation between GC12 and GC3 (p > 0.05). Correspondence analysis and ENc-plot results showed that natural selection dominated over mutation in the codon usage bias. The tree of cluster analysis based on RSCU was concordant with dendrogram based on genomic BLAST by neighbor-joining method. By comparative analysis, about 50 highly expressed genes that were orthologs across all 12 strains were found in the top 5% of high CAI value. Based on these CAI values, we infer that RA contains a number of predicted highly expressed coding sequences, involved in transcriptional regulation and metabolism, reflecting their requirement for dealing with diverse environmental conditions. These results provide some useful information on the mechanisms that contribute to codon usage bias and evolution of RA. PMID:27517915

  15. The Code of Silence: Widespread Associations Between Synonymous Codon Biases and Gene Function.

    Science.gov (United States)

    Supek, Fran

    2016-01-01

    Some mutations in gene coding regions exchange one synonymous codon for another, and thus do not alter the amino acid sequence of the encoded protein. Even though they are often called 'silent,' these mutations may exhibit a plethora of effects on the living cell. Therefore, they are often selected during evolution, causing synonymous codon usage biases in genomes. Comparative analyses of bacterial, archaeal, fungal, and human cancer genomes have found many links between a gene's biological role and the accrual of synonymous mutations during evolution. In particular, highly expressed genes in certain functional categories are enriched with optimal codons, which are decoded by the abundant tRNAs, thus enhancing the speed and accuracy of the translating ribosome. The set of genes exhibiting codon adaptation differs between genomes, and these differences show robust associations to organismal phenotypes. In addition to selection for translation efficiency, other distinct codon bias patterns have been found in: amino acid starvation genes, cyclically expressed genes, tissue-specific genes in animals and plants, oxidative stress response genes, cellular differentiation genes, and oncogenes. In addition, genomes of organisms harboring tRNA modifications exhibit particular codon preferences. The evolutionary trace of codon bias patterns across orthologous genes may be examined to learn about a gene's relevance to various phenotypes, or, more generally, its function in the cell. PMID:26538122

  16. Genome-Wide Analysis of the Synonymous Codon Usage Patterns in Riemerella anatipestifer

    Directory of Open Access Journals (Sweden)

    Jibin Liu

    2016-08-01

    Full Text Available Riemerella anatipestifer (RA belongs to the Flavobacteriaceae family and can cause a septicemia disease in poultry. The synonymous codon usage patterns of bacteria reflect a series of evolutionary changes that enable bacteria to improve tolerance of the various environments. We detailed the codon usage patterns of RA isolates from the available 12 sequenced genomes by multiple codon and statistical analysis. Nucleotide compositions and relative synonymous codon usage (RSCU analysis revealed that A or U ending codons are predominant in RA. Neutrality analysis found no significant correlation between GC12 and GC3 (p > 0.05. Correspondence analysis and ENc-plot results showed that natural selection dominated over mutation in the codon usage bias. The tree of cluster analysis based on RSCU was concordant with dendrogram based on genomic BLAST by neighbor-joining method. By comparative analysis, about 50 highly expressed genes that were orthologs across all 12 strains were found in the top 5% of high CAI value. Based on these CAI values, we infer that RA contains a number of predicted highly expressed coding sequences, involved in transcriptional regulation and metabolism, reflecting their requirement for dealing with diverse environmental conditions. These results provide some useful information on the mechanisms that contribute to codon usage bias and evolution of RA.

  17. Gaining insights into the codon usage patterns of TP53 gene across eight mammalian species.

    Directory of Open Access Journals (Sweden)

    Tarikul Huda Mazumder

    Full Text Available TP53 gene is known as the "guardian of the genome" as it plays a vital role in regulating cell cycle, cell proliferation, DNA damage repair, initiation of programmed cell death and suppressing tumor growth. Non uniform usage of synonymous codons for a specific amino acid during translation of protein known as codon usage bias (CUB is a unique property of the genome and shows species specific deviation. Analysis of codon usage bias with compositional dynamics of coding sequences has contributed to the better understanding of the molecular mechanism and the evolution of a particular gene. In this study, the complete nucleotide coding sequences of TP53 gene from eight different mammalian species were used for CUB analysis. Our results showed that the codon usage patterns in TP53 gene across different mammalian species has been influenced by GC bias particularly GC3 and a moderate bias exists in the codon usage of TP53 gene. Moreover, we observed that nature has highly favored the most over represented codon CTG for leucine amino acid but selected against the ATA codon for isoleucine in TP53 gene across all mammalian species during the course of evolution.

  18. A Comparative Analysis of Synonymous Codon Usage Bias Pattern in Human Albumin Superfamily

    Directory of Open Access Journals (Sweden)

    Hoda Mirsafian

    2014-01-01

    Full Text Available Synonymous codon usage bias is an inevitable phenomenon in organismic taxa across the three domains of life. Though the frequency of codon usage is not equal across species and within genome in the same species, the phenomenon is non random and is tissue-specific. Several factors such as GC content, nucleotide distribution, protein hydropathy, protein secondary structure, and translational selection are reported to contribute to codon usage preference. The synonymous codon usage patterns can be helpful in revealing the expression pattern of genes as well as the evolutionary relationship between the sequences. In this study, synonymous codon usage bias patterns were determined for the evolutionarily close proteins of albumin superfamily, namely, albumin, α-fetoprotein, afamin, and vitamin D-binding protein. Our study demonstrated that the genes of the four albumin superfamily members have low GC content and high values of effective number of codons (ENC suggesting high expressivity of these genes and less bias in codon usage preferences. This study also provided evidence that the albumin superfamily members are not subjected to mutational selection pressure.

  19. Absolute frequency synthesis of pulsed coherent light waves through phase-modulation active optical feedback.

    Science.gov (United States)

    Shimizu, K; Horiguchi, T; Koyamada, Y

    1996-11-15

    A novel method for the broadband absolute frequency synthesis of pulsed coherent lightwaves is demonstrated. It is based on pulse recirculation around an active optical feedback ring containing a delay-line fiber, an external phase modulator, an acousto-optic frequency shifter (AOFS), and a high-finesse Fabry-Perot étalon. The modulation frequency F(M) and the frequency shift F(AO) that are due to AOFS are designed so that their sum or difference equals the free-spectral range of the étalon and F(AO) is set at larger than the half-width at full maximum of its resonant peaks. If one of the peak frequencies is tuned to the frequency of the initial pulse, the frequency of the recirculating pulse jumps to the next peak for each round trip. In the experiment the absolute frequency is synthesized over a frequency span of 700 GHz around the initial stabilized frequency of the master laser.

  20. Selective androgen receptor modulator activity of a steroidal antiandrogen TSAA-291 and its cofactor recruitment profile.

    Science.gov (United States)

    Hikichi, Yukiko; Yamaoka, Masuo; Kusaka, Masami; Hara, Takahito

    2015-10-15

    Selective androgen receptor modulators (SARMs) specifically bind to the androgen receptor and exert agonistic or antagonistic effects on target organs. In this study, we investigated the SARM activity of TSAA-291, previously known as a steroidal antiandrogen, in mice because TSAA-291 was found to possess partial androgen receptor agonist activity in reporter assays. In addition, to clarify the mechanism underlying its tissue selectivity, we performed comprehensive cofactor recruitment analysis of androgen receptor using TSAA-291 and dihydrotestosterone (DHT), an endogenous androgen. The androgen receptor agonistic activity of TSAA-291 was more obvious in reporter assays using skeletal muscle cells than in those using prostate cells. In castrated mice, TSAA-291 increased the weight of the levator ani muscle without increasing the weight of the prostate and seminal vesicle. Comprehensive cofactor recruitment analysis via mammalian two-hybrid methods revealed that among a total of 112 cofactors, 12 cofactors including the protein inhibitor of activated STAT 1 (PIAS1) were differently recruited to androgen receptor in the presence of TSAA-291 and DHT. Prostate displayed higher PIAS1 expression than skeletal muscle. Forced expression of the PIAS1 augmented the transcriptional activity of the androgen receptor, and silencing of PIAS1 by siRNAs suppressed the secretion of prostate-specific antigen, an androgen responsive marker. Our results demonstrate that TSAA-291 has SARM activity and suggest that TSAA-291 may induce different conformational changes of the androgen receptor and recruitment profiles of cofactors such as PIAS1, compared with DHT, to exert tissue-specific activity.

  1. Look who's judging-Feedback source modulates brain activation to performance feedback in social anxiety.

    Science.gov (United States)

    Peterburs, Jutta; Sandrock, Carolin; Miltner, Wolfgang H R; Straube, Thomas

    2016-06-01

    It is as yet unknown if behavioral and neural correlates of performance monitoring in socially anxious individuals are affected by whether feedback is provided by a person or a computer. This fMRI study investigated modulation of feedback processing by feedback source (person vs. computer) in participants with high (HSA) (N=16) and low social anxiety (LSA) (N=16). Subjects performed a choice task in which they were informed that they would receive positive or negative feedback from a person or the computer. Subjective ratings indicated increased arousal and anxiety in HSA versus LSA, most pronounced for social and negative feedback. FMRI analyses yielded hyperactivation in ventral medial prefrontal cortex (vmPFC)/anterior cingulate cortex (ACC) and insula for social relative to computer feedback, and in mPFC/ventral ACC for positive relative to negative feedback in HSA as compared to LSA. These activation patterns are consistent with increased interoception and self-referential processing in social anxiety, especially during processing of positive feedback. Increased ACC activation in HSA to positive feedback may link to unexpectedness of (social) praise as posited in social anxiety disorder (SAD) psychopathology. Activation in rostral ACC showed a reversed pattern, with decreased activation to positive feedback in HSA, possibly indicating altered action values depending on feedback source and valence. The present findings corroborate a crucial role of mPFC for performance monitoring in social anxiety.

  2. Modulation of CP2 family transcriptional activity by CRTR-1 and sumoylation.

    Directory of Open Access Journals (Sweden)

    Sarah To

    Full Text Available CRTR-1 is a member of the CP2 family of transcription factors. Unlike other members of the family which are widely expressed, CRTR-1 expression shows specific spatio-temporal regulation. Gene targeting demonstrates that CRTR-1 plays a central role in the maturation and function of the salivary glands and the kidney. CRTR-1 has also recently been identified as a component of the complex transcriptional network that maintains pluripotency in embryonic stem (ES cells. CRTR-1 was previously shown to be a repressor of transcription. We examine the activity of CRTR-1 in ES and other cells and show that CRTR-1 is generally an activator of transcription and that it modulates the activity of other family members, CP2, NF2d9 and altNF2d9, in a cell specific manner. We also demonstrate that CRTR-1 activity is regulated by sumoylation at a single major site, residue K30. These findings imply that functional redundancy with other family members may mask important roles for CRTR-1 in other tissues, including the blastocyst stage embryo and embryonic stem cells.

  3. Tetraspanin CD9 modulates human lymphoma cellular proliferation via histone deacetylase activity

    Energy Technology Data Exchange (ETDEWEB)

    Herr, Michael J. [Vascular Biology Center of Excellence, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Molecular Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Longhurst, Celia M.; Baker, Benjamin [Vascular Biology Center of Excellence, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Homayouni, Ramin [Department of Biology, Bioinformatics Program, University of Memphis, Memphis, TN 38152 (United States); Speich, Henry E.; Kotha, Jayaprakash [Vascular Biology Center of Excellence, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Jennings, Lisa K., E-mail: ljennings@uthsc.edu [Vascular Biology Center of Excellence, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Molecular Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Department of Biology, Bioinformatics Program, University of Memphis, Memphis, TN 38152 (United States)

    2014-05-16

    Highlights: • CD9 is differentially expressed in human Burkitt’s lymphoma cells. • We found that CD9 expression promotes these cells proliferation. • CD9 expression also increases HDAC activity. • HDAC inhibition decreased both cell proliferation and importantly CD9 expression. • CD9 may dictate HDAC efficacy and play a role in HDAC regulation. - Abstract: Non-Hodgkin Lymphoma (NHL) is a type of hematological malignancy that affects two percent of the overall population in the United States. Tetraspanin CD9 is a cell surface protein that has been thoroughly demonstrated to be a molecular facilitator of cellular phenotype. CD9 expression varies in two human lymphoma cell lines, Raji and BJAB. In this report, we investigated the functional relationship between CD9 and cell proliferation regulated by histone deacetylase (HDAC) activity in these two cell lines. Introduction of CD9 expression in Raji cells resulted in significantly increased cell proliferation and HDAC activity compared to Mock transfected Raji cells. The increase in CD9–Raji cell proliferation was significantly inhibited by HDAC inhibitor (HDACi) treatment. Pretreatment of BJAB cells with HDAC inhibitors resulted in a significant decrease in endogenous CD9 mRNA and cell surface expression. BJAB cells also displayed decreased cell proliferation after HDACi treatment. These results suggest a significant relationship between CD9 expression and cell proliferation in human lymphoma cells that may be modulated by HDAC activity.

  4. Melatonin and nitric oxide modulate glutathione content and glutathione reductase activity in sunflower seedling cotyledons accompanying salt stress.

    Science.gov (United States)

    Kaur, Harmeet; Bhatla, Satish C

    2016-09-30

    The present findings demonstrate significant modulation of total glutathione content, reduced glutathione (GSH) content, oxidized glutathione (GSSG) content, GSH/GSSG ratio and glutathione reductase (GR; EC 1.6.4.2) activity in dark-grown seedling cotyledons in response to salt-stress (120 mM NaCl) in sunflower (Helianthus annuus L.) seedlings. A differential spatial distribution of GR activity (monitored by confocal laser scanning microscopic (CLSM) imaging) is also evident. Melatonin and nitric oxide (NO) differentially ameliorate salt stress effect by modulating GR activity and GSH content in seedling cotyledons. Total glutathione content (GSH + GSSG) exhibit a seedling age-dependent increase in the cotyledons, more so in salt-stressed conditions and when subjected to melatonin treatment. Seedlings raised in presence of 15 μM of melatonin exhibit significant increase in GR activity in cotyledon homogenates (10,000 g supernatant) coinciding with significant increase in GSH content. GSSG content and GSH/GSSG ratio also increased due to melatonin treatment. A correlation is thus evident in NaCl-sensitized modulation of GSH content and GR activity by melatonin. GSH content is down regulated by NO provided as 250 μM of sodium nitroprusside (SNP) although total glutathione content remained in similar range. A reversal of response (enhanced total glutathione accumulation) by NO scavenger (cPTIO) highlights the critical role of NO in modulating glutathione homeostasis. SNP lowers the activity of hydroxyindole-O-methyltransferase (HIOMT) - a regulatory enzyme in melatonin biosynthesis in control seedlings whereas its activity is upregulated in salt-stressed seedling cotyledons. Melatonin content of seedling cotyledons is also modulated by NO. NO and melatonin thus seem to modulate GR activity and GSH content during seedling growth under salt stress. PMID:27432590

  5. Tumor-Suppressive Activity of Lunatic Fringe in Prostate through Differential Modulation of Notch Receptor Activation

    Directory of Open Access Journals (Sweden)

    Shubing Zhang

    2014-02-01

    Full Text Available Elevated Notch ligand and receptor expression has been associated with aggressive forms of prostate cancer, suggesting a role for Notch signaling in regulation of prostate tumor initiation and progression. Here, we report a critical role for Lunatic Fringe (Lfng, which encodes an O-fucosylpeptide 3-ß-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats of Notch receptor proteins, in regulation of prostate epithelial differentiation and proliferation, as well as in prostate tumor suppression. Deletion of Lfng in mice caused altered Notch activation in the prostate, associated with elevated accumulation of Notch1, Notch2, and Notch4 intracellular domains, decreased levels of the putative Notch3 intracellular fragment, as well as increased expression of Hes1, Hes5, and Hey2. Loss of Lfng resulted in expansion of the basal layer, increased proliferation of both luminal and basal cells, and ultimately, prostatic intraepithelial neoplasia. The Lfng-null prostate showed down-regulation of prostatic tumor suppressor gene NKX3.1 and increased androgen receptor expression. Interestingly, expression of LFNG and NKX3.1 were positively correlated in publically available human prostate cancer data sets. Knockdown of LFNG in DU-145 prostate cancer cells led to expansion of CD44+CD24− and CD49f+CD24− stem/progenitor-like cell population associated with enhanced prostatosphere-forming capacity. Taken together, these data revealed a tumor-suppressive role for Lfng in the prostate through differential regulation of Notch signaling.

  6. P53 codon 11, 72, and 248 gene polymorphisms in endometriosis

    Directory of Open Access Journals (Sweden)

    Yao-Yuan Hsieh , Chich-Sheng Lin

    2006-01-01

    Full Text Available Objective: Mutated p53 gene is related to the instability of cell growth and cell cycle progression. We aimed to evaluate the association between endometriosis and p53 codon 11, 72 and 248 gene polymorphisms. Patients and methods: Women were divided into two groups: (1 moderate/severe endometriosis (n=148, and (2 non-endometriosis groups (n=150. P53 gene polymorphisms include codon11 Glu/Gln or Lys (GAG->CAG or AAG, codon 72 Arg/Pro (CGC->CCC, and codon 248 Arg/Thr (CGG->TCG. These gene polymorphisms were amplified by polymerase chain reaction and detected by electrophoresis after restriction enzyme (Taq I, BstU I, Hap II digestions. Associations between the endometriosis and p53 polymorphisms were evaluated. Results: The distributions of p53 codon 72 polymorphisms in both groups were significantly different. The proportions of Arg homozygotes/heterozygotes/Pro homozygotes in both groups were 9.5/66.2/24.3% and 30.7/50/19.3%. The proportions of Arg/Pro alleles were 42.6/57.4% and 56/44%. The distributions of p53 codon 11 and 248 polymorphisms in both groups were non-significantly different. All individuals appeared the wild genotypes (Glu11 and Arg248 homozygotes. Conclusion: Association between endometriosis and p53 codon 72 polymorphism exists. P53 codon 72*Pro-related genotype and allele are related with higher susceptibility of endometriosis. P53 codon 11 and 248 polymorphisms are not related with endometriosis susceptibility.

  7. Codon 201Gly Polymorphic Type of the DCC Gene is Related to Disseminated Neuroblastoma

    Directory of Open Access Journals (Sweden)

    Xiao-Tang Kong

    2001-01-01

    Full Text Available The deleted in colorectal carcinoma (DCC gene is a potential tumor- suppressor gene on chromosome 18821.3. The relatively high frequency of loss of heterozygosity (LOH and loss of expression of this gene in neuroblastoma, especially in the advanced stages, imply the possibility of involvement of the DCC gene in progression of neuroblastoma. However, only few typical mutations have been identified in this gene, indicating that other possible mechanisms for the inactivation of this gene may exist. A polymorphic change (Arg to Gly at DCC codon 201 is related to advanced colorectal carcinoma and increases in the tumors with absent DCC protein expression. In order to understand whether this change is associated with the development or progression of neuroblastoma, we investigated codon 201 polymorphism of the DCC gene in 102 primary neuroblastomas by polymerase chain reaction single-strand conformation polymorphism. We found no missense or nonsense mutations, but a polymorphic change from CGA (Arg to GGA (Gly at codon 201 resulting in three types of polymorphism: codon 201Gly type, codon 201Arg/Gly type, and codon 201Arg type. The codon 201Gly type occurred more frequently in disseminated (stages IV and IVs neuroblastomas (72% than in localized (stages I, II, and III tumors (48% (P=.035, and normal controls (38% (P=.024. In addition, the codon 201Gly type was significantly more common in tumors found clinically (65% than in those found by mass screening (35% (P=.002. The results suggested that the codon 201Gly type of the DCC gene might be associated with a higher risk of disseminating neuroblastoma.

  8. Efficient Reassignment of a Frequent Serine Codon in Wild-Type Escherichia coli.

    Science.gov (United States)

    Ho, Joanne M; Reynolds, Noah M; Rivera, Keith; Connolly, Morgan; Guo, Li-Tao; Ling, Jiqiang; Pappin, Darryl J; Church, George M; Söll, Dieter

    2016-02-19

    Expansion of the genetic code through engineering the translation machinery has greatly increased the chemical repertoire of the proteome. This has been accomplished mainly by read-through of UAG or UGA stop codons by the noncanonical aminoacyl-tRNA of choice. While stop codon read-through involves competition with the translation release factors, sense codon reassignment entails competition with a large pool of endogenous tRNAs. We used an engineered pyrrolysyl-tRNA synthetase to incorporate 3-iodo-l-phenylalanine (3-I-Phe) at a number of different serine and leucine codons in wild-type Escherichia coli. Quantitative LC-MS/MS measurements of amino acid incorporation yields carried out in a selected reaction monitoring experiment revealed that the 3-I-Phe abundance at the Ser208AGU codon in superfolder GFP was 65 ± 17%. This method also allowed quantification of other amino acids (serine, 33 ± 17%; phenylalanine, 1 ± 1%; threonine, 1 ± 1%) that compete with 3-I-Phe at both the aminoacylation and decoding steps of translation for incorporation at the same codon position. Reassignments of different serine (AGU, AGC, UCG) and leucine (CUG) codons with the matching tRNA(Pyl) anticodon variants were met with varying success, and our findings provide a guideline for the choice of sense codons to be reassigned. Our results indicate that the 3-iodo-l-phenylalanyl-tRNA synthetase (IFRS)/tRNA(Pyl) pair can efficiently outcompete the cellular machinery to reassign select sense codons in wild-type E. coli. PMID:26544153

  9. Efficient Reassignment of a Frequent Serine Codon in Wild-Type Escherichia coli.

    Science.gov (United States)

    Ho, Joanne M; Reynolds, Noah M; Rivera, Keith; Connolly, Morgan; Guo, Li-Tao; Ling, Jiqiang; Pappin, Darryl J; Church, George M; Söll, Dieter

    2016-02-19

    Expansion of the genetic code through engineering the translation machinery has greatly increased the chemical repertoire of the proteome. This has been accomplished mainly by read-through of UAG or UGA stop codons by the noncanonical aminoacyl-tRNA of choice. While stop codon read-through involves competition with the translation release factors, sense codon reassignment entails competition with a large pool of endogenous tRNAs. We used an engineered pyrrolysyl-tRNA synthetase to incorporate 3-iodo-l-phenylalanine (3-I-Phe) at a number of different serine and leucine codons in wild-type Escherichia coli. Quantitative LC-MS/MS measurements of amino acid incorporation yields carried out in a selected reaction monitoring experiment revealed that the 3-I-Phe abundance at the Ser208AGU codon in superfolder GFP was 65 ± 17%. This method also allowed quantification of other amino acids (serine, 33 ± 17%; phenylalanine, 1 ± 1%; threonine, 1 ± 1%) that compete with 3-I-Phe at both the aminoacylation and decoding steps of translation for incorporation at the same codon position. Reassignments of different serine (AGU, AGC, UCG) and leucine (CUG) codons with the matching tRNA(Pyl) anticodon variants were met with varying success, and our findings provide a guideline for the choice of sense codons to be reassigned. Our results indicate that the 3-iodo-l-phenylalanyl-tRNA synthetase (IFRS)/tRNA(Pyl) pair can efficiently outcompete the cellular machinery to reassign select sense codons in wild-type E. coli.

  10. tRNA properties help shape codon pair preferences in open reading frames

    OpenAIRE

    Buchan, J. Ross; Aucott, Lorna S; Stansfield, Ian

    2006-01-01

    Translation elongation is an accurate and rapid process, dependent upon efficient juxtaposition of tRNAs in the ribosomal A- and P-sites. Here, we sought evidence of A- and P-site tRNA interaction by examining bias in codon pair choice within open reading frames from a range of genomes. Three distinct and marked effects were revealed once codon and dipeptide biases had been subtracted. First, in the majority of genomes, codon pair preference is primarily determined by a tetranucleotide combin...

  11. The characteristics of synonymous codon usage in the initial and terminal translation regions of encephalomyocarditis virus.

    Science.gov (United States)

    Ma, X-X; Feng, Y-P; Liu, J-L; Zhao, Y-Q; Chen, L; Guo, P-H; Guo, J-Z; Ma, Z-R

    2014-01-01

    The synonymous codon usage patterns in the initial and terminal translation regions (ITR, TTR) of the whole coding sequence of encephalomyocarditis virus (EMCV) were analyzed in relation to those in its natural hosts using the sequences accessible in databases. In general, some low-usage host codons were found over-represented in the ITR and TTR of the virus, while some high-usage host codons were found under-represented in the two viral regions. These relationships are thought to participate in the regulation of the speed of translation of viral proteins and in the suppression of ribosomal traffic jams, both aiming at the increase of virus yields. PMID:24720745

  12. A point mutation in a silencer module reduces the promoter activity for the human mercaptopyruvate sulfurtransferase.

    Science.gov (United States)

    Nagahara, Noriyuki; Sreeja, V G; Li, Qing; Shimizu, Takako; Tsuchiya, Terumasa; Fujii-Kuriyama, Yoshiaki

    2004-11-01

    A promoter region of human mercaptopyruvate sulfurtransferase (MST) [EC 2.8.1.2] is G+C-rich and TATA-less, showing features of a house-keeping gene. In the core promoter, a GC box (-284:GGGGCGTGGC:-275) and an initiator (-219:TTATATG:-225) are found. A cap site hunting analysis for human liver cDNA revealed four possible transcriptional start sites, nucleotides -223, -159, -35 and -25. Point mutagenesis and deletion studies suggest that a module of the silencer element is -394:GCTG:-391. A replacement of -391G to C lost the silencer function; on the other hand, a replacement of -394G to T or C, -393C to T or -392T to G markedly reduced the promoter activity. PMID:15507321

  13. EV71-infected CD14(+) cells modulate the immune activity of T lymphocytes in rhesus monkeys.

    Science.gov (United States)

    Wang, Jingjing; Pu, Jing; Huang, Hongtai; Zhang, Ying; Liu, Longding; Yang, Erxia; Zhou, Xiaofang; Ma, Na; Zhao, Hongling; Wang, Lichun; Xie, Zhenfeng; Tang, Donghong; Li, Qihan

    2013-07-01

    Preliminary studies of the major pathogen enterovirus 71 (EV71), a member of the Picornaviridae family, have suggested that EV71 may be a major cause of fatal hand, foot and mouth disease cases. Currently, the role of the pathological changes induced by EV71 infection in the immunopathogenic response remains unclear. Our study focused on the interaction between this virus and immunocytes and indicated that this virus has the ability to replicate in CD14(+) cells. Furthermore, these EV71-infected CD14(+) cells have the capacity to stimulate the proliferation of T cells and to enhance the release of certain functional cytokines. An adaptive immune response induced by the back-transfusion of EV71-infected CD14(+) cells was observed in donor neonatal rhesus monkeys. Based on these observations, the proposed hypothesis is that CD14(+) cells infected by the EV71 virus might modulate the anti-EV71 adaptive immune response by inducing simultaneous T-cell activation.

  14. Bovine colostrum modulates immune activation cascades in human peripheral blood mononuclear cells in vitro

    DEFF Research Database (Denmark)

    Jenny, Marcel; Pedersen, Ninfa R; Hidayat, Budi J;

    2010-01-01

    Bovine colostrum (BC) is the thick yellow fluid a lactating cow Oyes to a suckling calf during its first days of life to support the growth of the calf and prevent gastrointestinal infections until the calf has synthesized its own active immune defense system. BC contains a complex system of immune...... factors and has a long history of use in traditional medicine. In an approach to evaluate the effects of bovine colostrum (BC) on the T-cell/macrophage interplay, we investigated and compared the capacity of BC containing low and high amounts of lactose and lactoferrin to modulate tryptophan degradation...... and neopterin formation in unstimulated and mitogen-stimulated human peripheral blood mononuclear cells (PBMC). The present study shows significant immunomodulatory effects of these BC preparations in human PBMC, either by enhancing or suppressing the occurrence of a Th-1 type immune response. The amount...

  15. Anticancer Activities of Medicinal Plants: Modulation of p53 Expression and Induction of Apoptosis.

    Science.gov (United States)

    Parveen, Amna; Akash, Muhammad Sajid Hamid; Rehman, Kanwal; Kyunn, Whang Wan

    2016-01-01

    For the treatment of several types of cancers, tumors and malignancies, scientists are investigating natural sources to discover novel therapeutic agents from medicinal plants having diverse anticancer properties. Research on natural products is being conducted to identify unexplored phytochemical constituents that have been proven to have diverse pharmacological activities. Several medicinal plants have been reported to regulate the progression of different types of cancers, tumors, and malignancies. In this article, we briefly summarize the recent progress in exploring the anticancer properties of various medicinal plants reported to modulate the expression of p53 and the induction of apoptosis. These plants provide a rich source of chemo-protective agents that can ultimately be used to manage cancer progression. PMID:27650989

  16. Development of Reduced Activation Ferritic-Martensitic Steels and fabrication technologies for Indian test blanket module

    Energy Technology Data Exchange (ETDEWEB)

    Raj, Baldev [Indira Gandhi Centre for Atomic Research, Kalpakkam 603 102 (India); Jayakumar, T., E-mail: tjk@igcar.gov.in [Indira Gandhi Centre for Atomic Research, Kalpakkam 603 102 (India)

    2011-10-01

    For the development of Reduced Activation Ferritic-Martensitic Steel (RAFMS), for the Indian Test Blanket Module for ITER, a 3-phase programme has been adopted. The first phase consists of melting and detailed characterization of a laboratory scale heat conforming to Eurofer 97 composition, to demonstrate the capability of the Indian industry for producing fusion grade steel. In the second phase which is currently in progress, the chemical composition will be optimized with respect to tungsten and tantalum for better combination of mechanical properties. Characterization of the optimized commercial scale India-specific RAFM steel will be carried out in the third phase. The first phase of the programme has been successfully completed and the tensile, impact and creep properties are comparable with Eurofer 97. Laser and electron beam welding parameters have been optimized and welding consumables were developed for Narrow Gap - Gas Tungsten Arc welding and for laser-hybrid welding.

  17. The self-pleasantness judgment modulates the encoding performance and the Default Mode Network activity

    Directory of Open Access Journals (Sweden)

    Perrone-Bertolotti eMarcela

    2016-03-01

    Full Text Available In this functional magnetic resonance imaging (fMRI study, we evaluated the effect of self-relevance on cerebral activity and behavioral performance during an incidental encoding task. Recent findings suggest that pleasantness judgments reliably induce self-oriented (internal thoughts and increase default mode network (DMN activity. We hypothesized that this increase in DMN activity would relate to increased memory recognition for pleasantly-judged stimuli (which depend on internally-oriented attention but decreased recognition for unpleasantly-judged items (which depend on externally-oriented attention. To test this hypothesis, brain activity was recorded from 21 healthy participants while they performed a pleasantness judgment requiring them to rate visual stimuli as pleasant or unpleasant. One hour later, participants performed a surprise memory recognition test outside of the scanner. Thus, we were able to evaluate the effects of pleasant and unpleasant judgments on cerebral activity and incidental encoding. The behavioral results showed that memory recognition was better for items rated as pleasant than items rated as unpleasant. The whole brain analysis indicated that successful encoding activates the inferior frontal and lateral temporal cortices, whereas unsuccessful encoding recruits two key medial posterior DMN regions, the posterior cingulate cortex and precuneus. A region of interest analysis including classic DMN areas, revealed significantly greater involvement of the medial Prefrontal Cortex in pleasant compared to unpleasant judgments, suggesting this region’s involvement in self-referential (i.e., internal processing. This area may be responsible for the greater recognition performance seen for pleasant stimuli. Furthermore, a significant interaction between the encoding performance (successful vs. unsuccessful and pleasantness was observed for the posterior cingulate cortex, precuneus and inferior frontal gyrus. Overall, our

  18. Modulation of Ca2+ oscillation and melatonin secretion by BKCa channel activity in rat pinealocytes.

    Science.gov (United States)

    Mizutani, Hiroya; Yamamura, Hisao; Muramatsu, Makoto; Hagihara, Yumiko; Suzuki, Yoshiaki; Imaizumi, Yuji

    2016-05-01

    The pineal glands regulate circadian rhythm through the synthesis and secretion of melatonin. The stimulation of nicotinic acetylcholine receptor due to parasympathetic nerve activity causes an increase in intracellular Ca(2+) concentration and eventually downregulates melatonin production. Our previous report shows that rat pinealocytes have spontaneous and nicotine-induced Ca(2+) oscillations that are evoked by membrane depolarization followed by Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCCs). These Ca(2+) oscillations are supposed to contribute to the inhibitory mechanism of melatonin secretion. Here we examined the involvement of large-conductance Ca(2+)-activated K(+) (BKCa) channel conductance on the regulation of Ca(2+) oscillation and melatonin production in rat pinealocytes. Spontaneous Ca(2+) oscillations were markedly enhanced by BKCa channel blockers (1 μM paxilline or 100 nM iberiotoxin). Nicotine (100 μM)-induced Ca(2+) oscillations were also augmented by paxilline. In contrast, spontaneous Ca(2+) oscillations were abolished by BKCa channel opener [3 μM 12,14-dichlorodehydroabietic acid (diCl-DHAA)]. Under whole cell voltage-clamp configurations, depolarization-elicited outward currents were significantly activated by diCl-DHAA and blocked by paxilline. Expression analyses revealed that the α and β3 subunits of BKCa channel were highly expressed in rat pinealocytes. Importantly, the activity of BKCa channels modulated melatonin secretion from whole pineal gland of the rat. Taken together, BKCa channel activation attenuates these Ca(2+) oscillations due to depolarization-synchronized Ca(2+) influx through VDCCs and results in a recovery of reduced melatonin secretion during parasympathetic nerve activity. BKCa channels may play a physiological role for melatonin production via a negative-feedback mechanism. PMID:26791489

  19. Associations between prefrontal cortex activation and H-reflex modulation during dual task gait

    Directory of Open Access Journals (Sweden)

    Daan eMeester

    2014-02-01

    Full Text Available Walking, although a largely automatic process, is controlled by the cortex and the spinal cord; with corrective reflexes modulated through integration of neural signals from central and peripheral inputs at supraspinal level throughout the gait cycle. However the full mechanism is not described. In this study we used an additional cognitive task to interfere with the automatic processing during walking in order to explore the neural mechanisms involved in healthy young adults. Participants were asked to walk on a treadmill at two speeds, both with and without additional cognitive load. We evaluated the impact of speed and cognitive load by analysing activity of the pre-frontal cortex (PFC using functional Near-Infrared Spectroscopy (fNIRS alongside with spinal cord reflex activity measured by soleus H-reflex amplitude and gait changes obtained by using an inertial measuring unit. Repeated measures ANOVA revealed that fNIRS Oxy-Hb concentrations significantly increased in the PFC with dual task (walking while performing a cognitive task compared to a single talk only (walking (p< 0.05. PFC activity was unaffected by increases of walking speed. H-reflex amplitude and gait variables did not change in response to either dual task or increases of walking speed. When walking under additional cognitive load we observed that participants adapted by using greater activity in the PFC, but that this adaption did not detrimentally affect H-reflex amplitude or gait variables. Our findings suggests that in a healthy young population central mechanisms (PFC are activated in response to cognitive loads but that H-reflex activity and gait performance can successfully be maintained. This study provides insight in the mechanisms behind healthy individuals safely performing dual task walking

  20. Dioxin modulates expression of receptor for activated C kinase (RACK-1) in developing neurons

    Energy Technology Data Exchange (ETDEWEB)

    Yang, J.H.; Kim, S.Y.; Lee, H.G.; Kim, M.Y.; Lee, J.H.; Chae, W.G. [Catholic Univ. of Daegu, Dept. of Pharmacology/Toxicology, Daegu (Korea)

    2004-09-15

    TCDD is sensitive to the central nerve system of the developing brain. The TCDD-induced neurodevelopmental deficits include the cognitive disability and motor dysfunction. While TCDD may lead to neurodevelopmental and neurobehavioral deficit, it is not known which molecular substances are intracellular targets for TCDD. Since TCDD accumulates in brain and the brain contains the Ah receptor, it is possible that TCDD may act at the target site such as cerebellum, which is responsible for cognitive abilities and motor function. A recent in vitro studies using cerebellar granule cells demonstrated a translocation of PKC-{alpha} and {epsilon} following the TCDD or PCB exposure. One of the most pivotal second messenger molecules involved in neuronal function and development is protein kinase C (PKC). PKC signaling pathways have been implicated as an important factor in learning and memory processes. PKC signaling events are optimized by the adaptor proteins, which organize PKCs near their selective substrates and away from others. RACK-1(receptor for activated C-kinase) is one of adaptor proteins that anchor the activated PKC at the site of translocation 6. RACKs bind PKC only in the presence of PKC activators. RACKs are 30- and 36-kDa proteins located in cytoskeletal compartment and play a key role in PKC activation and in membrane amchoring. Since different PKC isoforms translocate to distinct subcellular sites on activation, it is suggested that isoform-specific RACK may be present. Activation of certain PKC isoforms (PKC-a and {beta}II) is preferentially associated with RACK-1. While TCDD modulates PKC signaling pathway, role of RACK-1 on TCDD-mediated signaling pathway is not known. To identify the intracellular target for TCDD and understand a mechanism of signaling pathway in the developing brain, the present study attempted to analyze effects of RACK-1 in the cerebellar granule cells following TCDD exposure.

  1. Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension*

    Science.gov (United States)

    Zhang, Lili; Xie, Peng; Wang, Jingzhou; Yang, Qingwu; Fang, Chuanqin; Zhou, Shuang; Li, Jingcheng

    2010-01-01

    The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-γ in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-γ expression and excessive VSMC phenotypic modulation identified by reduced contractile proteins, α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α), and enhanced proliferation and migration. PPAR-γ overexpression rescued the expression of α-SMA and SM22α, and inhibited the proliferation and migration in SHR-derived VSMCs. In contrast, PPAR-γ silencing exerted the opposite effect. Activating PPAR-γ using rosiglitazone in vivo up-regulated aortic α-SMA and SM22α expression and attenuated aortic remodeling in SHRs. Increased activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was observed in SHR-derived VSMCs. PI3K inhibitor LY294002 rescued the impaired expression of contractile proteins, and inhibited proliferation and migration in VSMCs from SHRs, whereas constitutively active PI3K mutant had the opposite effect. Overexpression or silencing of PPAR-γ inhibited or excited PI3K/Akt activity, respectively. LY294002 counteracted the PPAR-γ silencing induced proliferation and migration in SHR-derived VSMCs, whereas active PI3K mutant had the opposite effect. In contrast, reduced proliferation and migration by PPAR-γ overexpression were reversed by the active PI3K mutant, and further inhibited by LY294002. We conclude that PPAR-γ inhibits VSMC phenotypic modulation through inhibiting PI3K/Akt signaling. Impaired PPAR-γ expression is responsible for VSMC phenotypic modulation during hypertension. These findings highlight an attractive therapeutic target for

  2. Pathogenic Mycobacterium bovis strains differ in their ability to modulate the proinflammatory activation phenotype of macrophages

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    Andrade Marcelle RM

    2012-08-01

    Full Text Available Abstract Background Tuberculosis, caused by Mycobacterium tuberculosis or Mycobacterium bovis, remains one of the leading infectious diseases worldwide. The ability of mycobacteria to rapidly grow in host macrophages is a factor contributing to enhanced virulence of the bacteria and disease progression. Bactericidal functions of phagocytes are strictly dependent on activation status of these cells, regulated by the infecting agent and cytokines. Pathogenic mycobacteria can survive the hostile environment of the phagosome through interference with activation of bactericidal responses. To study the mechanisms employed by highly virulent mycobacteria to promote their intracellular survival, we investigated modulating effects of two pathogenic M. bovis isolates and a reference M. tuberculosis H37Rv strain, differing in their ability to multiply in macrophages, on activation phenotypes of the cells primed with major cytokines regulating proinflammatory macrophage activity. Results Bone marrow- derived macrophages obtained from C57BL/6 mice were infected by mycobacteria after a period of cell incubation with or without treatment with IFN-γ, inducing proinflammatory type-1 macrophages (M1, or IL-10, inducing anti-inflammatory type-2 cells (M2. Phenotypic profiling of M1 and M2 was then evaluated. The M. bovis strain MP287/03 was able to grow more efficiently in the untreated macrophages, compared with the strains B2 or H37Rv. This strain induced weaker secretion of proinflammatory cytokines, coinciding with higher expression of M2 cell markers, mannose receptor (MR and arginase-1 (Arg-1. Treatment of macrophages with IFN-γ and infection by the strains B2 and H37Rv synergistically induced M1 polarization, leading to high levels of inducible nitric oxide synthase (iNOS expression, and reduced expression of the Arg-1. In contrast, the cells infected with the strain MP287/03 expressed high levels of Arg-1 which competed with iNOS for the common substrate

  3. The effect of multiple evolutionary selections on synonymous codon usage of genes in the Mycoplasma bovis genome.

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    Jian-hua Zhou

    Full Text Available Mycoplasma bovis is a major pathogen causing arthritis, respiratory disease and mastitis in cattle. A better understanding of its genetic features and evolution might represent evidences of surviving host environments. In this study, multiple factors influencing synonymous codon usage patterns in M. bovis (three strains' genomes were analyzed. The overall nucleotide content of genes in the M. bovis genome is AT-rich. Although the G and C contents at the third codon position of genes in the leading strand differ from those in the lagging strand (p<0.05, the 59 synonymous codon usage patterns of genes in the leading strand are highly similar to those in the lagging strand. The over-represented codons and the under-represented codons were identified. A comparison of the synonymous codon usage pattern of M. bovis and cattle (susceptible host indicated the independent formation of synonymous codon usage of M. bovis. Principal component analysis revealed that (i strand-specific mutational bias fails to affect the synonymous codon usage pattern in the leading and lagging strands, (ii mutation pressure from nucleotide content plays a role in shaping the overall codon usage, and (iii the major trend of synonymous codon usage has a significant correlation with the gene expression level that is estimated by the codon adaptation index. The plot of the effective number of codons against the G+C content at the third codon position also reveals that mutation pressure undoubtedly contributes to the synonymous codon usage pattern of M. bovis. Additionally, the formation of the overall codon usage is determined by certain evolutionary selections for gene function classification (30S protein, 50S protein, transposase, membrane protein, and lipoprotein and translation elongation region of genes in M. bovis. The information could be helpful in further investigations of evolutionary mechanisms of the Mycoplasma family and heterologous expression of its functionally

  4. Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells

    International Nuclear Information System (INIS)

    The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3′diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ∼ 5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0 μM (P < 0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP

  5. Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Verma, Vikas; Sharma, Vikas; Singh, Vishal [Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Sharma, Siddharth; Bishnoi, Ajay Kumar [Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Chandra, Vishal; Maikhuri, J.P.; Dwivedi, Anila [Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Kumar, Atul [Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Gupta, Gopal, E-mail: g_gupta@cdri.res.in [Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031 (India)

    2014-10-15

    The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3′diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ∼ 5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0 μM (P < 0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP.

  6. Modulation of Na+/K+ ATPase Activity by Hydrogen Peroxide Generated through Heme in L. amazonensis.

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    Nathália Rocco-Machado

    Full Text Available Leishmania amazonensis is a protozoan parasite that occurs in many areas of Brazil and causes skin lesions. Using this parasite, our group showed the activation of Na+/K+ ATPase through a signaling cascade that involves the presence of heme and protein kinase C (PKC activity. Heme is an important biomolecule that has pro-oxidant activity and signaling capacity. Reactive oxygen species (ROS can act as second messengers, which are required in various signaling cascades. Our goal in this work is to investigate the role of hydrogen peroxide (H2O2 generated in the presence of heme in the Na+/K+ ATPase activity of L. amazonensis. Our results show that increasing concentrations of heme stimulates the production of H2O2 in a dose-dependent manner until a concentration of 2.5 μM heme. To confirm that the effect of heme on the Na+/K+ ATPase is through the generation of H2O2, we measured enzyme activity using increasing concentrations of H2O2 and, as expected, the activity increased in a dose-dependent manner until a concentration of 0.1 μM H2O2. To investigate the role of PKC in this signaling pathway, we observed the production of H2O2 in the presence of its activator phorbol 12-myristate 13-acetate (PMA and its inhibitor calphostin C. Both showed no effect on the generation of H2O2. Furthermore, we found that PKC activity is increased in the presence of H2O2, and that in the presence of calphostin C, H2O2 is unable to activate the Na+/K+ ATPase. 100 μM of Mito-TEMPO was capable of abolishing the stimulatory effect of heme on Na+/K+ ATPase activity, indicating that mitochondria might be the source of the hydrogen peroxide production induced by heme. The modulation of L. amazonensis Na+/K+ ATPase by H2O2 opens new possibilities for understanding the signaling pathways of this parasite.

  7. Modulation of Na+/K+ ATPase Activity by Hydrogen Peroxide Generated through Heme in L. amazonensis.

    Science.gov (United States)

    Rocco-Machado, Nathália; Cosentino-Gomes, Daniela; Meyer-Fernandes, José Roberto

    2015-01-01

    Leishmania amazonensis is a protozoan parasite that occurs in many areas of Brazil and causes skin lesions. Using this parasite, our group showed the activation of Na+/K+ ATPase through a signaling cascade that involves the presence of heme and protein kinase C (PKC) activity. Heme is an important biomolecule that has pro-oxidant activity and signaling capacity. Reactive oxygen species (ROS) can act as second messengers, which are required in various signaling cascades. Our goal in this work is to investigate the role of hydrogen peroxide (H2O2) generated in the presence of heme in the Na+/K+ ATPase activity of L. amazonensis. Our results show that increasing concentrations of heme stimulates the production of H2O2 in a dose-dependent manner until a concentration of 2.5 μM heme. To confirm that the effect of heme on the Na+/K+ ATPase is through the generation of H2O2, we measured enzyme activity using increasing concentrations of H2O2 and, as expected, the activity increased in a dose-dependent manner until a concentration of 0.1 μM H2O2. To investigate the role of PKC in this signaling pathway, we observed the production of H2O2 in the presence of its activator phorbol 12-myristate 13-acetate (PMA) and its inhibitor calphostin C. Both showed no effect on the generation of H2O2. Furthermore, we found that PKC activity is increased in the presence of H2O2, and that in the presence of calphostin C, H2O2 is unable to activate the Na+/K+ ATPase. 100 μM of Mito-TEMPO was capable of abolishing the stimulatory effect of heme on Na+/K+ ATPase activity, indicating that mitochondria might be the source of the hydrogen peroxide production induced by heme. The modulation of L. amazonensis Na+/K+ ATPase by H2O2 opens new possibilities for understanding the signaling pathways of this parasite. PMID:26070143

  8. Modulation of inflammasome activity by Porphyromonas gingivalis in periodontitis and associated systemic diseases

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    Ingar Olsen

    2016-02-01

    Full Text Available Inflammasomes are large multiprotein complexes localized in the cytoplasm of the cell. They are responsible for the maturation of pro-inflammatory cytokines such as interleukin-1β (IL-1β and IL-18 as well as for the activation of inflammatory cell death, the so-called pyroptosis. Inflammasomes assemble in response to cellular infection, cellular stress, or tissue damage; promote inflammatory responses and are of great importance in regulating the innate immune system in chronic inflammatory diseases such as periodontitis and several chronic systemic diseases. In addition to sensing cellular integrity, inflammasomes are involved in the homeostatic mutualism between the indigenous microbiota and the host. There are several types of inflammasomes of which NLRP3 is best characterized in microbial pathogenesis. Many opportunistic bacteria try to evade the innate immune system in order to survive in the host cells. One of these is the periodontopathogen Porphyromonas gingivalis which has been shown to have several mechanisms of modulating innate immunity by limiting the activation of the NLRP3 inflammasome. Among them, ATP-/P2X7- signaling is recently associated not only with periodontitis but also with development of several systemic diseases. The present paper reviews multiple mechanisms through which P. gingivalis can modify innate immunity by affecting inflammasome activity.

  9. Modulation of microRNA activity by semi-microRNAs (smiRNAs

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    Isabelle ePlante

    2012-06-01

    Full Text Available The ribonuclease Dicer plays a central role in the microRNA pathway by catalyzing the formation of 19 to 24-nucleotide (nt long microRNAs. Subsequently incorporated into Ago2 effector complexes, microRNAs are known to regulate messenger RNA (mRNA translation. Whether shorter RNA species derived from microRNAs exist and play a role in mRNA regulation remains unknown. Here, we report the serendipitous discovery of a 12-nt long RNA species corresponding to the 5’ region of the microRNA let-7, and tentatively termed semi-microRNA, or smiRNA. Using a smiRNA derived from the precursor of miR-223 as a model, we show that 12-nt long smiRNA species are devoid of any direct mRNA regulatory activity, as assessed in a reporter gene activity assay in transfected cultured human cells. However, smiR-223 was found to modulate the ability of the microRNA from which it derives to mediate translational repression or cleavage of reporter mRNAs. Our findings suggest that smiRNAs may be generated along the microRNA pathway and participate to the control of gene expression by regulating the activity of the related full-length mature microRNA in vivo.

  10. Pharmacological activation of CB1 receptor modulates long term potentiation by interfering with protein synthesis.

    Science.gov (United States)

    Navakkode, Sheeja; Korte, Martin

    2014-04-01

    Cognitive impairment is one of the most important side effects associated with cannabis drug abuse, as well as the serious issue concerning the therapeutic use of cannabinoids. Cognitive impairments and neuropsychiatric symptoms are caused by early synaptic dysfunctions, such as loss of synaptic connections in different brain structures including the hippocampus, a region that is believed to play an important role in certain forms of learning and memory. We report here that metaplastic priming of synapses with a cannabinoid type 1 receptor (CB1 receptor) agonist, WIN55,212-2 (WIN55), significantly impaired long-term potentiation in the apical dendrites of CA1 pyramidal neurons. Interestingly, the CB1 receptor exerts its effect by altering the balance of protein synthesis machinery towards higher protein production. Therefore the activation of CB1 receptor, prior to strong tetanization, increased the propensity to produce new proteins. In addition, WIN55 priming resulted in the expression of late-LTP in a synaptic input that would have normally expressed early-LTP, thus confirming that WIN55 priming of LTP induces new synthesis of plasticity-related proteins. Furthermore, in addition to the effects on protein translation, WIN55 also induced synaptic deficits due to the ability of CB1 receptors to inhibit the release of acetylcholine, mediated by both muscarinic and nicotinic acetylcholine receptors. Taken together this supports the notion that the modulation of cholinergic activity by CB1 receptor activation is one mechanism that regulates the synthesis of plasticity-related proteins.

  11. Disintegrins: integrin selective ligands which activate integrin-coupled signaling and modulate leukocyte functions

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    Barja-Fidalgo C.

    2005-01-01

    Full Text Available Extracellular matrix proteins and cell adhesion receptors (integrins play essential roles in the regulation of cell adhesion and migration. Interactions of integrins with the extracellular matrix proteins lead to phosphorylation of several intracellular proteins such as focal adhesion kinase, activating different signaling pathways responsible for the regulation of a variety of cell functions, including cytoskeleton mobilization. Once leukocytes are guided to sites of infection, inflammation, or antigen presentation, integrins can participate in the initiation, maintenance, or termination of the immune and inflammatory responses. The modulation of neutrophil activation through integrin-mediated pathways is important in the homeostatic control of the resolution of inflammatory states. In addition, during recirculation, T lymphocyte movement through distinct microenvironments is mediated by integrins, which are critical for cell cycle, differentiation and gene expression. Disintegrins are a family of low-molecular weight, cysteine-rich peptides first identified in snake venom, usually containing an RGD (Arg-Gly-Asp motif, which confers the ability to selectively bind to integrins, inhibiting integrin-related functions in different cell systems. In this review we show that, depending on the cell type and the microenvironment, disintegrins are able to antagonize the effects of integrins or to act agonistically by activating integrin-mediated signaling. Disintegrins have proven useful as tools to improve the understanding of the molecular events regulated by integrin signaling in leukocytes and prototypes in order to design therapies able to interfere with integrin-mediated effects.

  12. Intracellular modulation, extracellular disposal and serum increase of MiR-150 mark lymphocyte activation.

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    Paola de Candia

    Full Text Available Activated lymphocytes release nano-sized vesicles (exosomes containing microRNAs that can be monitored in the bloodstream. We asked whether elicitation of immune responses is followed by release of lymphocyte-specific microRNAs. We found that, upon activation in vitro, human and mouse lymphocytes down-modulate intracellular miR-150 and accumulate it in exosomes. In vivo, miR-150 levels increased significantly in serum of humans immunized with flu vaccines and in mice immunized with ovalbumin, and this increase correlated with elevation of antibody titers. Immunization of immune-deficient mice, lacking MHCII, resulted neither in antibody production nor in elevation of circulating miR-150. This study provides proof of concept that serum microRNAs can be detected, with minimally invasive procedure, as biomarkers of vaccination and more in general of adaptive immune responses. Furthermore, the prompt reduction of intracellular level of miR-150, a key regulator of mRNAs critical for lymphocyte differentiation and functions, linked to its release in the external milieu suggests that the selective extracellular disposal of microRNAs can be a rapid way to regulate gene expression during lymphocyte activation.

  13. Activity-dependent modulation of odorant receptor gene expression in the mouse olfactory epithelium.

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    Shaohua Zhao

    Full Text Available Activity plays critical roles in development and maintenance of the olfactory system, which undergoes considerable neurogenesis throughout life. In the mouse olfactory epithelium, each olfactory sensory neuron (OSN stably expresses a single odorant receptor (OR type out of a repertoire of ∼1200 and the OSNs with the same OR identity are distributed within one of the few broadly-defined zones. However, it remains elusive whether and how activity modulates such OR expression patterns. Here we addressed this question by investigating OR gene expression via in situ hybridization when sensory experience or neuronal excitability is manipulated. We first examined the expression patterns of fifteen OR genes in mice which underwent neonatal, unilateral naris closure. After four-week occlusion, the cell density in the closed (sensory-deprived side was significantly lower (for four ORs, similar (for three ORs, or significantly higher (for eight ORs as compared to that in the open (over-stimulated side, suggesting that sensory inputs have differential effects on OSNs expressing different OR genes. We next examined the expression patterns of seven OR genes in transgenic mice in which mature OSNs had reduced neuronal excitability. Neuronal silencing led to a significant reduction in the cell density for most OR genes tested and thinner olfactory epithelium with an increased density of apoptotic cells. These results suggest that sensory experience plays important roles in shaping OR gene expression patterns and the neuronal activity is critical for survival of OSNs.

  14. 3β-Acetyl Tormentic Acid (3ATA a Novel Modulator of ABCC Proteins Activity

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    Cerli Rocha Gattass

    2012-06-01

    Full Text Available Multidrug resistance (MDR is considered the main cause of cancer chemotherapy failure and patient relapse. The active drug efflux mediated by transporter proteins of the ABC (ATP-binding cassette family is the most investigated mechanism leading to MDR. With the aim of inhibiting this transport and circumventing MDR, a great amount of work has been dedicated to identifying pharmacological inhibitors of specific ABC transporters. We recently showed that 3β-acetyl tormentic acid (3ATA had no effect on P-gp/ABCB1 activity. Herein, we show that 3ATA strongly inhibited the activity of MRP1/ABCC1. In the B16/F10 and Ma104 cell lines, this effect was either 20X higher or similar to that observed with MK571, respectively. Nevertheless, the low inhibitory effect of 3ATA on A549, a cell line that expresses MRP1-5, suggests that it may not inhibit other MRPs. The use of cells transfected with ABCC2, ABCC3 or ABCC4 showed that 3ATA was also able to modulate these transporters, though with an inhibition ratio lower than that observed for MRP1/ABCC1. These data point to 3ATA as a new ABCC inhibitor and call attention to its potential use as a tool to investigate the function of MRP/ABCC proteins or as a co-adjuvant in the treatment of MDR tumors.

  15. Inflows towards active regions and the modulation of the solar cycle: a parameter study

    CERN Document Server

    Martin-Belda, David

    2016-01-01

    Aims: We aim to investigate how converging flows towards active regions affect the surface transport of magnetic flux, as well as their impact on the generation of the Sun's poloidal field. The inflows constitute a potential non-linear mechanism for the saturation of the global dynamo and may contribute to the modulation of the solar cycle in the Babcock-Leighton framework. Methods: We build a surface flux transport code incorporating a parametrized model of the inflows and run simulations spanning several cycles. We carry out a parameter study to assess how the strength and extension of the inflows affect the build-up of the global dipole field. We also perform simulations with different levels of activity to investigate the potential role of the inflows in the saturation of the global dynamo. Results: We find that the interaction of neighbouring active regions can lead to the occasional formation of single-polarity magnetic flux clumps inconsistent with observations. We propose the darkening caused by pores...

  16. Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance.

    Science.gov (United States)

    Kwatra, Deep; Venugopal, Anand; Standing, David; Ponnurangam, Sivapriya; Dhar, Animesh; Mitra, Ashim; Anant, Shrikant

    2013-12-01

    Recently, we demonstrated that extracts of bitter melon (BME) can be used as a preventive/therapeutic agent in colon cancers. Here, we determined BME effects on anticancer activity and bioavailability of doxorubicin (DOX) in colon cancer cells. BME enhanced the effect of DOX on cell proliferation and sensitized the cells toward DOX upon pretreatment. Furthermore, there was both increased drug uptake and reduced drug efflux. We also observed a reduction in the expression of multidrug resistance conferring proteins (MDRCP) P-glycoprotein, MRP-2, and BCRP. Further BME suppressed DOX efflux in MDCK cells overexpressing the three efflux proteins individually, suggesting that BME is a potent inhibitor of MDR function. Next, we determined the effect of BME on PXR, a xenobiotic sensing nuclear receptor and a transcription factor that controls the expression of the three MDR genes. BME suppressed PXR promoter activity thereby suppressing its expression. Finally, we determined the effect of AMPK pathway on drug efflux because we have previously demonstrated that BME affects the pathway. However, inhibiting AMPK did not affect drug resistance, suggesting that BME may use different pathways for the anticancer and MDR modulating activities. Together, these results suggest that BME can enhance the bioavailability and efficacy of conventional chemotherapy.

  17. Prediction-error in the context of real social relationships modulates reward system activity

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    Joshua ePoore

    2012-08-01

    Full Text Available The human reward system is sensitive to both social (e.g., validation and non-social rewards (e.g., money and is likely integral for relationship development and reputation building. However, data is sparse on the question of whether implicit social reward processing meaningfully contributes to explicit social representations such as trust and attachment security in pre-existing relationships. This event-related fMRI experiment examined reward system prediction-error activity in response to a potent social reward—social validation—and this activity’s relation to both attachment security and trust in the context of real romantic relationships. During the experiment, participants’ expectations for their romantic partners’ positive regard of them were confirmed (validated or violated, in either positive or negative directions. Primary analyses were conducted using predefined regions of interest, the locations of which were taken from previously published research. Results indicate that activity for mid-brain and striatal reward system regions of interest was modulated by social reward expectation violation in ways consistent with prior research on reward prediction-error. Additionally, activity in the striatum during viewing of disconfirmatory information was associated with both increases in post-scan reports of attachment anxiety and decreases in post-scan trust, a finding that follows directly from representational models of attachment and trust.

  18. Modulation of western North Pacific tropical cyclone activity by the Atlantic Meridional Mode

    Science.gov (United States)

    Zhang, Wei; Vecchi, Gabriel A.; Villarini, Gabriele; Murakami, Hiroyuki; Rosati, Anthony; Yang, Xiaosong; Jia, Liwei; Zeng, Fanrong

    2016-05-01

    This study examines the year-to-year modulation of the western North Pacific (WNP) tropical cyclones (TC) activity by the Atlantic Meridional Mode (AMM) using both observations and the Geophysical Fluid Dynamics Laboratory Forecast-oriented Low Ocean Resolution Version of CM2.5 (FLOR) global coupled model. 1. The positive (negative) AMM phase suppresses (enhances) WNP TC activity in observations. The anomalous occurrence of WNP TCs results mainly from changes in TC genesis in the southeastern part of the WNP. 2. The observed responses of WNP TC activity to the AMM are connected to the anomalous zonal vertical wind shear (ZVWS) caused by AMM-induced changes to the Walker circulation. During the positive AMM phase, the warming in the North Atlantic induces strong descending flow in the tropical eastern and central Pacific, which intensifies the Walker cell in the WNP. The intensified Walker cell is responsible for the suppressed (enhanced) TC genesis in the eastern (western) part of the WNP by strengthening (weakening) ZVWS. 3. The observed WNPTC-AMM linkage is examined by the long-term control and idealized perturbations experiment with FLOR-FA. A suite of sensitivity experiments strongly corroborate the observed WNPTC-AMM linkage and underlying physical mechanisms.

  19. Dopamine exerts activation-dependent modulation of spinal locomotor circuits in the neonatal mouse.

    Science.gov (United States)

    Humphreys, Jennifer M; Whelan, Patrick J

    2012-12-01

    Monoamines can modulate the output of a variety of invertebrate and vertebrate networks, including the spinal cord networks that control walking. Here we examined the multiple changes in the output of locomotor networks induced by dopamine (DA). We found that DA can depress the activation of locomotor networks in the neonatal mouse spinal cord following ventral root stimulation. By examining disinhibited rhythms, where the Renshaw cell pathway was blocked, we found that DA depresses a putative recurrent excitatory pathway that projects onto rhythm-generating circuitry of the spinal cord. This depression was D(2) but not D(1) receptor dependent and was not due exclusively to depression of excitatory drive to motoneurons. Furthermore, the depression in excitation was not dependent on network activity. We next compared the modulatory effects of DA on network function by focusing on a serotonin and a N-methyl-dl-aspartate-evoked rhythm. In contrast to the depressive effects on a ventral root-evoked rhythm, we found that DA stabilized a drug-evoked rhythm, reduced the frequency of bursting, and increased amplitude. Overall, these data demonstrate that DA can potentiate network activity while at the same time reducing the gain of recurrent excitatory feedback loops from motoneurons onto the network.

  20. Structure-function analysis indicates that sumoylation modulates DNA-binding activity of STAT1

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    Grönholm Juha

    2012-10-01

    Full Text Available Abstract Background STAT1 is an essential transcription factor for interferon-γ-mediated gene responses. A distinct sumoylation consensus site (ψKxE 702IKTE705 is localized in the C-terminal region of STAT1, where Lys703 is a target for PIAS-induced SUMO modification. Several studies indicate that sumoylation has an inhibitory role on STAT1-mediated gene expression but the molecular mechanisms are not fully understood. Results Here, we have performed a structural and functional analysis of sumoylation in STAT1. We show that deconjugation of SUMO by SENP1 enhances the transcriptional activity of STAT1, confirming a negative regulatory effect of sumoylation on STAT1 activity. Inspection of molecular model indicated that consensus site is well exposed to SUMO-conjugation in STAT1 homodimer and that the conjugated SUMO moiety is directed towards DNA, thus able to form a sterical hindrance affecting promoter binding of dimeric STAT1. In addition, oligoprecipitation experiments indicated that sumoylation deficient STAT1 E705Q mutant has higher DNA-binding activity on STAT1 responsive gene promoters than wild-type STAT1. Furthermore, sumoylation deficient STAT1 E705Q mutant displayed enhanced histone H4 acetylation on interferon-γ-responsive promoter compared to wild-type STAT1. Conclusions Our results suggest that sumoylation participates in regulation of STAT1 responses by modulating DNA-binding properties of STAT1.

  1. Transcranial Direct Current Stimulation Modulates Cortical Neuronal Activity in Alzheimer's Disease

    Science.gov (United States)

    Marceglia, Sara; Mrakic-Sposta, Simona; Rosa, Manuela; Ferrucci, Roberta; Mameli, Francesca; Vergari, Maurizio; Arlotti, Mattia; Ruggiero, Fabiana; Scarpini, Elio; Galimberti, Daniela; Barbieri, Sergio; Priori, Alberto

    2016-01-01

    . Our findings disclosed that tDCS induces significant modulations in the cortical EEG activity in AD patients. The abnormal pattern of EEG activity observed in AD during memory processing is partially reversed by applying anodal tDCS, suggesting that anodal tDCS benefits in AD patients during working memory tasks are supported by the modulation of cortical activity. PMID:27065792

  2. Commensal Streptococcus salivarius Modulates PPARγ Transcriptional Activity in Human Intestinal Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Benoît Couvigny

    Full Text Available The impact of commensal bacteria in eukaryotic transcriptional regulation has increasingly been demonstrated over the last decades. A multitude of studies have shown direct effects of commensal bacteria from local transcriptional activity to systemic impact. The commensal bacterium Streptococcus salivarius is one of the early bacteria colonizing the oral and gut mucosal surfaces. It has been shown to down-regulate nuclear transcription factor (NF-кB in human intestinal cells, a central regulator of the host mucosal immune system response to the microbiota. In order to evaluate its impact on a further important transcription factor shown to link metabolism and inflammation in the intestine, namely PPARγ (peroxisome proliferator-activated receptor, we used human intestinal epithelial cell-lines engineered to monitor PPARγ transcriptional activity in response to a wide range of S. salivarius strains. We demonstrated that different strains from this bacterial group share the property to inhibit PPARγ activation independently of the ligand used. First attempts to identify the nature of the active compounds showed that it is a low-molecular-weight, DNase-, proteases- and heat-resistant metabolite secreted by S. salivarius strains. Among PPARγ-targeted metabolic genes, I-FABP and Angptl4 expression levels were dramatically reduced in intestinal epithelial cells exposed to S. salivarius supernatant. Both gene products modulate lipid accumulation in cells and down-regulating their expression might consequently affect host health. Our study shows that species belonging to the salivarius group of streptococci impact both host inflammatory and metabolic regulation suggesting a possible role in the host homeostasis and health.

  3. Commensal Streptococcus salivarius Modulates PPARγ Transcriptional Activity in Human Intestinal Epithelial Cells.

    Science.gov (United States)

    Couvigny, Benoît; de Wouters, Tomas; Kaci, Ghalia; Jacouton, Elsa; Delorme, Christine; Doré, Joël; Renault, Pierre; Blottière, Hervé M; Guédon, Eric; Lapaque, Nicolas

    2015-01-01

    The impact of commensal bacteria in eukaryotic transcriptional regulation has increasingly been demonstrated over the last decades. A multitude of studies have shown direct effects of commensal bacteria from local transcriptional activity to systemic impact. The commensal bacterium Streptococcus salivarius is one of the early bacteria colonizing the oral and gut mucosal surfaces. It has been shown to down-regulate nuclear transcription factor (NF-кB) in human intestinal cells, a central regulator of the host mucosal immune system response to the microbiota. In order to evaluate its impact on a further important transcription factor shown to link metabolism and inflammation in the intestine, namely PPARγ (peroxisome proliferator-activated receptor), we used human intestinal epithelial cell-lines engineered to monitor PPARγ transcriptional activity in response to a wide range of S. salivarius strains. We demonstrated that different strains from this bacterial group share the property to inhibit PPARγ activation independently of the ligand used. First attempts to identify the nature of the active compounds showed that it is a low-molecular-weight, DNase-, proteases- and heat-resistant metabolite secreted by S. salivarius strains. Among PPARγ-targeted metabolic genes, I-FABP and Angptl4 expression levels were dramatically reduced in intestinal epithelial cells exposed to S. salivarius supernatant. Both gene products modulate lipid accumulation in cells and down-regulating their expression might consequently affect host health. Our study shows that species belonging to the salivarius group of streptococci impact both host inflammatory and metabolic regulation suggesting a possible role in the host homeostasis and health. PMID:25946041

  4. Temporal modulations of agonist and antagonist muscle activities accompanying improved performance of ballistic movements.

    Science.gov (United States)

    Liang, Nan; Yamashita, Takamasa; Ni, Zhen; Takahashi, Makoto; Murakami, Tsuneji; Yahagi, Susumu; Kasai, Tatsuya

    2008-02-01

    Although many studies have examined performance improvements of ballistic movement through practice, it is still unclear how performance advances while maintaining maximum velocity, and how the accompanying triphasic electromyographic (EMG) activity is modified. The present study focused on the changes in triphasic EMG activity, i.e., the first agonist burst (AG1), the second agonist burst (AG2), and the antagonist burst (ANT), that accompanied decreases in movement time and error. Twelve healthy volunteers performed 100 ballistic wrist flexion movements in ten 10-trial sessions under the instruction to "maintain maximum velocity throughout the experiment and to stop the limb at the target as fast and accurately as possible". Kinematic parameters (position and velocity) and triphasic EMG activities from the agonist (flexor carpi radialis) and antagonist (extensor carpi radialis) muscles were recorded. Comparison of the results obtained from the first and the last 10 trials, revealed that movement time, movement error, and variability of amplitudes reduced with practice, and that maximum velocity and time to maximum velocity remained constant. EMG activities showed that AG1 and AG2 durations were reduced, whereas ANT duration did not change. Additionally, ANT and AG2 latencies were reduced. Integrated EMG of AG1 was significantly reduced as well. Analysis of the alpha angle (an index of the rate of recruitment of the motoneurons) showed that there was no change in either AG1 or AG2. Correlation analysis of alpha angles between these two bursts further revealed that the close relationship of AG1 and AG2 was kept constant through practice. These findings led to the conclusion that performance improvement in ballistic movement is mainly due to the temporal modulations of agonist and antagonist muscle activities when maximum velocity is kept constant. Presumably, a specific strategy is consistently applied during practice.

  5. PRE-ACTIVITY MODULATION OF LOWER EXTREMITY MUSCLES WITHIN DIFFERENT TYPES AND HEIGHTS OF DEEP JUMP

    Directory of Open Access Journals (Sweden)

    Vladimir Mrdakovic

    2008-06-01

    Full Text Available The purpose of this study was to determine modulation of pre- activity related to different types and heights of deep jump. Sixteen male soccer players without experience in deep jumps training (the national competition; 15.0 ± 0.5yrs; weight 61.9 ± 6.1kg; height 1.77 ± 0.07m, who participated in the study, performed three types of deep jump (bounce landing, counter landing, and bounce drop jump from three different heights (40cm, 60cm, and 80cm. Surface EMG device (1000Hz was used to estimate muscle activity (maximal amplitude of EMG - AmaxEMG; integral EMG signal - iEMG of five muscles (mm.gastrocnemii, m.soleus, m.tibialis anterior, m.vastus lateralis within 150ms before touchdown. All the muscles, except m. gastrocnemius medialis, showed systematic increase in pre-activity when platform height was raised. For most of the lower extremity muscles, the most significant differences were between values of pre-activity obtained for 40 cm and 80 cm platforms. While the amount of muscle pre-activity in deep jumps from the heights above and beneath the optimal one did not differ significantly from that generated in deep jumps from the optimal drop height of 60 cm, the patterns of muscle pre-activity obtained for the heights above the optimal one did differ from those obtained for the optimal drop height. That suggests that deep jumps from the heights above the optimal one do not seem to be an adequate exercise for adjusting muscle activity for the impact. Muscle pre-activity in bounce drop jumps differed significantly from that in counter landing and bounce landing respectively, which should indicate that a higher amount of pre-activity generated during bounce drop jumps was used for performing take-offs. As this study included the subjects who were not familiar with deep jumps training, the prospective studies should reveal the results of athletes with previous experience

  6. Amino Acid Deletion at Codon 67 and Thr-to-Gly Change at Codon 69 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Novel Drug Resistance Profiles

    Science.gov (United States)

    Imamichi, Tomozumi; Murphy, Michael A.; Imamichi, Hiromi; Lane, H. Clifford

    2001-01-01

    The potential roles of an amino acid deletion at codon 67 (Δ67) and a Thr-to-Gly change at codon 69 (T69G) in the reverse transcriptase of human immunodeficiency virus (HIV) type 1 in drug sensitivity and relative replication fitness were studied. Our results suggest that the Δ67 and T69G changes can be categorized as mutations associated with multidrug resistance. The combination of both mutations with an L74I change (Δ67+T69G/L74I) leads to a novel 3′-azido-3′-deoxythymidine resistance motif and compensates for impaired HIV replication. PMID:11264389

  7. Plasminogen N-terminal activation peptide modulates the activity of angiostatin-related peptides on endothelial cell proliferation and migration.

    Science.gov (United States)

    Hayashi, Moyuru; Tamura, Yosuke; Dohmae, Naoshi; Kojima, Soichi; Shimonaka, Motoyuki

    2008-05-01

    Angiostatin, a potent inhibitor of angiogenesis, is derived from the fibrinolytic proenzyme, plasminogen, by enzymatic processing. Plasminogen N-terminal activation peptide (PAP) is one of the products concomitantly released aside from angiostatin (kringles 1-4) and mini-plasminogen (kringle 5 plus the catalytic domain) when plasminogen is processed. To determine whether PAP alone or together with the angiostatin-related peptides derived from the processing of plasminogen modulate the proliferation and motility of endothelial cells, we have generated a recombinant PAP and used it to study its effects on endothelial cells in the presence and absence of the angiostatin-related peptides. Our results showed that PAP alone slightly increased the migration but not the proliferation of endothelial cells. However, in the presence of the angiostatin-related peptides, PAP attenuated the inhibitory activity of the angiostatin-related peptides on the proliferation and migration of endothelial cells. The inhibitory effect of PAP on the angiostatin-related peptides could be due to its binding to the kringle domains of the latter peptides. PMID:18294956

  8. Plasminogen N-terminal activation peptide modulates the activity of angiostatin-related peptides on endothelial cell proliferation and migration

    International Nuclear Information System (INIS)

    Angiostatin, a potent inhibitor of angiogenesis, is derived from the fibrinolytic proenzyme, plasminogen, by enzymatic processing. Plasminogen N-terminal activation peptide (PAP) is one of the products concomitantly released aside from angiostatin (kringles 1-4) and mini-plasminogen (kringle 5 plus the catalytic domain) when plasminogen is processed. To determine whether PAP alone or together with the angiostatin-related peptides derived from the processing of plasminogen modulate the proliferation and motility of endothelial cells, we have generated a recombinant PAP and used it to study its effects on endothelial cells in the presence and absence of the angiostatin-related peptides. Our results showed that PAP alone slightly increased the migration but not the proliferation of endothelial cells. However, in the presence of the angiostatin-related peptides, PAP attenuated the inhibitory activity of the angiostatin-related peptides on the proliferation and migration of endothelial cells. The inhibitory effect of PAP on the angiostatin-related peptides could be due to its binding to the kringle domains of the latter peptides

  9. Comparative studies on codon usage pattern of chloroplasts and their host nuclear genes in four plant species

    Indian Academy of Sciences (India)

    Qingpo Liu; Qingzhong Xue

    2005-04-01

    A detailed comparison was made of codon usage of chloroplast genes with their host (nuclear) genes in the four angiosperm species Oryza sativa, Zea mays, Triticum aestivum and Arabidopsis thaliana. The average GC content of the entire genes, and at the three codon positions individually, was higher in nuclear than in chloroplast genes, suggesting different genomic organization and mutation pressures in nuclear and chloroplast genes. The results of Nc-plots and neutrality plots suggested that nucleotide compositional constraint had a large contribution to codon usage bias of nuclear genes in O. sativa, Z. mays, and T. aestivum, whereas natural selection was likely to be playing a large role in codon usage bias in chloroplast genomes. Correspondence analysis and chi-test showed that regardless of the genomic environment (species) of the host, the codon usage pattern of chloroplast genes differed from nuclear genes of their host species by their AU-richness. All the chloroplast genomes have predominantly A- and/or U-ending codons, whereas nuclear genomes have G-, C- or U-ending codons as their optimal codons. These findings suggest that the chloroplast genome might display particular characteristics of codon usage that are different from its host nuclear genome. However, one feature common to both chloroplast and nuclear genomes in this study was that pyrimidines were found more frequently than purines at the synonymous codon position of optimal codons.

  10. Mutation analysis of codons 345 and 347 of rhodopsin gene in Indian retinitis pigmentosa patients

    Indian Academy of Sciences (India)

    Madhurima Dikshit; Rakhi Agarwal

    2001-08-01

    More than 100 mutations have been reported till date in the rhodopsin gene in patients with retinitis pigmentosa. The present study was undertaken to detect the reported rhodopsin gene point mutations in Indian retinitis pigmentosa patients. We looked for presence or absence of codon 345 and 347 mutations in exon 5 of the gene using the technique of allele-specific polymerase chain reaction by designing primers for each mutation. We have examined 100 patients from 76 families irrespective of genetic categories. Surprisingly, in our sample the very widely reported highly frequent mutations of codon 347 (P → S/A/R/Q/L/T) were absent while the codon 345 mutation V → M was seen in three cases in one family (autosomal dominant form) and in one sporadic case (total two families). This is the first report on codon 345 and 347 mutation in Indian retinitis pigmentosa subjects.

  11. CodHonEditor: Spreadsheets for Codon Optimization and Editing of Protein Coding Sequences.

    Science.gov (United States)

    Takai, Kazuyuki

    2016-05-01

    Gene synthesis is getting more important with the growing availability of low-cost commercial services. The coding sequences are often "optimized" as for the relative synonymous codon usage (RSCU) before synthesis, which is generally included in the commercial services. However, the codon optimization processes are different among different providers and are often hidden from the users. Here, the d'Hondt method, which is widely adopted as a method for determining the number of seats for each party in proportional-representation public elections, is applied to RSCU fitting. This allowed me to make a set of electronic spreadsheets for manual design of protein coding sequences for expression in Escherichia coli, with which users can see the process of codon optimization and can manually edit the codons after the automatic optimization. The spreadsheets may also be useful for molecular biology education. PMID:27002987

  12. Lack of correlation between p53 codon 72 polymorphism and anal cancer risk

    Institute of Scientific and Technical Information of China (English)

    Simone S Contu; Grasiela Agnes; Andrea P Damin; Paulo C Contu; Mário A Rosito; Claudio O Alexandre; Daniel C Damin

    2009-01-01

    AIM: To investigate the potential role of p53 codon 72 polymorphism as a risk factor for development of anal cancer.METHODS: Thirty-two patients with invasive anal carcinoma and 103 healthy blood donors were included in the study. p53 codon 72 polymorphism was analyzed in blood samples through polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing.RESULTS: The relative frequency of each allele was 0.60 for Arg and 0.40 for Pro in patients with anal cancer,and 0.61 for Arg and 0.39 for Pro in normal controls.No significant differences in distribution of the codon 72 genotypes between patients and controls were found.CONCLUSION: These results do not support a role for the p53 codon 72 polymorphism in anal carcinogenesis.

  13. mGluR5 positive modulators both potentiate activation and restore inhibition in NMDA receptors by PKC dependent pathway

    Directory of Open Access Journals (Sweden)

    Liao Pei-Fei

    2011-02-01

    Full Text Available Abstract Background In order to understand the interaction between the metabotropic glutamate subtype 5 (mGluR5 and N-methyl-D-aspartate (NMDA receptors, the influence of mGluR5 positive modulators in the inhibition of NMDA receptors by the noncompetitive antagonist ketamine, the competitive antagonist D-APV and the selective NR2B inhibitor ifenprodil was investigated. Methods This study used the multi-electrode dish (MED system to observe field potentials in hippocampal slices of mice. Results Data showed that the mGluR5 agonist (RS-2-chloro-5-hydroxyphenylglycine (CHPG, as well as the positive allosteric modulators 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl benzamide (CDPPB and 3,3'-difluorobenzaldazine (DFB alone did not alter the basal field potentials, but enhanced the amplitude of field potentials induced by NMDA. The inhibitory action of ketamine on NMDA-induced response was reversed by CHPG, DFB, and CDPPB, whereas the blockade of NMDA receptor by D-APV was restored by CHPG and CDPPB, but not by DFB. Alternatively, activation of NMDA receptors prior to the application of mGluR5 modulators, CHPG was able to enhance NMDA-induced field potentials and reverse the suppressive effect of ketamine and D-APV, but not ifenprodil. In addition, chelerythrine chloride (CTC, a protein kinase C (PKC inhibitor, blocked the regulation of mGluR5 positive modulators in enhancing NMDA receptor activation and recovering NMDA receptor inhibition. The PKC activator (PMA mimicked the effects of mGluR5 positive modulators on enhancing NMDA receptor activation and reversing NMDA antagonist-evoked NMDA receptor suppression. Conclusion Our results demonstrate that the PKC-dependent pathway may be involved in the positive modulation of mGluR5 resulting in potentiating NMDA receptor activation and reversing NMDA receptor suppression induced by NMDA antagonists.

  14. Prophylactic thyroidectomy for asymptomatic 3-year-old boy with positive multiple endocrine neoplasia type 2A mutation (codon 634

    Directory of Open Access Journals (Sweden)

    Ješić Maja D.

    2014-01-01

    Full Text Available Introduction. The multiple endocrine neoplasia type 2A (MEN 2A syndrome, comprising medullary thyroid carcinoma (MTC, pheochromocytoma and primary hyperparathyroidism (PHPT is most frequently caused by codon 634 activating mutations of the RET (rearranged during transfection proto-oncogene on chromosome 10. For this codon-mutation carriers, earlier thyroidectomy (before the age of 5 years would be advantageous in limiting the potential for the development of MTC as well as parathyroid adenomas. Case Outline. This is a case report of 3-year-old boy from the MEN 2A family (the boy’s father and grandmother and paternal aunt in which cysteine substitutes for phenylalanine at codon 634 in exon 11 of the RET proto-oncogene, who underwent thyroidectomy solely on the basis of genetic information. A boy had no thyromegaly, thyroidal irregularities or lymphadenopathy and no abnormality on the neck ultrasound examination. The pathology finding of thyroid gland was negative for MTC. Two years after total thyroidectomy, 5-year-old boy is healthy with permanent thyroxine replacement. His serum calcitonin level is <2 pg/ml (normal <13 pg/ml, has normal serum calcium and parathyroid hormone levels and negative urinary catecholamines. Long-term follow-up of this patient is required to determine whether very early thyroidectomy improves the long-term outcome of PHPT. Conclusion. Children with familial antecedents of MEN 2A should be genetically studied for the purpose of determining the risk of MTC and assessing the possibilities of making prophylactic thyroidectomy before the age of 5 years.

  15. Effective population size does not predict codon usage bias in mammals

    OpenAIRE

    Kessler, Michael D; Dean, Matthew D.

    2014-01-01

    Synonymous codons are not used at equal frequency throughout the genome, a phenomenon termed codon usage bias (CUB). It is often assumed that interspecific variation in the intensity of CUB is related to species differences in effective population sizes (N e), with selection on CUB operating less efficiently in species with small N e. Here, we specifically ask whether variation in N e predicts differences in CUB in mammals and report two main findings. First, across 41 mammalian genomes, CUB ...

  16. Autobiographical Planning and the Brain: Activation and Its Modulation by Qualitative Features.

    Science.gov (United States)

    Spreng, R Nathan; Gerlach, Kathy D; Turner, Gary R; Schacter, Daniel L

    2015-11-01

    To engage in purposeful behavior, it is important to make plans, which organize subsequent actions. Most studies of planning involve "look-ahead" puzzle tasks that are unrelated to personal goals. We developed a task to assess autobiographical planning, which involves the formulation of personal plans in response to real-world goals, and examined autobiographical planning in 63 adults during fMRI scanning. Autobiographical planning was found to engage the default network, including medial-temporal lobe and midline structures, and executive control regions in lateral pFC and parietal cortex and caudate. To examine how specific qualitative features of autobiographical plans modulate neural activity, we performed parametric modulation analyses. Ratings of plan detail, novelty, temporal distance, ease of plan formulation, difficulty in goal completion, and confidence in goal accomplishment were used as covariates in six hierarchical linear regression models. This modeling procedure removed shared variance among the ratings, allowing us to determine the independent relationship between ratings of interest and trial-wise BOLD signal. We found that specific autobiographical planning, describing a detailed, achievable, and actionable planning process for attaining a clearly envisioned future, recruited both default and frontoparietal brain regions. In contrast, abstract autobiographical planning, plans that were constructed from more generalized semantic or affective representations of a less tangible and distant future, involved interactions among default, sensory perceptual, and limbic brain structures. Specific qualities of autobiographical plans are important predictors of default and frontoparietal control network engagement during plan formation and reflect the contribution of mnemonic and executive control processes to autobiographical planning.

  17. Common modulation of limbic network activation underlies musical emotions as they unfold.

    Science.gov (United States)

    Singer, Neomi; Jacoby, Nori; Lin, Tamar; Raz, Gal; Shpigelman, Lavi; Gilam, Gadi; Granot, Roni Y; Hendler, Talma

    2016-11-01

    Music is a powerful means for communicating emotions among individuals. Here we reveal that this continuous stream of affective information is commonly represented in the brains of different listeners and that particular musical attributes mediate this link. We examined participants' brain responses to two naturalistic musical pieces using functional Magnetic Resonance imaging (fMRI). Following scanning, as participants listened to the musical pieces for a second time, they continuously indicated their emotional experience on scales of valence and arousal. These continuous reports were used along with a detailed annotation of the musical features, to predict a novel index of Dynamic Common Activation (DCA) derived from ten large-scale data-driven functional networks. We found an association between the unfolding music-induced emotionality and the DCA modulation within a vast network of limbic regions. The limbic-DCA modulation further corresponded with continuous changes in two temporal musical features: beat-strength and tempo. Remarkably, this "collective limbic sensitivity" to temporal features was found to mediate the link between limbic-DCA and the reported emotionality. An additional association with the emotional experience was found in a left fronto-parietal network, but only among a sub-group of participants with a high level of musical experience (>5years). These findings may indicate two processing-levels underlying the unfolding of common music emotionality; (1) a widely shared core-affective process that is confined to a limbic network and mediated by temporal regularities in music and (2) an experience based process that is rooted in a left fronto-parietal network that may involve functioning of the 'mirror-neuron system'. PMID:27389788

  18. Aqueous Extracts of Selected Potentilla Species Modulate Biological Activity of Human Normal Colon Cells.

    Science.gov (United States)

    Paduch, Roman; Wiater, Adrian; Locatelli, Marcello; Pleszczyńska, Malgorzata; Tomczyk, Michal

    2015-01-01

    Potentilla L. (Rosaceae) species have been used in traditional and in folk medicine for many years. This study characterized the activity of extracts from aerial parts of selected Potentilla species: P. argentea, P. anserina, P. grandiflora and P. erecta as well as one species of closely related to the genus Potentilla, Drymocallis rupestris (syn. P. rupestris). The biological activities were analyzed using MTT, NR and DPPH assays on CCD 841 CoTr and CCD-18Co cells. Moreover, cell morphology and cytoskeletal actin F-filaments organization and IL-6 and IL-10 levels by ELISA were analyzed after 24 h of incubation. Potentilla extracts at dose levels between 25 and 250 µg/mL were analyzed. For ELISA, 15 µg/mL and 30 μg/mL were chosen. When mitochondrial succinyl dehydrogenase activity was tested (MTT assay) only extract obtained from P. erecta at lower concentrations (up to 125 µg/mL) suppressed metabolism of myofibroblasts, while epithelial cells mitochondrial enzyme activity increased after incubation with all extracts. In Neutral Red (NR) method cellular membrane disturbance of both cell cultures was found after D. rupestris and P. grandiflora addition. Moreover, strong influence on epithelial cells was also found for P. anserina. All extracts showed similar, concentration-dependent free radical scavenging (DPPH) effect. Potentilla extracts, especially at lower concentration, decreased IL-6 production in myofibroblasts but the level of the cytokine was found to be stable in epithelial cells. IL-10 analysis revealed that P. argentea, D. rupestris, P. erecta extracts decrease cytokine level in myofibroblasts, while only when higher concentration were applied, decreased cytokine level produced by epithelial cells was found. F-actin filaments staining revealed that Potentilla extracts significantly influence on cellular cytoskeleton organization. Potentilla extracts influence on cells of human colon wall lining modulating the main features of them (viability

  19. Rhythmic Components in Extracranial Brain Signals Reveal Multifaceted Task Modulation of Overlapping Neuronal Activity.

    Directory of Open Access Journals (Sweden)

    Roemer van der Meij

    Full Text Available Oscillatory neuronal activity is implicated in many cognitive functions, and its phase coupling between sensors may reflect networks of communicating neuronal populations. Oscillatory activity is often studied using extracranial recordings and compared between experimental conditions. This is challenging, because there is overlap between sensor-level activity generated by different sources, and this can obscure differential experimental modulations of these sources. Additionally, in extracranial data, sensor-level phase coupling not only reflects communicating populations, but can also be generated by a current dipole, whose sensor-level phase coupling does not reflect source-level interactions. We present a novel method, which is capable of separating and characterizing sources on the basis of their phase coupling patterns as a function of space, frequency and time (trials. Importantly, this method depends on a plausible model of a neurobiological rhythm. We present this model and an accompanying analysis pipeline. Next, we demonstrate our approach, using magnetoencephalographic (MEG recordings during a cued tactile detection task as a case study. We show that the extracted components have overlapping spatial maps and frequency content, which are difficult to resolve using conventional pairwise measures. Because our decomposition also provides trial loadings, components can be readily contrasted between experimental conditions. Strikingly, we observed heterogeneity in alpha and beta sources with respect to whether their activity was suppressed or enhanced as a function of attention and performance, and this happened both in task relevant and irrelevant regions. This heterogeneity contrasts with the common view that alpha and beta amplitude over sensory areas are always negatively related to attention and performance.

  20. IκB Kinases Modulate the Activity of the Androgen Receptor in Prostate Carcinoma Cell Lines

    Directory of Open Access Journals (Sweden)

    Garima Jain

    2012-03-01

    Full Text Available Enhanced nuclear localization of nuclear factor κB (NF-κB in prostate cancer (PCa samples and constitutive NF-κB signaling in a class of PCa cell lines with low androgen receptor (AR expression (PC3 and DU-145 imply an important role of the IκB kinase (IKK/NF-κB system in PCa. However, most PCa and PCa cell lines depend on the activity of the AR, and the role of NF-κB in these AR-expressing PCa remains unclear. Here, we demonstrate that inhibition of NF-κB signaling by the IKK inhibitor BMS345541 reduced proliferation and increased apoptosis in AR-expressing PCa cell lines. Furthermore, AR activity and target gene expression were distinctively reduced, whereas AR protein levels remained unaltered on BMS345541 treatment. Similar effects were observed particularly after small interfering RNA (siRNA-mediated knockdown of IKK1, but not by siRNA-mediated suppression of IKK2. Moreover, IKK1 overexpression augmented 5α-dihydrotestosterone-induced nuclear AR translocation, whereas nuclear AR was reduced by IKK1 knockdown or BMS345541. However, because IKK1 also enhances the activity of a chronically nuclear AR mutant, modulation of the subcellular distribution seems not to be the only mechanism by which IKK1 enhances AR activity. Finally, reduced in vivo AR phosphorylation after BMS345541 treatment and in vitro AR phosphorylation by IKK1 or IKK2 imply that AR constitutes a novel IKK target. Taken together, our data identify IKK1 as a potentially target structure for future therapeutic intervention in PCa.

  1. Modulation of peritoneal macrophage activity by the saturation state of the fatty acid moiety of phosphatidylcholine

    Directory of Open Access Journals (Sweden)

    F.C.C. Grando

    2009-07-01

    Full Text Available To determine the effects of saturated and unsaturated fatty acids in phosphatidylcholine (PC on macrophage activity, peritoneal lavage cells were cultured in the presence of phosphatidylcholine rich in saturated or unsaturated fatty acids (sat PC and unsat PC, respectively, both used at concentrations of 32 and 64 µM. The treatment of peritoneal macrophages with 64 µM unsat PC increased the production of hydrogen peroxide by 48.3% compared to control (148.3 ± 16.3 vs 100.0 ± 1.8%, N = 15, and both doses of unsat PC increased adhesion capacity by nearly 50%. Moreover, 64 µM unsat PC decreased neutral red uptake by lysosomes by 32.5% compared to the untreated group (67.5 ± 6.8 vs 100.0 ± 5.5%, N = 15, while both 32 and 64 µM unsat PC decreased the production of lipopolysaccharide-elicited nitric oxide by 30.4% (13.5 ± 2.6 vs 19.4 ± 2.5 µM and 46.4% (10.4 ± 3.1 vs 19.4 ± 2.5 µM, respectively. Unsat PC did not affect anion production in non-stimulated cells or phagocytosis of unopsonized zymosan particles. A different result pattern was obtained for macrophages treated with sat PC. Phorbol 12-miristate 13-acetate-elicited superoxide production and neutral red uptake were decreased by nearly 25% by 32 and 64 µM sat PC, respectively. Sat PC did not affect nitric oxide or hydrogen peroxide production, adhesion capacity or zymosan phagocytosis. Thus, PC modifies macrophage activity, but this effect depends on cell activation state, fatty acid saturation and esterification to PC molecule and PC concentration. Taken together, these results indicate that the fatty acid moiety of PC modulates macrophage activity and, consequently, is likely to affect immune system regulation in vivo.

  2. Bone Microenvironment Modulates Expression and Activity of Cathepsin B in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Izabela Podgorski

    2005-03-01

    Full Text Available Prostate cancers metastasize to bone leading to osteolysis. Here we assessed proteolysis of DOcollagen I (a bone matrix protein and, for comparison, DO-collagen IV, by living human prostate carcinoma cells in vitro. Both collagens were degraded, this degradation was reduced by inhibitors of matrix metallo, serine, cysteine proteases. Because secretion of the cysteine protease cathepsin B is increased in human breast fibroblasts grown on collagen I gels, we analyzed cathepsin B levels and secretion in prostate cells grown on collagen I gels. Levels and secretion were increased only in DU145 cells-cells that expressed the highest baseline levels of cathepsin B. Secretion of cathepsin B was also elevated in DU145 cells grown in vitro on human bone fragments. We further investigated the effect of the bone microenvironment on cathepsin B expression and activity in vivo in a SCID-human model of prostate bone metastasis. High levels of cathepsin B protein and activity were found in DU145, PC3, LNCaP bone tumors, although the PC3 and LNCaP cells had exhibited low cathepsin B expression in vitro. Our results suggest that tumor-stromal interactions in the context of the bone microenvironment can modulate the expression of the cysteine protease cathepsin B.

  3. Green Tea and Bone Marrow Transplantation: From Antioxidant Activity to Enzymatic and Multidrug-resistance Modulation.

    Science.gov (United States)

    Peluso, Ilaria; Palmery, Maura; Vitalone, Annabella

    2016-10-25

    Epigallocatechin-3-gallate (EGCG), the main flavonoid of green tea (GT), could play an active role in the prevention of oxidative-stress-related diseases, such as hematologic malignancies. Some effects of EGCG are not imputable to antioxidant activity, but involve modulation of antioxidant enzymes and uric acid (UA) levels. The latter is the major factor responsible of the plasma non-enzymatic antioxidant capacity (NEAC). However, hyperuricemia is a frequent clinical feature caused by tumor lysis syndrome or cyclosporine side effects, both before and after bone marrow transplantation (BMT). Besides this, food-drug interactions could be associated with GT consumption and could have clinical implications. The molecular mechanisms involved in the redox and drug metabolizing/transporting pathways were discussed, with particular reference to the potential role of GT and EGCG in BMT. Moreover, on reviewing data on NEAC, isoprostanes, uric acid, and various enzymes from human studies on GT, its extract, or EGCG, an increase in NEAC, without effect on isoprostanes, and contrasting results on UA and enzymes were observed. Currently, few and contrasting available evidences suggest caution for GT consumption in BMT patients and more studies are needed to better understand the potential impact of EGCG on oxidative stress and metabolizing/transporting systems. PMID:26047551

  4. JNK Pathway Activation Modulates Acquired Resistance to EGFR/HER2-Targeted Therapies.

    Science.gov (United States)

    Manole, Simin; Richards, Edward J; Meyer, Aaron S

    2016-09-15

    Resistance limits the effectiveness of receptor tyrosine kinase (RTK)-targeted therapies. Combination therapies targeting resistance mechanisms can considerably improve response, but will require an improved understanding of when particular combinations will be effective. One common form of resistance is bypass signaling, wherein RTKs not targeted by an inhibitor can direct reactivation of pathways essential for survival. Although this mechanism of resistance is well appreciated, it is unclear which downstream signaling events are responsible. Here, we apply a combined experimental- and statistical modeling-based approach to identify a set of pathway reactivation essential for RTK-mediated bypass resistance. Differences in the downstream pathway activation provided by particular RTKs lead to qualitative differences in the capacity of each receptor to drive therapeutic resistance. We identify and validate that the JNK pathway is activated during and strongly modulates bypass resistance. These results identify effective therapeutic combinations that block bypass-mediated resistance and provide a basic understanding of this network-level change in kinase dependence that will inform the design of prognostic assays for identifying effective therapeutic combinations in individual patients. Cancer Res; 76(18); 5219-28. ©2016 AACR. PMID:27450453

  5. Augmented vagal heart rate modulation in active hypoestrogenic pre-menopausal women with functional hypothalamic amenorrhoea.

    Science.gov (United States)

    O'Donnell, Emma; Goodman, Jack M; Morris, Beverly L; Floras, John S; Harvey, Paula J

    2015-11-01

    Compared with eumenorrhoeic women, exercise-trained women with functional hypothalamic amenorrhoea (ExFHA) exhibit low heart rates (HRs) and absent reflex renin-angiotensin-system activation and augmentation of their muscle sympathetic nerve response to orthostatic stress. To test the hypothesis that their autonomic HR modulation is altered concurrently, three age-matched (pooled mean, 24 ± 1 years; mean ± S.E.M.) groups of women were studied: active with either FHA (ExFHA; n=11) or eumenorrhoeic cycles (ExOv; n=17) and sedentary with eumenorrhoeic cycles (SedOv; n=17). Blood pressure (BP), HR and HR variability (HRV) in the frequency domain were determined during both supine rest and graded lower body negative pressure (LBNP; -10, -20 and -40 mmHg). Very low (VLF), low (LF) and high (HF) frequency power spectra (ms(2)) were determined and, owing to skewness, log10-transformed. LF/HF ratio and total power (VLF + LF + HF) were calculated. At baseline, HR and systolic BP (SBP) were lower (P0.05). At each stage, HR correlated inversely (Ppost-menopausal women.

  6. A biased activation theory of the cognitive and attentional modulation of emotion.

    Science.gov (United States)

    Rolls, Edmund T

    2013-01-01

    Cognition can influence emotion by biasing neural activity in the first cortical region in which the reward value and subjective pleasantness of stimuli is made explicit in the representation, the orbitofrontal cortex (OFC). The same effect occurs in a second cortical tier for emotion, the anterior cingulate cortex (ACC). Similar effects are found for selective attention, to for example the pleasantness vs. the intensity of stimuli, which modulates representations of reward value and affect in the orbitofrontal and anterior cingulate cortices. The mechanisms for the effects of cognition and attention on emotion are top-down biased competition and top-down biased activation. Affective and mood states can in turn influence memory and perception, by backprojected biasing influences. Emotion-related decision systems operate to choose between gene-specified rewards such as taste, touch, and beauty. Reasoning processes capable of planning ahead with multiple steps held in working memory in the explicit system can allow the gene-specified rewards not to be selected, or to be deferred. The stochastic, noisy, dynamics of decision-making systems in the brain may influence whether decisions are made by the selfish-gene-specified reward emotion system, or by the cognitive reasoning system that explicitly calculates reward values that are in the interests of the individual, the phenotype.

  7. Active optics null test system based on a liquid crystal programmable spatial light modulator.

    Science.gov (United States)

    Ares, Miguel; Royo, Santiago; Sergievskaya, Irina; Riu, Jordi

    2010-11-10

    We present an active null test system adapted to test lenses and wavefronts with complex shapes and strong local deformations. This system provides greater flexibility than conventional static null tests that match only a precisely positioned, individual wavefront. The system is based on a cylindrical Shack-Hartmann wavefront sensor, a commercial liquid crystal programmable phase modulator (PPM), which acts as the active null corrector, enabling the compensation of large strokes with high fidelity in a single iteration, and a spatial filter to remove unmodulated light when steep phase changes are compensated. We have evaluated the PPM's phase response at 635 nm and checked its performance by measuring its capability to generate different amounts of defocus aberration, finding root mean squared errors below λ/18 for spherical wavefronts with peak-to-valley heights of up to 78.7λ, which stands as the limit from which diffractive artifacts created by the PPM have been found to be critical under no spatial filtering. Results of a null test for a complex lens (an ophthalmic customized progressive addition lens) are presented and discussed. PMID:21068848

  8. VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity.

    Science.gov (United States)

    Rao, Meghana; Song, Wenqiang; Jiang, Aixiang; Shyr, Yu; Lev, Sima; Greenstein, David; Brantley-Sieders, Dana; Chen, Jin

    2012-01-01

    VAPB (VAMP- associated protein B) is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.

  9. VAMP-associated protein B (VAPB promotes breast tumor growth by modulation of Akt activity.

    Directory of Open Access Journals (Sweden)

    Meghana Rao

    Full Text Available VAPB (VAMP- associated protein B is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.

  10. Oscillatory Activity in Developing Prefrontal Networks Results from Theta-Gamma-Modulated Synaptic Inputs

    Directory of Open Access Journals (Sweden)

    Sebastian H. Bitzenhofer

    2015-04-01

    Full Text Available The hippocampus-driven entrainment of neonatal prefrontal circuits in theta-gamma oscillations contributes to the maturation of cognitive abilities, yet the underlying synaptic mechanisms are still unknown. Here we combine patch-clamp recordings from morphologically and neurochemically characterized layer V pyramidal neurons and interneurons in vivo, with extracellular recordings from the prelimbic cortex (PL of awake and lightly anesthetized neonatal rats, to elucidate the synaptic framework of early network oscillations. We demonstrate that all neurons spontaneously fire bursts of action potentials. They receive barrages of fast and slow glutamatergic as well as GABAergic synaptic inputs. Oscillatory theta activity results from long-range coupling of pyramidal neurons, presumably within prelimbic-hippocampal circuits, and from local interactions between interneurons. In contrast, beta-low gamma activity requires external glutamatergic drive on prelimbic interneurons. High-frequency oscillations in layer V are independent of interactions at chemical synapses. Thus, specific theta-gamma-modulated synaptic interactions represent the substrate of network oscillations in the developing PL.

  11. A biased activation theory of the cognitive and attentional modulation of emotion

    Directory of Open Access Journals (Sweden)

    Edmund eRolls

    2013-03-01

    Full Text Available Cognition can influence emotion by biasing neural activity in the first cortical region in which the reward value and subjective pleasantness of stimuli is made explicit in the representation, the orbitofrontal cortex. The same effect occurs in a second cortical tier for emotion, the anterior cingulate cortex. Similar effects are found for selective attention, to for example the pleasantness vs the intensity of stimuli, which modulates representations of reward value and affect in the orbitofrontal and anterior cingulate cortices. The mechanisms for the effects of cognition and attention on emotion are top-down biased competition and top-down biased activation. Affective and mood states can in turn influence memory and perception, by backprojected biasing influences. Emotion-related decision systems operate to choose between gene-specified rewards such as taste, touch, and beauty. Reasoning processes capable of planning ahead with multiple steps held in working memory in the explicit system can allow the gene-specified rewards not to be selected, or to be deferred. The stochastic, noisy, dynamics of decision-making systems in the brain may influence whether decisions are made by the selfish-gene-specified reward emotion system, or by the cognitive reasoning system that explicitly calculates reward values that are in the interests of the individual, the phenotype.

  12. Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans.

    Science.gov (United States)

    Rabinak, Christine A; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R; Liberzon, Israel; Phan, K Luan

    2014-09-01

    Pre-extinction administration of Δ9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely occurs via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24 h after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders.

  13. Anthropogenically-Induced Superficial Seismic Activity Modulated By Slow-Slip Events in Guerrero, Mexico

    Science.gov (United States)

    Frank, W.; Shapiro, N.; Husker, A. L.; Kostoglodov, V.; Campillo, M.

    2014-12-01

    We use the data of the MASE seismic experiment operated during 2.5 years in Guerrero, Mexico to create a large catalog of seismic multiplets. This catalog is dominated by families of Low-Frequency Earthquakes (LFE) occurring in vicinity of the main subduction interface. In addition to more than one thousand LFE families, we detected nine repeating seismic event families that are located in the upper crust and are anthropogenically induced (AI) by mining blasts. Analysis of the recurrence of these AI events in time shows that their activity significantly increases during the strong Slow-Slip Event (SSE) in 2006. Modeled static stress perturbations induced by the SSE at the surface are ~5 kPa that is on the same order of magnitude as dynamic stress perturbations observed to trigger other low stress drop phenomena, such as tectonic tremor. We propose therefore that strong SSEs in Guerrero impose an extensional regime throughout the continental crust, modifying the stress field near the surface and increasing AI activity. This modulation of the recurrence of the crustal seismic events by the SSE-induced stress might be related to another recent observation: the SSE-induced reduction of seismic velocities linked to nonlinear elastic effects caused by opening of cracks (Rivet et al., 2011, 2014).

  14. Active optics null test system based on a liquid crystal programmable spatial light modulator

    Energy Technology Data Exchange (ETDEWEB)

    Ares, Miguel; Royo, Santiago; Sergievskaya, Irina; Riu, Jordi

    2010-11-10

    We present an active null test system adapted to test lenses and wavefronts with complex shapes and strong local deformations. This system provides greater flexibility than conventional static null tests that match only a precisely positioned, individual wavefront. The system is based on a cylindrical Shack-Hartmann wavefront sensor, a commercial liquid crystal programmable phase modulator (PPM), which acts as the active null corrector, enabling the compensation of large strokes with high fidelity in a single iteration, and a spatial filter to remove unmodulated light when steep phase changes are compensated. We have evaluated the PPM's phase response at 635 nm and checked its performance by measuring its capability to generate different amounts of defocus aberration, finding root mean squared errors below {lambda}/18 for spherical wavefronts with peak-to-valley heights of up to 78.7{lambda}, which stands as the limit from which diffractive artifacts created by the PPM have been found to be critical under no spatial filtering. Results of a null test for a complex lens (an ophthalmic customized progressive addition lens) are presented and discussed.

  15. Analysis of synonymous codon usage in chloroplast genome of Populus alba

    Institute of Scientific and Technical Information of China (English)

    ZHOU Meng; LONG Wei; LI Xia

    2008-01-01

    The pattern of codon usage in the chloroplast genome of Populus alba was investigated.Correspondence analysis (a commonly used multivariate statistical approach) and method of effective number of codons (ENc)-plot were conducted to analyze synonymous codon usage.The results of correspondence analysis showed that the distribution of genes on the major axis was significantly correlated with the frequency of use of G+C in synonymously variable third position of sense codon (GC3S),(r=0.349),and the positions of genes on the axis 2 and axis 3 were significantly correlated with CAI (r=-0.348,p<0.01 and r=0.602,p<0.01).The ENc for most genes was similar to that for the expected ENc based on the GC3S,but several genes with low ENC values were lying below the expected curve.All of these data indicated that codon usage was dominated by a mutational bias in chloroplast genome of P.alba.The selection in nature for translational efficiency only played a minor role in shaping codon usage in the chloroplast genome of P.alba.

  16. The TP53 Codon 72 Polymorphism and Risk of Sporadic Prostate Cancer among Iranian Patients.

    Directory of Open Access Journals (Sweden)

    Farhad Babaei

    2015-04-01

    Full Text Available The TP53 gene is one of the most frequently mutated genes amongst human malignancies, particularly TP53 codon 72 polymorphism. Furthermore, an association between the TP53 codon 72 variants and prostate cancer has been reported in several studies. Although some studies have indicated an association between the TP53 Arg/Arg variant and an increased risk for prostate cancer, other studies have shown a positive correlation between the TP53 Pro/Pro genotype instead. Therefore, to clarify if this polymorphism is associated with an increased risk of prostate cancer in Iranian men, we conducted a case-control study of 40 sporadic prostate cancer patients and 80 benign prostate hyperplasia cases.The TP53 codon 72 was genotyped using an allele specific PCR.A significant association between the TP53 codon 72 genotype and prostate cancer risk was found (OR = 6.8, 95% CI = [1.8-25.1], P = 0.005. However, the results of this study did not support an association between age, the Gleason score nor TP53 genotype at codon 72 in prostate cancer patients.TP53 codon 72 polymorphism may have a great impact in the development of prostate cancer.

  17. Codon 129 polymorphism of prion protein gene in is not a risk factor for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Jerusa Smid

    2013-07-01

    Full Text Available Interaction of prion protein and amyloid-b oligomers has been demonstrated recently. Homozygosity at prion protein gene (PRNP codon 129 is associated with higher risk for Creutzfeldt-Jakob disease. This polymorphism has been addressed as a possible risk factor in Alzheimer disease (AD. Objective To describe the association between codon 129 polymorphisms and AD. Methods We investigated the association of codon 129 polymorphism of PRNP in 99 AD patients and 111 controls, and the association between this polymorphism and cognitive performance. Other polymorphisms of PRNP and additive effect of apolipoprotein E gene (ApoE were evaluated. Results Codon 129 genotype distribution in AD 45.5% methionine (MM, 42.2% methionine valine (MV, 12.1% valine (VV; and 39.6% MM, 50.5% MV, 9.9% VV among controls (p>0.05. There were no differences of cognitive performance concerning codon 129. Stratification according to ApoE genotype did not reveal difference between groups. Conclusion Codon 129 polymorphism is not a risk factor for AD in Brazilian patients.

  18. Polyamines cause plasma membrane depolarization, activate Ca2+-, and modulate H+-ATPase pump activity in pea roots.

    Science.gov (United States)

    Pottosin, Igor; Velarde-Buendía, Ana María; Bose, Jayakumar; Fuglsang, Anja T; Shabala, Sergey

    2014-06-01

    Polyamines regulate a variety of cation and K(+) channels, but their potential effects on cation-transporting ATPases are underexplored. In this work, noninvasive microelectrode ion flux estimation and conventional microelectrode techniques were applied to study the effects of polyamines on Ca(2+) and H(+) transport and membrane potential in pea roots. Externally applied spermine or putrescine (1mM) equally activated eosin yellow (EY)-sensitive Ca(2+) pumping across the root epidermis and caused net H(+) influx or efflux. Proton influx induced by spermine was suppressed by EY, supporting the mechanism in which Ca(2+) pump imports 2 H(+) per each exported Ca(2+). Suppression of the Ca(2+) pump by EY diminished putrescine-induced net H(+) efflux instead of increasing it. Thus, activities of Ca(2+) and H(+) pumps were coupled, likely due to the H(+)-pump inhibition by intracellular Ca(2+). Additionally, spermine but not putrescine caused a direct inhibition of H(+) pumping in isolated plasma membrane vesicles. Spermine, spermidine, and putrescine (1mM) induced membrane depolarization by 70, 50, and 35 mV, respectively. Spermine-induced depolarization was abolished by cation transport blocker Gd(3+), was insensitive to anion channels' blocker niflumate, and was dependent on external Ca(2+). Further analysis showed that uptake of polyamines but not polyamine-induced cationic (K(+)+Ca(2+)+H(+)) fluxes were a main cause of membrane depolarization. Polyamine increase is a common component of plant stress responses. Activation of Ca(2+) efflux by polyamines and contrasting effects of polyamines on net H(+) fluxes and membrane potential can contribute to Ca(2+) signalling and modulate a variety of transport processes across the plasma membrane under stress. PMID:24723394

  19. The Self-Pleasantness Judgment Modulates the Encoding Performance and the Default Mode Network Activity.

    Science.gov (United States)

    Perrone-Bertolotti, Marcela; Cerles, Melanie; Ramdeen, Kylee T; Boudiaf, Naila; Pichat, Cedric; Hot, Pascal; Baciu, Monica

    2016-01-01

    In this functional magnetic resonance imaging (fMRI) study, we evaluated the effect of self-relevance on cerebral activity and behavioral performance during an incidental encoding task. Recent findings suggest that pleasantness judgments reliably induce self-oriented (internal) thoughts and increase default mode network (DMN) activity. We hypothesized that this increase in DMN activity would relate to increased memory recognition for pleasantly-judged stimuli (which depend on internally-oriented attention) but decreased recognition for unpleasantly-judged items (which depend on externally-oriented attention). To test this hypothesis, brain activity was recorded from 21 healthy participants while they performed a pleasantness judgment requiring them to rate visual stimuli as pleasant or unpleasant. One hour later, participants performed a surprise memory recognition test outside of the scanner. Thus, we were able to evaluate the effects of pleasant and unpleasant judgments on cerebral activity and incidental encoding. The behavioral results showed that memory recognition was better for items rated as pleasant than items rated as unpleasant. The whole brain analysis indicated that successful encoding (SE) activates the inferior frontal and lateral temporal cortices, whereas unsuccessful encoding (UE) recruits two key medial posterior DMN regions, the posterior cingulate cortex (PCC) and precuneus (PCU). A region of interest (ROI) analysis including classic DMN areas, revealed significantly greater involvement of the medial prefrontal cortex (mPFC) in pleasant compared to unpleasant judgments, suggesting this region's involvement in self-referential (i.e., internal) processing. This area may be responsible for the greater recognition performance seen for pleasant stimuli. Furthermore, a significant interaction between the encoding performance (successful vs. unsuccessful) and pleasantness was observed for the PCC, PCU and inferior frontal gyrus (IFG). Overall, our

  20. CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression.

    Directory of Open Access Journals (Sweden)

    Michael P Schnetz

    2010-07-01

    Full Text Available CHD7 is one of nine members of the chromodomain helicase DNA-binding domain family of ATP-dependent chromatin remodeling enzymes found in mammalian cells. De novo mutation of CHD7 is a major cause of CHARGE syndrome, a genetic condition characterized by multiple congenital anomalies. To gain insights to the function of CHD7, we used the technique of chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq to map CHD7 sites in mouse ES cells. We identified 10,483 sites on chromatin bound by CHD7 at high confidence. Most of the CHD7 sites show features of gene enhancer elements. Specifically, CHD7 sites are predominantly located distal to transcription start sites, contain high levels of H3K4 mono-methylation, found within open chromatin that is hypersensitive to DNase I digestion, and correlate with ES cell-specific gene expression. Moreover, CHD7 co-localizes with P300, a known enhancer-binding protein and strong predictor of enhancer activity. Correlations with 18 other factors mapped by ChIP-seq in mouse ES cells indicate that CHD7 also co-localizes with ES cell master regulators OCT4, SOX2, and NANOG. Correlations between CHD7 sites and global gene expression profiles obtained from Chd7(+/+, Chd7(+/-, and Chd7(-/- ES cells indicate that CHD7 functions at enhancers as a transcriptional rheostat to modulate, or fine-tune the expression levels of ES-specific genes. CHD7 can modulate genes in either the positive or negative direction, although negative regulation appears to be the more direct effect of CHD7 binding. These data indicate that enhancer-binding proteins can limit gene expression and are not necessarily co-activators. Although ES cells are not likely to be affected in CHARGE syndrome, we propose that enhancer-mediated gene dysregulation contributes to disease pathogenesis and that the critical CHD7 target genes may be subject to positive or negative regulation.

  1. Belief about Nicotine Modulates Subjective Craving and Insula Activity in Deprived Smokers

    Science.gov (United States)

    Gu, Xiaosi; Lohrenz, Terry; Salas, Ramiro; Baldwin, Philip R.; Soltani, Alireza; Kirk, Ulrich; Cinciripini, Paul M.; Montague, P. Read

    2016-01-01

    Little is known about the specific neural mechanisms through which cognitive factors influence craving and associated brain responses, despite the initial success of cognitive therapies in treating drug addiction. In this study, we investigated how cognitive factors such as beliefs influence subjective craving and neural activities in nicotine-addicted individuals using model-based functional magnetic resonance imaging (fMRI) and neuropharmacology. Deprived smokers (N = 24) participated in a two-by-two balanced placebo design, which crossed beliefs about nicotine (told “nicotine” vs. told “no nicotine”) with the nicotine content in a cigarette (nicotine vs. placebo) which participants smoked immediately before performing a fMRI task involving reward learning. Subjects’ reported craving was measured both before smoking and after the fMRI session. We found that first, in the presence of nicotine, smokers demonstrated significantly reduced craving after smoking when told “nicotine in cigarette” but showed no change in craving when told “no nicotine.” Second, neural activity in the insular cortex related to craving was only significant when smokers were told “nicotine” but not when told “no nicotine.” Both effects were absent in the placebo condition. Third, insula activation related to computational learning signals was modulated by belief about nicotine regardless of nicotine’s presence. These results suggest that belief about nicotine has a strong impact on subjective craving and insula responses related to both craving and learning in deprived smokers, providing insights into the complex nature of belief–drug interactions. PMID:27468271

  2. Testosterone administration in females modulates moral judgment and patterns of brain activation and functional connectivity.

    Science.gov (United States)

    Chen, Chenyi; Decety, Jean; Huang, Pin-Chia; Chen, Chin-Yau; Cheng, Yawei

    2016-10-01

    Morality is defined as prescriptive norms regarding how people should treat one another, and includes concepts of fairness, justice, and rights. One recent study with moral dilemmas suggested that testosterone administration increases utilitarian judgments, which depends on second-to-fourth (2D: 4D) digit ratio, as a proxy of prenatal priming. However, the neural mechanism by which acute testosterone modulates moral reasoning remains to be determined. Using a placebo-controlled within-subject design, the current study examined the neuromodulatory effect of testosterone in young females by combining moral dilemmas, 2D: 4D, functional magnetic resonance imaging (fMRI), and subjective ratings of morally laden scenarios. Results showed that testosterone administration elicited more utilitarian responses to evitable dilemmas. The high 2D: 4D group scored more punishments for moral evaluation, whereas the low 2D: 4D group did the opposite. The activity in the amygdala, anterior insular cortex, and dorsolateral prefrontal cortex (dlPFC) was increased when participants evaluated morally unorthodox actions (intentional harm). The activity in the posterior superior temporal sulcus/temporoparietal junction (pSTS/TPJ) to accidental harm was decreased, specific to the high 2D: 4D group. The functional connectivity between the amygdala and dlPFC was reduced. The activity in the pSTS/TPJ to perceived agency predicted utilitarian responses to evitable dilemmas. The findings demonstrate the acute effect of testosterone on neural responses associated with moral judgment, and provide evidence to support that prenatal sex-hormones priming could be important for early neurodevelopment, which plays a crucial role in the neural and behavioral manifestations of testosterone on adult moral reasoning. Hum Brain Mapp 37:3417-3430, 2016. © 2016 Wiley Periodicals, Inc. PMID:27145084

  3. Bhas 42 cell transformation activity of cigarette smoke condensate is modulated by selenium and arsenic.

    Science.gov (United States)

    Han, Sung Gu; Pant, Kamala; Bruce, Shannon W; Gairola, C Gary

    2016-04-01

    Cigarette smoking remains a major health risk worldwide. Development of newer tobacco products requires the use of quantitative toxicological assays. Recently, v-Ha-ras transfected BALB/c3T3 (Bhas 42) cell transformation assay was established that simulates the two-stage animal tumorigenesis model and measures tumor initiating and promoting activities of chemicals. The present study was performed to assess the feasibility of using this Bhas 42 cell transformation assay to determine the initiation and promotion activities of cigarette smoke condensate (CSC) and its water soluble fraction. Further, the modulating effects of selenium and arsenic on cigarette smoke-induced cell transformation were investigated. Dimethyl sulfoxide (DMSO) and water extracts of CSC (CSC-D and CSC-W, respectively) were tested at concentrations of 2.5-40 µg mL(-1) in the initiation or promotion assay formats. Initiation protocol of the Bhas 42 assay showed a 3.5-fold increase in transformed foci at 40 µg mL(-1) of CSC-D but not CSC-W. The promotion phase of the assay yielded a robust dose response with CSC-D (2.5-40 µg mL(-1)) and CSC-W (20-40 µg mL(-1)). Preincubation of cells with selenium (100 nM) significantly reduced CSC-induced increase in cell transformation in initiation assay. Co-treatment of cells with a sub-toxic dose of arsenic significantly enhanced cell transformation activity of CSC-D in promotion assay. The results suggest a presence of both water soluble and insoluble tumor promoters in CSC, a role of oxidative stress in CSC-induced cell transformation, and usefulness of Bhas 42 cell transformation assay in comparing tobacco product toxicities and in studying the mechanisms of tobacco carcinogenesis.

  4. Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation.

    Science.gov (United States)

    Lin, Ya-Tin; Liu, Tzu-Yu; Yang, Ching-Yao; Yu, Yu-Lian; Chen, Ting-Chun; Day, Yuan-Ji; Chang, Che-Chien; Huang, Guo-Jen; Chen, Jin-Chung

    2016-09-01

    Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra-paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder. PMID:27243477

  5. Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation.

    Science.gov (United States)

    Lin, Ya-Tin; Liu, Tzu-Yu; Yang, Ching-Yao; Yu, Yu-Lian; Chen, Ting-Chun; Day, Yuan-Ji; Chang, Che-Chien; Huang, Guo-Jen; Chen, Jin-Chung

    2016-09-01

    Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra-paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder.

  6. Identification of anabolic selective androgen receptor modulators with reduced activities in reproductive tissues and sebaceous glands.

    Science.gov (United States)

    Schmidt, Azriel; Harada, Shun-Ichi; Kimmel, Donald B; Bai, Chang; Chen, Fang; Rutledge, Su Jane; Vogel, Robert L; Scafonas, Angela; Gentile, Michael A; Nantermet, Pascale V; McElwee-Witmer, Sheila; Pennypacker, Brenda; Masarachia, Patricia; Sahoo, Soumya P; Kim, Yuntae; Meissner, Robert S; Hartman, George D; Duggan, Mark E; Rodan, Gideon A; Towler, Dwight A; Ray, William J

    2009-12-25

    Androgen replacement therapy is a promising strategy for the treatment of frailty; however, androgens pose risks for unwanted effects including virilization and hypertrophy of reproductive organs. Selective Androgen Receptor Modulators (SARMs) retain the anabolic properties of androgens in bone and muscle while having reduced effects in other tissues. We describe two structurally similar 4-aza-steroidal androgen receptor (AR) ligands, Cl-4AS-1, a full agonist, and TFM-4AS-1, which is a SARM. TFM-4AS-1 is a potent AR ligand (IC(50), 38 nm) that partially activates an AR-dependent MMTV promoter (55% of maximal response) while antagonizing the N-terminal/C-terminal interaction within AR that is required for full receptor activation. Microarray analyses of MDA-MB-453 cells show that whereas Cl-4AS-1 behaves like 5alpha-dihydrotestosterone (DHT), TFM-4AS-1 acts as a gene-selective agonist, inducing some genes as effectively as DHT and others to a lesser extent or not at all. This gene-selective agonism manifests as tissue-selectivity: in ovariectomized rats, Cl-4AS-1 mimics DHT while TFM-4AS-1 promotes the accrual of bone and muscle mass while having reduced effects on reproductive organs and sebaceous glands. Moreover, TFM-4AS-1 does not promote prostate growth and antagonizes DHT in seminal vesicles. To confirm that the biochemical properties of TFM-4AS-1 confer tissue selectivity, we identified a structurally unrelated compound, FTBU-1, with partial agonist activity coupled with antagonism of the N-terminal/C-terminal interaction and found that it also behaves as a SARM. TFM-4AS-1 and FTBU-1 represent two new classes of SARMs and will allow for comparative studies aimed at understanding the biophysical and physiological basis of tissue-selective effects of nuclear receptor ligands.

  7. Evidence that UGA is read as a tryptophan codon rather than as a stop codon by Mycoplasma pneumoniae, Mycoplasma genitalium, and Mycoplasma gallisepticum.

    OpenAIRE

    Inamine, J M; K C Ho; Loechel, S; Hu, P C

    1990-01-01

    Molecular cloning and sequencing showed that Mycoplasma gallisepticum, like Mycoplasma capricolum, contains both tRNA(UCA) and tRNA(CCA) genes, while Mycoplasma pneumoniae and Mycoplasma genitalium each appear to have only a tRNA(UCA) gene. Therefore, these mycoplasma species contain a tRNA with the anticodon UCA that can translate both UGA and UGG codons.

  8. Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells.

    Science.gov (United States)

    Johansson, Maria A; Björkander, Sophia; Mata Forsberg, Manuel; Qazi, Khaleda Rahman; Salvany Celades, Maria; Bittmann, Julia; Eberl, Matthias; Sverremark-Ekström, Eva

    2016-01-01

    Lactobacilli are probiotic commensal bacteria and potent modulators of immunity. When present in the gut or supplemented as probiotics, they beneficially modulate ex vivo immune responsiveness. Further, factors derived from several lactobacilli strains act immune regulatory in vitro. In contrast, Staphylococcus aureus (S. aureus) is known to induce excessive T cell activation. In this study, we aimed to investigate S. aureus-induced activation of human mucosal-associated invariant T cells (MAIT cells), γδ T cells, NK cells, as well as of conventional CD4(+) and CD8(+) T cells in vitro. Further, we investigated if lactobacilli-derived factors could modulate their activation. PBMC were cultured with S. aureus 161:2 cell-free supernatants (CFS), staphylococcal enterotoxin A or CD3/CD28-beads alone, or in combination with Lactobacillus rhamnosus GG-CFS or Lactobacillus reuteri DSM 17938-CFS and activation of T and NK cells was evaluated. S. aureus-CFS induced IFN-γ and CD107a expression as well as proliferation. Costimulation with lactobacilli-CFS dampened lymphocyte-activation in all cell types analyzed. Preincubation with lactobacilli-CFS was enough to reduce subsequent activation, and the absence of APC or APC-derived IL-10 did not prevent lactobacilli-mediated dampening. Finally, lactate selectively dampened activation of unconventional T cells and NK cells. In summary, we show that molecules present in the lactobacilli-CFS are able to directly dampen in vitro activation of conventional and unconventional T cells and of NK cells. This study provides novel insights on the immune-modulatory nature of probiotic lactobacilli and suggests a role for lactobacilli in the modulation of induced T and NK cell activation.

  9. Tonic activation of peripheral chemosensory function modulates vagal heart rate control in heart failure patients with paroxysmal atrialfibrillation

    NARCIS (Netherlands)

    Drexel, T.; Eickholt, C.; Muehlsteff, J.; Ritz, A.; Siekiera, M.; Kirmanoglou, K.; Shin, D.I.; Balzer, J.; Rassaf, T.; Kelm, M.; Meyer, C.

    2012-01-01

    Tonic activation of peripheral chemosensory function modulates vagalheart rate control in heart failure patients with paroxysmal atrialfibrillation Thomas Drexel1, Christian Eickholt1, Jens Mühlsteff2,Anita Ritz1, Markus Siekiera1, Kiriakos Kirmanoglou1, Dong-In Shin1,Jan Balzer1, Tienush Rassaf1, M

  10. Modulation of Posterior Alpha Activity by Spatial Attention Allows for Controlling A Continuous Brain-Computer Interface

    NARCIS (Netherlands)

    Horschig, J.M.; Oosterheert, W.; Oostenveld, R.; Jensen, O.

    2014-01-01

    Here we report that the modulation of alpha activity by covert attention can be used as a control signal in an online brain-computer interface, that it is reliable, and that it is robust. Subjects were instructed to orient covert visual attention to the left or right hemifield. We decoded the direct

  11. Two dimensional distribution of tritium breeding ratio and induced activity in Japanese water cooled and helium cooled test blanket modules

    International Nuclear Information System (INIS)

    Solid breeder blankets are regarded as a near-at-hand blanket concept for a fusion power demonstration plant in Japan. Test blanket module (TBM) to be tested in ITER is the most important milestone to establish the fusion demonstration blanket. For the candidate TBM's, two types of TBM, water cooled solid breeder TBM, and a helium gas cooled solid breeder TBM have been proposed and designed in JAERI. For detailed performance study under operation and after shut down, detailed neutronics analysis gives the most important design conditions, such as, distribution of tritium breeding ratio, nuclear heating rate during operation, and induced activation and decay heat after termination of irradiation. In the analysis, neutron and gamma transportation was calculated by two dimensional analysis code, DOT3.5, for two TBMs. Nuclear reaction rate and induced activation rate were evaluated by APPLE-3 and ACT-4, respectively. The analysis model included configurations of thermo-mechanical test modules and surrounding common frames for both of He cooled and water cooled TBMs. By the neutronics analysis, TBR and contact dose rate by induced activation till one year after termination of the module testing have been evaluated. For the evaluation of induced activation level change and decay heat change, the transient decreases in one year after termination of the module testing have been calculated. The time duration of the module testing before termination of testing is assumed to be 133 continuous days of full power operation. The result of TBR analysis showed that TBR distribution in the toroidal direction of TBM is not significant, however, the neutron flux decreases in the region of sidewall of common frame made of SS and water. This result shows that there is relatively large neutron loss from the TBM to the common frame. Thus, it is considered that the TBR value observed in the TBM testing may be smaller than the estimation by one dimensional neutronics analysis which does

  12. Do anticodons of misacylated tRNAs preferentially mismatch codons coding for the misloaded amino acid?

    Directory of Open Access Journals (Sweden)

    Seligmann Hervé

    2010-05-01

    Full Text Available Abstract Background Accurate amino acid insertion during peptide elongation requires tRNAs loaded by cognate amino acids and that anticodons match codons. However, tRNA misloading does not necessarily cause misinsertions: misinsertion is avoided when anticodons mismatch codons coding for misloaded amino acids. Presentation of the hypothesis Occasional compensation of misacylation by codon-anticodon mismatch necessarily occurs. Putatively, occasional error compensation may be enhanced beyond the random combination of independent errors in tRNA loading and codon-anticodon interactions: tRNA misacylation might alter potentials for codon-anticodon mismatches, perhaps specifically increasing potentials for mismatching those codons coding for the misacylated non-cognate amino acid. This hypothetical phenomenon is called 'error coordination', in distinction from 'error compensation' that assumes independence between misacylation and mismatch. Testing the hypothesis Eventually, the hypothesis should be tested for each combination of amino acid misacylation and codon-anticodon mismatch, by comparing stabilities or frequencies of mismatched codon-anticodon duplexes formed by tRNAs loaded by their cognate amino acid with stabilities formed by that tRNA when misloaded with the amino acid coded by the mismatched codon. Competitive mismatching experiments between misloaded and correctly loaded tRNAs could also be useful, yet more sophisticated experiments. Implications of the hypothesis Detecting error coordination implies estimating error compensation, which also promotes protein synthesis accuracy. Hence even in the absence of evidence for error coordination, experiments would yield very useful insights into misacylation and mismatch processes. In case experiments consider post-transcriptional RNA modifications (especially at wobble positions, results on codon-anticodon mismatches would enable significant improvements and sophistications of secondary

  13. CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Lau, Wen Min; Doucet, Michele; Huang, David; Weber, Kristy L.; Kominsky, Scott L., E-mail: kominsc@jhmi.edu

    2013-07-26

    Highlights: •The effects of elevated CITED2 on ER function in breast cancer cells are examined. •CITED2 enhances cell growth in the absence of estrogen and presence of tamoxifen. •CITED2 functions as a transcriptional co-activator of ER in breast cancer cells. -- Abstract: Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) is a member of the CITED family of non-DNA binding transcriptional co-activators of the p300/CBP-mediated transcription complex. Previously, we identified CITED2 as being overexpressed in human breast tumors relative to normal mammary epithelium. Upon further investigation within the estrogen receptor (ER)-positive subset of these breast tumor samples, we found that CITED2 mRNA expression was elevated in those associated with poor survival. In light of this observation, we investigated the effect of elevated CITED2 levels on ER function. While ectopic overexpression of CITED2 in three ER-positive breast cancer cell lines (MCF-7, T47D, and CAMA-1) did not alter cell proliferation in complete media, growth was markedly enhanced in the absence of exogenous estrogen. Correspondingly, cells overexpressing CITED2 demonstrated reduced sensitivity to the growth inhibitory effects of the selective estrogen receptor modulator, 4-hydroxytamoxifen. Subsequent studies revealed that basal ER transcriptional activity was elevated in CITED2-overexpressing cells and was further increased upon the addition of estrogen. Similarly, basal and estrogen-induced expression of the ER-regulated genes trefoil factor 1 (TFF1) and progesterone receptor (PGR) was higher in cells overexpressing CITED2. Concordant with this observation, ChIP analysis revealed higher basal levels of CITED2 localized to the TFF-1 and PGR promoters in cells with ectopic overexpression of CITED2, and these levels were elevated further in response to estrogen stimulation. Taken together, these data indicate that CITED2 functions as a transcriptional co-activator

  14. Scorpion venom component III inhibits cell proliferation by modulating NF-κB activation in human leukemia cells

    OpenAIRE

    SONG, XIANGFENG; Zhang, Guojun; SUN, AIPING; Guo, Jiqiang; TIAN, ZHONGWEI; Wang, Hui; Liu, Yufeng

    2012-01-01

    Scorpion venom contains various groups of compounds that exhibit anticancer activity against a variety of malignancies through a poorly understood mechanism. While the aberrant activation of nuclear factor κB (NF-κB) has been linked with hematopoietic malignancies, we hypothesized that scorpion venom mediates its effects by modulating the NF-κB signaling pathway. In the present study, we examined the effects of scorpion venom component III (SVCIII) on the human leukemia cell lines THP-1 and J...

  15. Planning Educational Activities and Teaching Strategies on Constructing a Conservation Educational Module

    Science.gov (United States)

    Dimopoulos, Dimitrios I.; Paraskevopoulos, Stefanos; Pantis, John D.

    2009-01-01

    This paper describes the design of an educational module which aims to raise awareness and change the attitudes of elementary school students about focal endangered species in protected areas. The proposed design builds on, and extends the General Teaching Model. The educational module which was developed through this approach was pilot-tested in…

  16. Balancing bilateral sensory activity: callosal processing modulates sensory transmission through the contralateral thalamus by altering the response threshold.

    Science.gov (United States)

    Li, Lu; Ebner, Ford F

    2006-07-01

    Rats tactually explore a nearly spherical space field around their heads with their whiskers. The information sampled by the two sets of whiskers is integrated bilaterally at the cortical level in an activity dependent manner via the corpus callosum. We have recently shown that sensory activity in one barrel field cortex (BFC) modulates the processing of incoming sensory information to the other BFC. Whether interhemispheric integration is dynamically linked with corticothalamic modulation of incoming sensory activity is an important hypothesis to test, since subcortical relay neurons are directly modulated by cortical neurons through top-down processes. In the present study, we compared the direct sensory responses of single thalamic relay neurons under urethane anesthesia before and after inactivating the BFC contralateral to a thalamic neuron. The data show that silencing one BFC reduces response magnitude in contralateral thalamic relay neurons, significantly and reversibly, in response to test stimuli applied to the principal whisker at two times response threshold (2T) intensity for each unit. Neurons in the ventral posterior medial (VPM) nucleus and the medial division of the posterior nucleus (POm) react in a similar manner, although POm neurons are more profoundly depressed by inactivation of the contralateral BFC than VPM neurons. The results support the novel idea that the subcortical relay of sensory information to one hemisphere is strongly modulated by activity levels in the contralateral as well as in the ipsilateral SI cortex. The mechanism of the modulation appears to be based on shifting the stimulus-response curves of thalamic neurons, thereby rendering them more or less sensitive to sensory stimuli. We conclude that global sensory processing is created by combining activity in each cerebral hemisphere and continually balancing the flow of information to cortex by adjusting the responsiveness of ascending sensory pathways.

  17. Modulation of activity of the adipocyte aquaglyceroporin channel by plant extracts.

    Science.gov (United States)

    Cals-Grierson, M-M

    2007-02-01

    The plasma membrane protein, aquaglyceroporin-7 (AQP7) is exclusively expressed in adipocytes and appears to be a channel for glycerol entry and exit. It is possible that by facilitating the opening of these channels, the loss of intracellular glycerol could be encouraged and thus reduce the size of the lipid reservoir. Human preadipocytes and mouse 3T3-L1 preadipocytes were induced to develop an adipocytic phenotype by culture in a semi-defined medium. After 7 days, the expression of AQP7 message had increased by 37-fold, a level which could be further up-regulated by troglitazone or retinoic acid or down-regulated by insulin. The mature adipocytes also expressed immunoreactive aquaporin (AQP) channel protein as assessed by immunocytochemistry and Western blot. The addition of adrenaline to the culture medium stimulated the release of glycerol (blockable by HgCl(2)). Plant extracts, with potential anti-cellulite properties, were tested for their effect on glycerol elimination. These included wild yam root (Dioscorea opposita), cocoa bean (Theobroma cacao), horse chestnut tree (Aesculus hippocastanum) seed and bark and tomato (Solanum lycopersicum). Of these, D. opposita appeared to induce a dose-dependent glycerol release. The results show that our assay can help to identify modulators of AQP7 channel expression and activation in adipocytes. PMID:18489306

  18. Modulation of Irisin and Physical Activity on Executive Functions in Obesity and Morbid obesity.

    Science.gov (United States)

    Fagundo, A B; Jiménez-Murcia, S; Giner-Bartolomé, C; Agüera, Z; Sauchelli, S; Pardo, M; Crujeiras, A B; Granero, R; Baños, R; Botella, C; de la Torre, R; Fernández-Real, J M; Fernández-García, J C; Frühbeck, G; Rodríguez, A; Mallorquí-Bagué, N; Tárrega, S; Tinahones, F J; Rodriguez, R; Ortega, F; Menchón, J M; Casanueva, F F; Fernández-Aranda, F

    2016-01-01

    Whether the executive profile is different between obesity (OB) and morbid obesity (MO) remains unclear. Recent evidence suggests that physical activity (PA) can act as a cognitive enhancer. Irisin is a recently discovered hormone associated with some of the positive effects of PA. The objective of the study was to investigate the executive profile in OB and MO, and to explore the role of PA and irisin. 114 participants were included (21 OB, 44 MO and 49 healthy controls-HC) in the study and assessed with the Wisconsin Card Sorting Test, Stroop Color and Word Test, and Iowa Gambling Task. All participants were female, aged between 18 and 60 years. Results showed a similar dysfunctional profile on decision making in OB and MO compared with HC. Thus, no specific neuropsychological profiles between OB and MO can be clearly observed in our sample. However, a negative correlation was found between irisin and executive functioning. These results demonstrate a specific executive profile in OB and a relevant and negative modulation of irisin on executive functioning. Although irisin might be a promising target for the treatment of obesity, its effects on cognition might be considered when thinking about its therapeutic use. PMID:27476477

  19. Event-related power modulations of brain activity preceding visually guided saccades.

    Science.gov (United States)

    Brignani, Debora; Maioli, Claudio; Maria Rossini, Paolo; Miniussi, Carlo

    2007-03-01

    To analyze the characteristics of the event-related desynchronization (ERD) and synchronization (ERS) of cortical rhythms during the preparation and execution of a lateralized eye movement, EEG was recorded in normal subjects during a visually guided task. Alpha and beta bands were investigated in three temporal intervals: a sensory period, a delay period and a saccade preparation period time locked with saccade onset. Modulations of ERD/ERS power, coupled with the task, reached the largest amplitudes over the frontal and parieto-occipital regions. Differences of oscillatory activity in the alpha bands revealed an intriguing pattern of asymmetry in parieto-occipital areas. Rightward saccades induced a larger desynchronization with respect to the leftward saccades in the left hemisphere, but not in the right. If representative, these findings are congruent to the established right-hemisphere dominance of the brain areas that direct attention. Moreover differences between the two alpha types emerged in the frontal areas before and during the saccade preparation periods, indicative of differential engagement of these areas depending on the task demands. In conclusion, the present approach shows that planning eye movements is linked with covert orienting of spatial attention and may supply a useful method for studying eye movements and selective attention-related processes. PMID:17196943

  20. Effect of modulated photo-activation on polymerization shrinkage behavior of dental restorative resin composites.

    Science.gov (United States)

    Tauböck, Tobias T; Feilzer, Albert J; Buchalla, Wolfgang; Kleverlaan, Cornelis J; Krejci, Ivo; Attin, Thomas

    2014-08-01

    This study investigated the influence of modulated photo-activation on axial polymerization shrinkage, shrinkage force, and hardening of light- and dual-curing resin-based composites. Three light-curing resin composites (SDR bulk-fill, Esthet X flow, and Esthet X HD) and one dual-curing material (Rebilda DC) were subjected to different irradiation protocols with identical energy density (27 J cm(-2) ): high-intensity continuous light (HIC), low-intensity continuous light (LIC), soft-start (SS), and pulse-delay curing (PD). Axial shrinkage and shrinkage force of 1.5-mm-thick specimens were recorded in real time for 15 min using custom-made devices. Knoop hardness was determined at the end of the observation period. Statistical analysis revealed no significant differences among the curing protocols for both Knoop hardness and axial shrinkage, irrespective of the composite material. Pulse-delay curing generated the significantly lowest shrinkage forces within the three light-curing materials SDR bulk-fill, Esthet X flow, and Esthet X HD. High-intensity continuous light created the significantly highest shrinkage forces within Esthet X HD and Rebilda DC, and caused significantly higher forces than LIC within Esthet X flow. In conclusion, both the composite material and the applied curing protocol control shrinkage force formation. Pulse-delay curing decreases shrinkage forces compared with high-intensity continuous irradiation without affecting hardening and axial polymerization shrinkage.

  1. Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production.

    Science.gov (United States)

    Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng; Lomberk, Gwen A; Zhou, Zhou; Sun, Lijie; Mathison, Angela J; Garcia-Barrio, Minerva T; Zhang, Ji; Zeng, Lixia; Li, Lei; Pennathur, Subramaniam; Willer, Cristen J; Rader, Daniel J; Urrutia, Raul; Chen, Y Eugene

    2015-10-01

    Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Krüppel-like factor 14 (KLF14) are strongly associated with HDL cholesterol (HDL-C) levels, metabolic syndrome, and coronary heart disease. However, the precise mechanisms by which KLF14 regulates lipid metabolism and affects atherosclerosis remain largely unexplored. Here, we report that KLF14 is dysregulated in the liver of 2 dyslipidemia mouse models. We evaluated the effects of both KLF14 overexpression and genetic inactivation and determined that KLF14 regulates plasma HDL-C levels and cholesterol efflux capacity by modulating hepatic ApoA-I production. Hepatic-specific Klf14 deletion in mice resulted in decreased circulating HDL-C levels. In an attempt to pharmacologically target KLF14 as an experimental therapeutic approach, we identified perhexiline, an approved therapeutic small molecule presently in clinical use to treat angina and heart failure, as a KLF14 activator. Indeed, in WT mice, treatment with perhexiline increased HDL-C levels and cholesterol efflux capacity via KLF14-mediated upregulation of ApoA-I expression. Moreover, perhexiline administration reduced atherosclerotic lesion development in apolipoprotein E-deficient mice. Together, these results provide comprehensive insight into the KLF14-dependent regulation of HDL-C and subsequent atherosclerosis and indicate that interventions that target the KLF14 pathway should be further explored for the treatment of atherosclerosis. PMID:26368306

  2. Modulation of NADPH oxidase activation in cerebral ischemia/reperfusion injury in rats.

    Science.gov (United States)

    Genovese, Tiziana; Mazzon, Emanuela; Paterniti, Irene; Esposito, Emanuela; Bramanti, Placido; Cuzzocrea, Salvatore

    2011-02-01

    NADPH oxidase is a major complex that produces reactive oxygen species (ROSs) during the ischemic period and aggravates brain damage and cell death after ischemic injury. Although many approaches have been tested for preventing production of ROSs by NADPH oxidase in ischemic brain injury, the regulatory mechanisms of NADPH oxidase activity after cerebral ischemia are still unclear. The aim of this study is identifying apocynin as a critical modulator of NADPH oxidase and elucidating its role as a neuroprotectant in an experimental model of brain ischemia in rat. Treatment of apocynin 5min before of reperfusion attenuated cerebral ischemia in rats. Administration of apocynin showed marked reduction in infarct size compared with that of control rats. Medial carotid artery occlusion (MCAo)-induced cerebral ischemia was also associated with an increase in, nitrotyrosine formation, as well as IL-1β expression, IκB degradation and ICAM expression in ischemic regions. These expressions were markedly inhibited by the treatment of apocynin. We also demonstrated that apocynin reduces levels of apoptosis (TUNEL, Bax and Bcl-2 expression) resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. This new understanding of apocynin induced adaptation to ischemic stress and inflammation could suggest novel avenues for clinical intervention during ischemic and inflammatory diseases. PMID:21138737

  3. Modulating Composition and Metabolic Activity of the Gut Microbiota in IBD Patients

    Directory of Open Access Journals (Sweden)

    Mario Matijašić

    2016-04-01

    Full Text Available The healthy intestine represents a remarkable interface where sterile host tissues come in contact with gut microbiota, in a balanced state of homeostasis. The imbalance of gut homeostasis is associated with the onset of many severe pathological conditions, such as inflammatory bowel disease (IBD, a chronic gastrointestinal disorder increasing in incidence and severely influencing affected individuals. Despite the recent development of next generation sequencing and bioinformatics, the current scientific knowledge of specific triggers and diagnostic markers to improve interventional approaches in IBD is still scarce. In this review we present and discuss currently available and emerging therapeutic options in modulating composition and metabolic activity of gut microbiota in patients affected by IBD. Therapeutic approaches at the microbiota level, such as dietary interventions alone or with probiotics, prebiotics and synbiotics, administration of antibiotics, performing fecal microbiota transplantation (FMT and the use of nematodes, all represent a promising opportunities towards establishing and maintaining of well-being as well as improving underlying IBD symptoms.

  4. Advantages of a mechanistic codon substitution model for evolutionary analysis of protein-coding sequences.

    Directory of Open Access Journals (Sweden)

    Sanzo Miyazawa

    Full Text Available BACKGROUND: A mechanistic codon substitution model, in which each codon substitution rate is proportional to the product of a codon mutation rate and the average fixation probability depending on the type of amino acid replacement, has advantages over nucleotide, amino acid, and empirical codon substitution models in evolutionary analysis of protein-coding sequences. It can approximate a wide range of codon substitution processes. If no selection pressure on amino acids is taken into account, it will become equivalent to a nucleotide substitution model. If mutation rates are assumed not to depend on the codon type, then it will become essentially equivalent to an amino acid substitution model. Mutation at the nucleotide level and selection at the amino acid level can be separately evaluated. RESULTS: The present scheme for single nucleotide mutations is equivalent to the general time-reversible model, but multiple nucleotide changes in infinitesimal time are allowed. Selective constraints on the respective types of amino acid replacements are tailored to each gene in a linear function of a given estimate of selective constraints. Their good estimates are those calculated by maximizing the respective likelihoods of empirical amino acid or codon substitution frequency matrices. Akaike and Bayesian information criteria indicate that the present model performs far better than the other substitution models for all five phylogenetic trees of highly-divergent to highly-homologous sequences of chloroplast, mitochondrial, and nuclear genes. It is also shown that multiple nucleotide changes in infinitesimal time are significant in long branches, although they may be caused by compensatory substitutions or other mechanisms. The variation of selective constraint over sites fits the datasets significantly better than variable mutation rates, except for 10 slow-evolving nuclear genes of 10 mammals. An critical finding for phylogenetic analysis is that

  5. Complete mitochondrial genome and codon usage of the Nepalese whiskered bat Myotis muricola (Vespertilionidae).

    Science.gov (United States)

    Yoon, K B; Park, Y C

    2015-01-01

    We sequenced and characterized the complete mitogenome of the Nepalese whiskered bat Myotis muricola (Vespertilionidae) to provide more data for comparative mitogenomics and codon usage in the genus Myotis (Vespertilionidae). The mitogenome of M. muricola is a circular molecule of 17,224 bp, consisting of a control region and a conserved set of 37 genes containing 13 protein-coding genes (PCGs), 22 tRNA genes, and two rRNA genes (12S rRNA and 16S rRNA). The mitogenome of M. muricola is AT-biased, with a nucleotide composition of 33.6% A, 29.7% T, 23.3% C, and 13.4% G. The total length of the 13 mitochondrial PCGs, excluding stop codons, is 11,376 bp, or 3792 amino acids. The relative synonymous codon usage (RSCU) of codons ending in A/T was generally higher than that for codons ending in G/C. The most frequently used codons are CTA(Leu) and CGA(Arg), with RSCU values greater than 2.0. The most rarely used codons, all terminating in G, are TCG(Ser), CCG(Pro), GCG(Ala), AAG(Lys), TGG(Try), CGG(Arg), and ACG(Thr), with RSCU values below 0.2. TCG(Ser) occurs only five times, and has the lowest RSCU value (0.091). These results are valuable for a better understanding of the molecular evolution of mitogenomes in the genus Myotis. PMID:26600523

  6. Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans.

    Science.gov (United States)

    Rabinak, Christine A; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R; Liberzon, Israel; Phan, K Luan

    2014-09-01

    Pre-extinction administration of Δ9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely occurs via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24 h after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders. PMID:24055595

  7. Quasi-biennial modulation of solar neutrino flux: connections with solar activity

    Science.gov (United States)

    Vecchio, A.; Laurenza, M.; D'alessi, L.; Carbone, V.; Storini, M.

    2011-12-01

    A quasi-biennial periodicity has been recently found (Vecchio et al., 2010) in the solar neutrino flux, as detected at the Homestake experiment, as well as in the flux of solar energetic protons, by means of the Empirical Modes Decomposition technique. Moreover, both fluxes have been found to be significantly correlated at the quasi-biennial timescale, thus supporting the hypothesis of a connection between solar neutrinos and solar activity. The origin of this connection is investigated, by modeling how the standard Mikheyev-Smirnov-Wolfenstein (MSW) effect (the process for which the well-known neutrino flavor oscillations are modified in passing through the material) could be influenced by matter fluctuations. As proposed by Burgess et al., 2004, by introducing a background magnetic field in the helioseismic model, density fluctuations can be excited in the radiative zone by the resonance between helioseismic g-modes and Alfvén waves. In particular, with reasonable values of the background magnetic field (10-100 kG), the distance between resonant layers could be of the same order of neutrino oscillation length. We study the effect over this distance of a background magnetic field which is variable with a ~2 yr period, in agreement with typical variations of solar activity. Our findings suggest that the quasi-biennial modulation of the neutrino flux is theoretically possible as a consequence of the magnetic field variations in the solar interior. A. Vecchio, M. Laurenza, V. Carbone, M. Storini, The Astrophysical Journal Letters, 709, L1-L5 (2010). C. Burgess, N. S. Dzhalilov, T. I. Rashba, V., B.Semikoz, J. W. F. Valle, Mon. Not. R. Astron. Soc., 348, 609-624 (2004).

  8. Learning to modulate one's own brain activity: The effect of spontaneous mental strategies

    Directory of Open Access Journals (Sweden)

    Silvia Erika Kober

    2013-10-01

    Full Text Available Using neurofeedback (NF, individuals can learn to modulate their own brain activity, in most cases electroencephalographic (EEG rhythms. Although a large body of literature reports positive effects of NF training on behavior and cognitive functions, there are hardly any reports on how participants can successfully learn to gain control over their own brain activity. About one third of people fail to gain significant control over their brain signals even after repeated training sessions. The reasons for this failure are still largely unknown. In this context, we investigated the effects of spontaneous mental strategies on NF performance. Twenty healthy participants performed either a SMR (sensorimotor rhythm, 12-15 Hz based or a Gamma (40-43 Hz based NF training over ten sessions. After the first and the last training session, they were asked to write down which mental strategy they have used for self-regulating their EEG. After the first session, all participants reported the use of various types of mental strategies such as visual strategies, concentration, or relaxation. After the last NF training session, four participants of the SMR group reported to employ no specific strategy. These four participants showed linear improvements in NF performance over the ten training sessions. In contrast, participants still reporting the use of specific mental strategies in the last NF session showed no changes in SMR based NF performance over the ten sessions. This effect could not be observed in the Gamma group. The Gamma group showed no prominent changes in Gamma power over the NF training sessions, regardless of the mental strategies used. These results indicate that successful SMR based NF performance is associated with implicit learning mechanisms. Participants stating vivid reports on strategies to control their SMR probably overload cognitive resources, which might be counterproductive in terms of increasing SMR power.

  9. Codon Optimization Significantly Improves the Expression Level of α-Amylase Gene from Bacillus licheniformis in Pichia pastoris

    Directory of Open Access Journals (Sweden)

    Jian-Rong Wang

    2015-01-01

    Full Text Available α-Amylase as an important industrial enzyme has been widely used in starch processing, detergent, and paper industries. To improve expression efficiency of recombinant α-amylase from Bacillus licheniformis (B. licheniformis, the α-amylase gene from B. licheniformis was optimized according to the codon usage of Pichia pastoris (P. pastoris and expressed in P. pastoris. Totally, the codons encoding 305 amino acids were optimized in which a total of 328 nucleotides were changed and the G+C content was increased from 47.6 to 49.2%. The recombinants were cultured in 96-deep-well microplates and screened by a new plate assay method. Compared with the wild-type gene, the optimized gene is expressed at a significantly higher level in P. pastoris after methanol induction for 168 h in 5- and 50-L bioreactor with the maximum activity of 8100 and 11000 U/mL, which was 2.31- and 2.62-fold higher than that by wild-type gene. The improved expression level makes the enzyme a good candidate for α-amylase production in industrial use.

  10. Codon optimization, promoter and expression system selection that achieved high-level production of Yarrowia lipolytica lipase in Pichia pastoris.

    Science.gov (United States)

    Zhou, Wen-Jing; Yang, Jiang-Ke; Mao, Lin; Miao, Li-Hong

    2015-04-01

    Lipase (EC 3.1.1.3) stands amongst the most important and promising biocatalysts for industrial applications. In this study, in order to realize a high-level expression of the Yarrowia lipolytica lipase gene in Pichia pastoris, we optimized the codon of LIP2 by de novo gene design and synthesis, which significantly improved the lipase expression when compared to the native lip2 gene. We also comparatively analyzed the effects of the promoter types (PAOX1 and PFLD1) and the Pichia expression systems, including the newly developed PichiaPink system, on lipase production and obtained the optimal recombinants. Bench-top scale fermentation studies indicated that the recombinant carrying the codon-optimized lipase gene syn-lip under the control of promoter PAOX1 has a significantly higher lipase production capacity in the fermenter than other types of recombinants. After undergoing methanol inducible expression for 96h, the wet cell weight of Pichia, the lipase activity and the protein content in the fermentation broth reached their highest values of 262g/L, 38,500U/mL and 2.82g/L, respectively. This study has not only greatly facilitated the bioapplication of lipase in industrial fields but the strategies utilized, such as de novo gene design and synthesis, the comparative analysis among promoters and different generations of Pichia expression systems will also be useful as references for future work in this field. PMID:25765312

  11. Endogenous opiates modulate the pulsatile secretion of biologically active luteinizing hormone in man.

    Science.gov (United States)

    Veldhuis, J D; Rogol, A D; Johnson, M L

    1983-12-01

    . We infer that modulation of the episodic GNRH signal by endogenous opiates provides another significant mechanism by which the hypothalamus can alter the biological activity of circulating gonadotropic hormone in man. Moreover, observed alterations in the pulsatile pattern of bioactive LH release were associated in turn with significant changes in testosterone concentrations. Thus, we hypothesize that alterations in the properties of the bioactive LH pulse signal can provide an important mechanism for regulating target-cell function within the gonad in states of health or disease. PMID:6315775

  12. Chimeric RXFP1 and RXFP2 Receptors Highlight the Similar Mechanism of Activation Utilizing Their N-Terminal Low-Density Lipoprotein Class A Modules

    OpenAIRE

    Bruell, Shoni; Kong, Roy C. K.; Petrie, Emma J.; Hoare, Brad; John D Wade; Scott, Daniel J.; Gooley, Paul R.; Bathgate, Ross A. D.

    2013-01-01

    Relaxin family peptide (RXFP) receptors 1 and 2 are unique G-protein coupled receptors in that they contain an N-terminal low-density lipoprotein type A (LDLa) module which is necessary for receptor activation. The current hypothesis suggests that upon ligand binding the LDLa module interacts with the transmembrane (TM) domain of a homodimer partner receptor to induce the active receptor conformations. We recently demonstrated that three residues in the N-terminus of the RXFP1 LDLa module are...

  13. Chimeric RXFP1 and RXFP2 receptors highlight the similar mechanism of activation utilizing their N-terminal low density lipoprotein class A modules

    OpenAIRE

    RossBathgate; EmmaJunePetrie; JohnDWade

    2013-01-01

    Relaxin family peptide (RXFP) receptors 1 and 2 are unique G-protein coupled receptors in that they contain an N-terminal low density lipoprotein type A (LDLa) module which is necessary for receptor activation. The current hypothesis suggests that upon ligand binding the LDLa module interacts with the transmembrane (TM) domain of a homodimer partner receptor to induce the active receptor conformations. We recently demonstrated that three residues in the N-terminus of the RXFP1 LDLa module are...

  14. Alternative Start Codon Connects eIF5A to Mitochondria.

    Science.gov (United States)

    Pereira, Karina Danielle; Tamborlin, Letícia; Meneguello, Letícia; de Proença, André Ricardo Gomes; Almeida, Isadora Cristina de Paula Andrade; Lourenço, Rogério Ferreira; Luchessi, Augusto Ducati

    2016-12-01

    Eukaryotic translation initiation factor 5A (eIF5A), a protein containing the amino acid residue hypusine required for its activity, is involved in a number of physiological and pathological cellular processes. In humans, several EIF5A1 transcript variants encode the canonical eIF5A1 isoform B, whereas the hitherto uncharacterized variant A is expected to code for a hypothetical eIF5A1 isoform, referred to as isoform A, which has an additional N-terminal extension. Herein, we validate the existence of eIF5A1 isoform A and its production from transcript variant A. In fact, variant A was shown to encode both eIF5A1 isoforms A and B. Mutagenic assays revealed different efficiencies in the start codons present in variant A, contributing to the production of isoform B at higher levels than isoform A. Immunoblotting and mass spectrometric analyses showed that isoform A can undergo hypusination and acetylation at specific lysine residues, as observed for isoform B. Examination of the N-terminal extension suggested that it might confer mitochondrial targeting. Correspondingly, we found that isoform A, but not isoform B, co-purified with mitochondria when the proteins were overproduced. These findings suggest that eIF5A1 isoform A has a role in mitochondrial function. J. Cell. Physiol. 231: 2682-2689, 2016. © 2016 Wiley Periodicals, Inc. PMID:27414022

  15. Modulation of Exciton Generation in Organic Active Planar pn Heterojunction: Toward Low Driving Voltage and High-Efficiency OLEDs Employing Conventional and Thermally Activated Delayed Fluorescent Emitters.

    Science.gov (United States)

    Chen, Dongcheng; Liu, Kunkun; Gan, Lin; Liu, Ming; Gao, Kuo; Xie, Gaozhan; Ma, Yuguang; Cao, Yong; Su, Shi-Jian

    2016-08-01

    Organic light-emitting diodes (OLEDs) combining low driving voltage and high efficiency are designed by employing conventional and thermally activated delayed fluorescence emitters through modulation of excitons generated at the planar p-n heterojunction region. To date, this approach enables the highest power efficiency for yellow-green emitting fluorescent OLEDs with a simplified structure.

  16. Mass spectrometry reveals thioredoxin-1 as a new partner of ADAM17 that can modulate its sheddase activity

    Energy Technology Data Exchange (ETDEWEB)

    Aragao, A.Z.B.; Simabuco, F.M.; Smetana, J.H.C. [Laboratorio Nacional de Biociencias - LNBIO, Campinas, SP (Brazil); Yokoo, S.; Paes Leme, A.F. [Laboratorio Nacional de Luz Sincrotron (LNLS), Campinas, SP (Brazil); Rodrigues, E.; Mercadante, A.Z. [Universidade Estadual de Campinas (UNICAMP), SP (Brazil)

    2012-07-01

    Full text: ADAMs are a family of membrane-associated metalloproteinases with a complex multi-domain structure: a metalloproteinase domain, a disintegrin domain, a cysteine-rich region, an epidermal growth factor-like repeat, a transmembrane domain and a cytoplasmic tail. These proteases are responsible for shedding the ectodomains of cell surface proteins, modulating regulatory mechanisms. Many ADAMs are highly associated with tumorigenesis and tumor progression. The aim of this study is identify novel binding partners that can modulate ADAM17 activation via cytoplasmatic domain. We performed the cloning and overexpression of the ADAM17 cytoplasmic tail in HEK-293 cell line and the ligands were determined by LC-MS/MS after proteins immunoprecipitation (IP) with anti-FLAG M2 Affinity Gel (Sigma). Thioredoxin-1 (Trx-1) and others ligands were identified at least in two independent experiments, and this binding is independent of phosphorylation. The IP of Trx-1 was confirmed by Western blot, furthermore Trx-1 immunolocalized with full length ADAM17-HA and cytoplasmic tail-FLAG recombinant proteins in HEK293 and HeLa cells. Trx-1 is part of the system peroxiredoxin/thioredoxin/thioredoxin reductase, one of the mechanisms by which cells maintain the reduced cellular environment, inactivating the reactive oxygen species (ROS). We investigate whether ADAM17 activity is modulate by Trx-1 on AP reporter assay that was performed using HEK293 and SCC-9 cells transfected stably with HB-EGF-AP in co-transfection with transient recombinant Trx-1-HA. The results indicate that Trx-1 can modulate negatively the activity or maturation of ADAM17 in presence of PMA, which is known to increase ROS. In summary, this study identifies Trx-1 and suggest that this protein can modulate ADAM17 activity in normal and tumorigenic cells lines. (author)

  17. Development of Active External Network Topology Module for Floodlight SDN Controller

    Directory of Open Access Journals (Sweden)

    A. A. Noskov

    2015-01-01

    Full Text Available Traditional network architecture is inflexible and complicated. This observation has led to a paradigm shift towards software-defined networking (SDN, where network management level is separated from data forwarding level. This change was made possible by control plane transfer from the switching equipment to software modules that run on a dedicated server, called the controller (or network operating system, or network applications, that work with this controller. Methods of representation, storage and communication interfaces with network topology elements are the most important aspects of network operating systems available to SDN user because performance of some key controller modules is heavily dependent on internal representation of the network topology. Notably, firewall and routing modules are examples of such modules. This article describes the methods used for presentation and storage of network topologies, as well as interface to the corresponding Floodlight modules. An alternative algorithm has been suggested and developed for message exchange conveying network topology alterations between the controller and network applications. Proposed algorithm makes implementation of module alerting based on subscription to the relevant events. API for interaction between controller and network applications has been developed. This algorithm and API formed the base for Topology Tracker module capable to inform network applications about the changes that had occurred in the network topology and also stores compact representation of the network to speed up the interaction process.

  18. Nutritional strategies to modulate inflammation and oxidative stress pathways via activation of the master antioxidant switch Nrf2.

    Science.gov (United States)

    Cardozo, Ludmila F M F; Pedruzzi, Liliana M; Stenvinkel, Peter; Stockler-Pinto, Milena B; Daleprane, Julio B; Leite, Maurilo; Mafra, Denise

    2013-08-01

    The nuclear factor E2-related factor 2 (Nrf2) plays an important role in cellular protection against cancer, renal, pulmonary, cardiovascular and neurodegenerative diseases where oxidative stress and inflammation are common conditions. The Nrf2 regulates the expression of detoxifying enzymes by recognizing the human Antioxidant Response Element (ARE) binding site and it can regulate antioxidant and anti-inflammatory cellular responses, playing an important protective role on the development of the diseases. Studies designed to investigate how effective Nrf2 activators or modulators are need to be initiated. Several recent studies have shown that nutritional compounds can modulate the activation of Nrf2-Keap1 system. This review aims to discuss some of the key nutritional compounds that promote the activation of Nrf2, which may have impact on the human health. PMID:23643732

  19. Modulation of antioxidant enzymatic activities by certain antiepileptic drugs (valproic acid, oxcarbazepine, and topiramate): evidence in humans and experimental models.

    Science.gov (United States)

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress.

  20. Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate: Evidence in Humans and Experimental Models

    Directory of Open Access Journals (Sweden)

    Noemí Cárdenas-Rodríguez

    2013-01-01

    Full Text Available It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity. This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS activation and the generation of reactive oxygen species (ROS. Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA, oxcarbazepine (OXC, and topiramate (TPM modulate oxidative stress.

  1. Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate): Evidence in Humans and Experimental Models

    Science.gov (United States)

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides III; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress. PMID:24454986

  2. Overview of results of the first phase of validation activities for the IFMIF High Flux Test Module

    Energy Technology Data Exchange (ETDEWEB)

    Arbeiter, Frederik, E-mail: frederik.arbeiter@kit.edu [Karlsruhe Institute of Technology, Karlsruhe (Germany); Chen Yuming; Dolensky, Bernhard; Freund, Jana; Heupel, Tobias; Klein, Christine; Scheel, Nicola; Schlindwein, Georg [Karlsruhe Institute of Technology, Karlsruhe (Germany)

    2012-08-15

    Highlights: Black-Right-Pointing-Pointer Validation of computational fluid dynamics (CFD) modeling approach for application in the IFMIF High Flux Test Module. Black-Right-Pointing-Pointer Fabrication of prototypes of the irradiation capsules of the IFMIF High Flux Test Module. - Abstract: The international fusion materials irradiation facility (IFMIF) is projected to create an experimentally validated database of material properties relevant for fusion reactor designs. The IFMIF High Flux Test Module is the dedicated experiment to irradiate alloys in the temperature range 250-550 Degree-Sign C and up to 50 displacements per atom per irradiation cycle. The High Flux Test Module is developed to maximize the specimen payload in the restricted irradiation volume, and to minimize the temperature spread within each specimen bundle. Low pressure helium mini-channel cooling is used to offer a high integration density. Due to the demanding thermo-hydraulic and mechanical conditions, the engineering design process (involving numerical neutronic, thermo-hydraulic and mechanical analyses) is supported by extensive experimental validation activities. This paper reports on the prototype manufacturing, thermo-hydraulic modeling experiments and component tests, as well as on mechanical testing. For the testing of the 1:1 prototype of the High Flux Test Module, a dedicated test facility, the Helium Loop Karlsruhe-Low Pressure (HELOKA-LP) has been taken into service.

  3. The Nucleosome Remodeling and Deacetylase Complex NuRD Is Built from Preformed Catalytically Active Sub-modules.

    Science.gov (United States)

    Zhang, W; Aubert, A; Gomez de Segura, J M; Karuppasamy, M; Basu, S; Murthy, A S; Diamante, A; Drury, T A; Balmer, J; Cramard, J; Watson, A A; Lando, D; Lee, S F; Palayret, M; Kloet, S L; Smits, A H; Deery, M J; Vermeulen, M; Hendrich, B; Klenerman, D; Schaffitzel, C; Berger, I; Laue, E D

    2016-07-17

    The nucleosome remodeling deacetylase (NuRD) complex is a highly conserved regulator of chromatin structure and transcription. Structural studies have shed light on this and other chromatin modifying machines, but much less is known about how they assemble and whether stable and functional sub-modules exist that retain enzymatic activity. Purification of the endogenous Drosophila NuRD complex shows that it consists of a stable core of subunits, while others, in particular the chromatin remodeler CHD4, associate transiently. To dissect the assembly and activity of NuRD, we systematically produced all possible combinations of different components using the MultiBac system, and determined their activity and biophysical properties. We carried out single-molecule imaging of CHD4 in live mouse embryonic stem cells, in the presence and absence of one of core components (MBD3), to show how the core deacetylase and chromatin-remodeling sub-modules associate in vivo. Our experiments suggest a pathway for the assembly of NuRD via preformed and active sub-modules. These retain enzymatic activity and are present in both the nucleus and the cytosol, an outcome with important implications for understanding NuRD function. PMID:27117189

  4. In vivo introduction of unpreferred synonymous codons into the Drosophila Adh gene results in reduced levels of ADH protein.

    Science.gov (United States)

    Carlini, David B; Stephan, Wolfgang

    2003-01-01

    The evolution of codon bias, the unequal usage of synonymous codons, is thought to be due to natural selection for the use of preferred codons that match the most abundant species of isoaccepting tRNA, resulting in increased translational efficiency and accuracy. We examined this hypothesis by introducing 1, 6, and 10 unpreferred codons into the Drosophila alcohol dehydrogenase gene (Adh). We observed a significant decrease in ADH protein production with number of unpreferred codons, confirming the importance of natural selection as a mechanism leading to codon bias. We then used this empirical relationship to estimate the selection coefficient (s) against unpreferred synonymous mutations and found the value (s >or= 10(-5)) to be approximately one order of magnitude greater than previous estimates from population genetics theory. The observed differences in protein production appear to be too large to be consistent with current estimates of the strength of selection on synonymous sites in D. melanogaster. PMID:12586711

  5. Genes adopt non-optimal codon usage to generate cell cycle-dependent oscillations in protein levels

    DEFF Research Database (Denmark)

    Frenkel-Morgenstern, Milana; Danon, Tamar; Christian, Thomas;

    2012-01-01

    The cell cycle is a temporal program that regulates DNA synthesis and cell division. When we compared the codon usage of cell cycle-regulated genes with that of other genes, we discovered that there is a significant preference for non-optimal codons. Moreover, genes encoding proteins that cycle at...... the protein level exhibit non-optimal codon preferences. Remarkably, cell cycle-regulated genes expressed in different phases display different codon preferences. Here, we show empirically that transfer RNA (tRNA) expression is indeed highest in the G2 phase of the cell cycle, consistent with the non......-optimal codon usage of genes expressed at this time, and lowest toward the end of G1, reflecting the optimal codon usage of G1 genes. Accordingly, protein levels of human glycyl-, threonyl-, and glutamyl-prolyl tRNA synthetases were found to oscillate, peaking in G2/M phase. In light of our findings, we propose...

  6. The preferential codon usages in variable and constant regions of immunoglobulin genes are quite distinct from each other.

    Science.gov (United States)

    Miyata, T; Hayashida, H; Yasunaga, T; Hasegawa, M

    1979-12-20

    The pattern of codon utilization in the variable and constant regions of immunoglobulin genes are compared. It is shown that, in these regions, codon utilizations are quite distinct from one another: For most degenerate codons, there is a selective bias that prefers C and/or G ending codons to U and/or A ending codons in the constant region compared with the bias in the variable region. This would strongly suggest that, in immunoglobulin genes, the bias in code word usage is determined by other factors than those concerning with the translational mechanism such as tRNA availability and codon-anticodon interaction. A possibility is also suggested that this differance of code word usage between them is due to the existence of secondary structure in the constant region but not in the variable region.

  7. All-trans retinoic acid modulates mitogen-activated protein kinase pathway activation in human scleral fibroblasts through retinoic acid receptor beta

    OpenAIRE

    Huo, Lijun; Cui, Dongmei; Yang, Xiao; Gao, Zhenya; Trier, Klaus; Zeng, Junwen

    2013-01-01

    Purpose All-trans retinoic acid (ATRA) is known to inhibit the proliferation of human scleral fibroblasts (HSFs) and to modulate the scleral intercellular matrix composition, and may therefore serve as a mediator for controlling eye growth. Cell proliferation is regulated by the mitogen-activated protein kinase (MAPK) pathway. The aim of the current study was to investigate whether changed activation of the MAPK pathway could be involved in the response of HSFs exposed to ATRA. Methods HSFs w...

  8. Lithium ions in nanomolar concentration modulate glycine-activated chloride current in rat hippocampal neurons.

    Science.gov (United States)

    Solntseva, E I; Bukanova, J V; Kondratenko, R V; Skrebitsky, V G

    2016-03-01

    Lithium salts are successfully used to treat bipolar disorder. At the same time, according to recent data lithium may be considered as a candidate medication for the treatment of neurodegenerative disorders. The mechanisms of therapeutic action of lithium have not been fully elucidated. In particular, in the literature there are no data on the effect of lithium on the glycine receptors. In the present study we investigated the effect of Li(+) on glycine-activated chloride current (IGly) in rat isolated pyramidal hippocampal neurons using patch-clamp technique. The effects of Li(+) were studied with two glycine concentrations: 100 μM (EC50) and 500 μM (nearly saturating). Li(+) was applied to the cell in two ways: first, by 600 ms co-application with glycine through micropipette (short application), and, second, by addition to an extracellular perfusate for 10 min (longer application). Li(+) was used in the range of concentrations of 1 nM-1 mM. Short application of Li(+) caused two effects: (1) an acceleration of desensitization (a decrease in the time of half-decay, or "τ") of IGly induced by both 100 μM and 500 μM glycine, and (2) a reduction of the peak amplitude of the IGly, induced by 100 μM, but not by 500 μM glycine. Both effects were not voltage-dependent. Dose-response curves for both effects were N-shaped with two maximums at 100 nM and 1 mM of Li(+) and a minimum at 1 μM of Li(+). This complex form of dose-response may indicate that the process activated by high concentrations of lithium inhibits the process that is sensitive to low concentrations of lithium. Longer application of Li(+)caused similar effects, but in this case 1 μM lithium was effective and the dose-effect curves were not N-shaped. The inhibitory effect of lithium ions on glycine-activated current suggests that lithium in low concentrations is able to modulate tonic inhibition in the hippocampus. This important property of lithium should be considered when using this drug as a

  9. Identification and characterization of the host protein DNAJC14 as a broadly active flavivirus replication modulator.

    Directory of Open Access Journals (Sweden)

    Zhigang Yi

    Full Text Available Viruses in the Flavivirus genus of the Flaviviridae family are arthropod-transmitted and contribute to staggering numbers of human infections and significant deaths annually across the globe. To identify cellular factors with antiviral activity against flaviviruses, we screened a cDNA library using an iterative approach. We identified a mammalian Hsp40 chaperone protein (DNAJC14 that when overexpressed was able to mediate protection from yellow fever virus (YFV-induced cell death. Further studies revealed that DNAJC14 inhibits YFV at the step of viral RNA replication. Since replication of bovine viral diarrhea virus (BVDV, a member of the related Pestivirus genus, is also known to be modulated by DNAJC14, we tested the effect of this host factor on diverse Flaviviridae family members. Flaviviruses, including the pathogenic Asibi strain of YFV, Kunjin, and tick-borne Langat virus, as well as a Hepacivirus, hepatitis C virus (HCV, all were inhibited by overexpression of DNAJC14. Mutagenesis showed that both the J-domain and the C-terminal domain, which mediates self-interaction, are required for anti-YFV activity. We found that