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Sample records for chaperonin activity modulates

  1. The chaperonin assisted and unassisted refolding of rhodanese can be modulated by its N-terminal peptide.

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    Mendoza, J A; Horowitz, P M

    1994-01-01

    The in vitro refolding of the monomeric, mitochondrial enzyme rhodanese (thiosulfate: cyanide sulfurtransferase, EC 2.8.1.1), which is assisted by the E. coli chaperonins, is modulated by the 23 amino acid peptide (VHQVLYRALVSTKWLAESVRAGK) corresponding to the amino terminal sequence (1-23) of rhodanese. In the absence of the peptide, a maximum recovery of active enzyme of about 65% is achieved after 90 min of initiation of the chaperonin assisted folding reaction. In contrast, this process is substantially inhibited in the presence of the peptide. The maximum recovery of active enzyme is peptide concentration-dependent. The peptide, however, does not prevent the interaction of rhodanese with the chaperonin 60 (cpn60), which leads to the formation of the cpn60-rhodanese complex. In addition, the peptide does not affect the rate of recovery of active enzyme, although it does affect the extent of recovery. Further, the unassisted refolding of rhodanese is also inhibited by the peptide. Thus, the peptide interferes with the folding of rhodanese in either the chaperonin assisted or the unassisted refolding of the enzyme. A 13 amino acid peptide (STKWLAESVRAGK) corresponding to the amino terminal sequence (11-23) of rhodanese does not show any significant effect on the chaperonin assisted or unassisted refolding of the enzyme. The results suggest that other sequences of rhodanese, in addition to the N-terminus, may be required for the binding of cpn60, in accord with a model in which cpn60 interacts with polypeptides through multiple binding sites.

  2. Modulation of STAT3 folding and function by TRiC/CCT chaperonin.

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    Moses Kasembeli

    2014-04-01

    Full Text Available Signal transducer and activator of transcription 3 (Stat3 transduces signals of many peptide hormones from the cell surface to the nucleus and functions as an oncoprotein in many types of cancers, yet little is known about how it achieves its native folded state within the cell. Here we show that Stat3 is a novel substrate of the ring-shaped hetero-oligomeric eukaryotic chaperonin, TRiC/CCT, which contributes to its biosynthesis and activity in vitro and in vivo. TRiC binding to Stat3 was mediated, at least in part, by TRiC subunit CCT3. Stat3 binding to TRiC mapped predominantly to the β-strand rich, DNA-binding domain of Stat3. Notably, enhancing Stat3 binding to TRiC by engineering an additional TRiC-binding domain from the von Hippel-Lindau protein (vTBD, at the N-terminus of Stat3, further increased its affinity for TRiC as well as its function, as determined by Stat3's ability to bind to its phosphotyrosyl-peptide ligand, an interaction critical for Stat3 activation. Thus, Stat3 levels and function are regulated by TRiC and can be modulated by manipulating its interaction with TRiC.

  3. Chaperonin filaments: The archael cytoskeleton

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    Trent, J.D.; Kagawa, H.K.; Yaoi, Takuro; Olle, E.; Zaluzec, N.J.

    1997-08-01

    Chaperonins are multi-subunit double-ring complexed composed of 60-kDa proteins that are believed to mediate protein folding in vivo. The chaperonins in the hyperthermophilic archaeon Sulfolobus shibatae are composed of the organism`s two most abundant proteins, which represent 4% of its total protein and have an intracellular concentration of {ge} 3.0 mg/ml. At concentrations of 1.0 mg/ml, purified chaperonin proteins aggregate to form ordered filaments. Filament formation, which requires Mg{sup ++} and nucleotide binding (not hydrolysis), occurs at physiological temperatures under conditions suggesting filaments may exist in vivo. If the estimated 4,600 chaperonins per cell, formed filaments in vivo, they could create a matrix of filaments that would span the diameter of an average S. shibatae cell 100 times. Direct observations of unfixed, minimally treated cells by intermediate voltage electron microscopy (300 kV) revealed an intracellular network of filaments that resembles chaperonin filaments produced in vitro. The hypothesis that the intracellular network contains chaperonins is supported by immunogold analyses. The authors propose that chaperonin activity may be regulated in vivo by filament formation and that chaperonin filaments may serve a cytoskeleton-like function in archaea and perhaps in other prokaryotes.

  4. Chaperonin Polymers in Archaea: The Cytoskeleton of Prokaryotes?

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    Trent, J. D.; Kagawa, H. K.; Zaluzec, N. J.

    1997-07-01

    Chaperonins are protein complexes that play a critical role in folding nascent polypeptides under normal conditions and refolding damaged proteins under stress conditions. In all organisms these complexes are composed of evolutionarily conserved 60-kDa proteins arranged in double-ring structures with between 7 and 9 protein subunits per ring. These double ring structures are assumed to be the functional units in vivo, although they have never been observed inside cells. Here the authors show that the purified chaperonin from the hyperthermophilic archaeon Sulfolobus shibatae, which is closely related to chaperonins in eukaryotes, has a double ring structure at low concentrations (0.1 mg/ml), but at more physiological concentrations, the rings stack end to end to form polymers. The polymers are stable at physiological temperatures (75 C) and closely resemble structures observed inside unfixed S. shibatae cells. The authors suggest that in vivo chaperonin activity may be regulated by polymerization and that chaperonin polymers may act as a cytoskeleton-like structure in archaea and bacteria.

  5. Ordered biological nanostructures formed from chaperonin polypeptides

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    Trent, Jonathan D. (Inventor); McMillan, R. Andrew (Inventor); Kagawa, Hiromi (Inventor); Paavola, Chad D. (Inventor)

    2010-01-01

    The following application relates to nanotemplates, nanostructures, nanoarrays and nanodevices formed from wild-type and mutated chaperonin polypeptides, methods of producing such compositions, methods of using such compositions and particular chaperonin polypeptides that can be utilized in producing such compositions.

  6. Chaperonin genes on the rise: new divergent classes and intense duplication in human and other vertebrate genomes

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    Macario Alberto JL

    2010-03-01

    Full Text Available Abstract Background Chaperonin proteins are well known for the critical role they play in protein folding and in disease. However, the recent identification of three diverged chaperonin paralogs associated with the human Bardet-Biedl and McKusick-Kaufman Syndromes (BBS and MKKS, respectively indicates that the eukaryotic chaperonin-gene family is larger and more differentiated than previously thought. The availability of complete genome sequences makes possible a definitive characterization of the complete set of chaperonin sequences in human and other species. Results We identified fifty-four chaperonin-like sequences in the human genome and similar numbers in the genomes of the model organisms mouse and rat. In mammal genomes we identified, besides the well-known CCT chaperonin genes and the three genes associated with the MKKS and BBS pathological conditions, a newly-defined class of chaperonin genes named CCT8L, represented in human by the two sequences CCT8L1 and CCT8L2. Comparative analyses from several vertebrate genomes established the monophyletic origin of chaperonin-like MKKS and BBS genes from the CCT8 lineage. The CCT8L gene originated from a later duplication also in the CCT8 lineage at the onset of mammal evolution and duplicated in primate genomes. The functionality of CCT8L genes in different species was confirmed by evolutionary analyses and in human by expression data. Detailed sequence analysis and structural predictions of MKKS, BBS and CCT8L proteins strongly suggested that they conserve a typical chaperonin-like core structure but that they are unlikely to form a CCT-like oligomeric complex. The characterization of many newly-discovered chaperonin pseudogenes uncovered the intense duplication activity of eukaryotic chaperonin genes. Conclusions In vertebrates, chaperonin genes, driven by intense duplication processes, have diversified into multiple classes and functionalities that extend beyond their well-known protein

  7. Serum antibody response to group II chaperonin from Methanobrevibacter oralis and human chaperonin CCT.

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    Hirai, Kimito; Maeda, Hiroshi; Omori, Kazuhiro; Yamamoto, Tadashi; Kokeguchi, Susumu; Takashiba, Shogo

    2013-06-01

    Both group I (HSP60) and group II (CCT) chaperonins are targets of autoantibodies. Autoimmune reactions to HSP60 have been well characterized, while immune reactions to group II chaperonin have not been clarified. Methanobrevibacter oralis is a suspected periodontal pathogen with group II chaperonin. In this study, serum responses to M. oralis chaperonin, human HSP60, and CCT subunits were examined using sera from patients with periodontitis and autoimmune diseases. In comparison with healthy controls, periodontitis patients showed significantly higher responses to CCT4 and CCT8 on dot blot analysis. Signals for CCT3 and CCT8 in autoimmune disease patients were significantly higher than in controls. Significant differences were also demonstrated by Western blotting in anti-CCT4 response in both patient groups. All subjects showed strong reactivity to M. oralis chaperonin and faint signals to human HSP60. Autoantibodies were raised against CCT rather than HSP60; and CCT3, CCT4, and CCT8 were shown to be the main targets. Host immune systems may be frequently exposed to chaperonins of Archaea in various habitats. Although further studies of the cross-reactivity between M. oralis chaperonin and human CCT are required, anti-CCT autoantibodies may be involved in the pathogenesis of periodontitis and autoimmune diseases.

  8. Essential Role of the Chaperonin CCT in Rod Outer Segment Biogenesis

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    Sinha, Satyabrata; Belcastro, Marycharmain; Datta, Poppy; Seo, Seongjin; Sokolov, Maxim

    2014-01-01

    Purpose. While some evidence suggests an essential role for the chaperonin containing t-complex protein 1 (CCT) in ciliogenesis, this function remains poorly understood mechanistically. We used transgenic mice, previously generated in our lab, and characterized by a genetically-induced suppression of CCT in rod photoreceptors as well as a malformation of the rod sensory cilia, the outer segments, to gain new insights into this underlying molecular mechanism. Methods. The CCT activity in rod photoreceptors of mice was suppressed by overexpressing the chaperonin inhibitor, phosducin-like protein short, and the ensuing changes of cellular morphology were analyzed by light and electron microscopy. Protein expression levels were studied by fluorescent microscopy and Western blotting. Results. Suppressing the chaperonin made the photoreceptors incompetent to build their outer segments. Specifically, the CCT-deficient rods appeared unable to expand the outer segment plasma membrane, and accommodate growth of this compartment. Seeking the molecular mechanisms underlying such a shortcoming, we found that the affected rods could not express normal levels of Bardet-Biedl Syndrome (BBS) proteins 2, 5, and 7 and, owing to that deficiency, were unable to assemble the BBSome, a multisubunit complex responsible for ciliary trafficking. A similar effect in response to the chaperonin suppression was also observed in cultured ciliated cells. Conclusions. Our data provide new evidence indicating the essential role of the chaperonin CCT in the biogenesis of vertebrate photoreceptor sensory cilia, and suggest that it may be due to the direct participation of the chaperonin in the posttranslational processing of selected BBS proteins and assembly of the BBSome. PMID:24854858

  9. Arabidopsis chloroplast chaperonin 10 is a calmodulin-binding protein

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    Yang, T.; Poovaiah, B. W.

    2000-01-01

    Calcium regulates diverse cellular activities in plants through the action of calmodulin (CaM). By using (35)S-labeled CaM to screen an Arabidopsis seedling cDNA expression library, a cDNA designated as AtCh-CPN10 (Arabidopsis thaliana chloroplast chaperonin 10) was cloned. Chloroplast CPN10, a nuclear-encoded protein, is a functional homolog of E. coli GroES. It is believed that CPN60 and CPN10 are involved in the assembly of Rubisco, a key enzyme involved in the photosynthetic pathway. Northern analysis revealed that AtCh-CPN10 is highly expressed in green tissues. The recombinant AtCh-CPN10 binds to CaM in a calcium-dependent manner. Deletion mutants revealed that there is only one CaM-binding site in the last 31 amino acids of the AtCh-CPN10 at the C-terminal end. The CaM-binding region in AtCh-CPN10 has higher homology to other chloroplast CPN10s in comparison to GroES and mitochondrial CPN10s, suggesting that CaM may only bind to chloroplast CPN10s. Furthermore, the results also suggest that the calcium/CaM messenger system is involved in regulating Rubisco assembly in the chloroplast, thereby influencing photosynthesis. Copyright 2000 Academic Press.

  10. Characterization of archaeal group II chaperonin-ADP-metal fluoride complexes: implications that group II chaperonins operate as a "two-stroke engine".

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    Iizuka, Ryo; Yoshida, Takao; Ishii, Noriyuki; Zako, Tamotsu; Takahashi, Kazunobu; Maki, Kosuke; Inobe, Tomonao; Kuwajima, Kunihiro; Yohda, Masafumi

    2005-12-01

    Group II chaperonins, found in Archaea and in the eukaryotic cytosol, act independently of a cofactor corresponding to GroES of group I chaperonins. Instead, the helical protrusion at the tip of the apical domain forms a built-in lid of the central cavity. Although many studies on the lid's conformation have been carried out, the conformation in each step of the ATPase cycle remains obscure. To clarify this issue, we examined the effects of ADP-aluminum fluoride (AlFx) and ADP-beryllium fluoride (BeFx) complexes on alpha-chaperonin from the hyperthermophilic archaeum, Thermococcus sp. strain KS-1. Biochemical assays, electron microscopic observations, and small angle x-ray scattering measurements demonstrate that alpha-chaperonin incubated with ADP and BeFx exists in an asymmetric conformation; one ring is open, and the other is closed. The result indicates that alpha-chaperonin also shares the inherent functional asymmetry of bacterial and eukaryotic cytosolic chaperonins. Most interestingly, addition of ADP and BeFx induced alpha-chaperonin to encapsulate unfolded proteins in the closed ring but did not trigger their folding. Moreover, alpha-chaperonin incubated with ATP and AlFx or BeFx adopted a symmetric closed conformation, and its functional turnover was inhibited. These forms are supposed to be intermediates during the reaction cycle of group II chaperonins.

  11. Difference in the distribution pattern of substrate enzymes in the metabolic network of Escherichia coli, according to chaperonin requirement

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    Niwa Tatsuya

    2011-06-01

    Full Text Available Abstract Background Chaperonins are important in living systems because they play a role in the folding of proteins. Earlier comprehensive analyses identified substrate proteins for which folding requires the chaperonin GroEL/GroES (GroE in Escherichia coli, and they revealed that many chaperonin substrates are metabolic enzymes. This result implies the importance of chaperonins in metabolism. However, the relationship between chaperonins and metabolism is still unclear. Results We investigated the distribution of chaperonin substrate enzymes in the metabolic network using network analysis techniques as a first step towards revealing this relationship, and found that as chaperonin requirement increases, substrate enzymes are more laterally distributed in the metabolic. In addition, comparative genome analysis showed that the chaperonin-dependent substrates were less conserved, suggesting that these substrates were acquired later on in evolutionary history. Conclusions This result implies the expansion of metabolic networks due to this chaperonin, and it supports the existing hypothesis of acceleration of evolution by chaperonins. The distribution of chaperonin substrate enzymes in the metabolic network is inexplicable because it does not seem to be associated with individual protein features such as protein abundance, which has been observed characteristically in chaperonin substrates in previous works. However, it becomes clear by considering this expansion process due to chaperonin. This finding provides new insights into metabolic evolution and the roles of chaperonins in living systems.

  12. Versatile platform for nanotechnology based on circular permutations of chaperonin protein

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    Paavola, Chad D. (Inventor); Trent, Jonathan D. (Inventor); Chan, Suzanne L. (Inventor); Li, Yi-Fen (Inventor); McMillan, R. Andrew (Inventor); Kagawa, Hiromi (Inventor)

    2010-01-01

    The present invention provides chaperonin polypeptides which are modified to include N-terminal and C-terminal ends that are relocated from the central pore region to various different positions in the polypeptide which are located on the exterior of the folded modified chaperonin polypeptide. In the modified chaperonin polypeptide, the naturally-occurring N-terminal and C-terminal ends are joined together directly or with an intervening linker peptide sequence. The relocated N-terminal or C-terminal ends can be covalently joined to, or bound with another molecule such as a nucleic acid molecule, a lipid, a carbohydrate, a second polypeptide, or a nanoparticle. The modified chaperonin polypeptides can assemble into double-ringed chaperonin structures. Further, the chaperonin structures can organize into higher order structures such as nanofilaments or nanoarrays which can be used to produce nanodevices and nanocoatings.

  13. Chaperonin Structure - The Large Multi-Subunit Protein Complex

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    Irena Roterman

    2009-03-01

    Full Text Available The multi sub-unit protein structure representing the chaperonins group is analyzed with respect to its hydrophobicity distribution. The proteins of this group assist protein folding supported by ATP. The specific axial symmetry GroEL structure (two rings of seven units stacked back to back - 524 aa each and the GroES (single ring of seven units - 97 aa each polypeptide chains are analyzed using the hydrophobicity distribution expressed as excess/deficiency all over the molecule to search for structure-to-function relationships. The empirically observed distribution of hydrophobic residues is confronted with the theoretical one representing the idealized hydrophobic core with hydrophilic residues exposure on the surface. The observed discrepancy between these two distributions seems to be aim-oriented, determining the structure-to-function relation. The hydrophobic force field structure generated by the chaperonin capsule is presented. Its possible influence on substrate folding is suggested.

  14. Explicit solvent molecular dynamics simulations of chaperonin-assisted rhodanese folding

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    Ying Ren; Jian Gao; Ji Xu; Wei Ge; Jinghai Li

    2009-01-01

    Chaperonins are known to facilitate the productive folding of numerous misfolded proteins, Despite their established importance, the mechanism of chaperonin-assisted protein folding remains unknown. In the present article, all-atom explicit solvent molecular dynamics (MD) simulations have been performed for the first time on rhodanese folding in a series of cavity-size and cavity-charge chaperonin mutants. A compromise between stability and flexibility of chaperonin structure during the substrate folding has been observed and the key factors affecting this dynamic process are discussed.

  15. The chaperonin CCT inhibits assembly of α-synuclein amyloid fibrils by a specific, conformation-dependent interaction

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    Sot, Begoña; Rubio-Muñoz, Alejandra; Leal-Quintero, Ahudrey; Martínez-Sabando, Javier; Marcilla, Miguel; Roodveldt, Cintia; Valpuesta, José M.

    2017-01-01

    The eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington’s disease. This raises the possibility that CCT modulates other amyloidopathies, a still-unaddressed question. We show here that CCT inhibits amyloid fibre assembly of α-synuclein A53T, one of the mutants responsible for Parkinson’s disease. We evaluated fibrillation blockade in α-synuclein A53T deletion mutants and CCT interactions of full-length A53T in distinct oligomeric states to define an inhibition mechanism specific for α-synuclein. CCT interferes with fibre assembly by interaction of its CCTζ and CCTγ subunits with the A53T central hydrophobic region (NAC). This interaction is specific to NAC conformation, as it is produced once soluble α-synuclein A53T oligomers form and blocks the reaction before fibres begin to grow. Finally, we show that this association inhibits α-synuclein A53T oligomer toxicity in neuroblastoma cells. In summary, our results and those for huntingtin suggest that CCT is a general modulator of amyloidogenesis via a specific mechanism. PMID:28102321

  16. Dataset concerning GroEL chaperonin interaction with proteins

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    V.V. Marchenkov

    2016-03-01

    Full Text Available GroEL chaperonin is well-known to interact with a wide variety of polypeptide chains. Here we show the data related to our previous work (http://dx.doi.org/10.1016/j.pep.2015.11.020 [1], and concerning the interaction of GroEL with native (lysozyme, α-lactalbumin and denatured (lysozyme, α-lactalbumin and pepsin proteins in solution. The use of affinity chromatography on the base of denatured pepsin for GroEL purification from fluorescent impurities is represented as well.

  17. [Role of GroEL/GroES chaperonin system and Lon protease in regulation of expression Vibrio fischeri lux genes in Escherichia coli cells].

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    Manukhov, I V; Kotova, V Iu; Zavil'genskiĭ, G B

    2006-01-01

    It was shown that the chaperonin GroEL/GroES and protease Lon influence the expression of the Vibrio fischeri lux regulon in Escherichia coli cells: E. coli groE mutants bearing hybrid plasmid with the lux regulon were weakly luminescent; cells of the E. coli lon- comprising the entire lux regulon display very intense bioluminescence, with no lag period in the induction curve characteristic of lon+ strains. The luxR gene was cloned from the Vibrio fischeri genome in the pGEX-KG vector. It was shown that the active fusion protein GST-LuxR by affinity chromatography on glutathione-sucrose colony is purified only with proteins GroEL and Lon. The present results showed that the LuxR, transcriptional activator of the V. fischeri lux operon, really complexes with GroEL chaperonin and Lon protease. We suppose, that the GroEL/GroES chaperonin systems is required for the folding of LuxR into an active protein, and the LuxR is the target for the ATP-dependent serine Lon protease of E. coli.

  18. Ring Separation Highlights the Protein-Folding Mechanism Used by the Phage EL-Encoded Chaperonin.

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    Molugu, Sudheer K; Hildenbrand, Zacariah L; Morgan, David Gene; Sherman, Michael B; He, Lilin; Georgopoulos, Costa; Sernova, Natalia V; Kurochkina, Lidia P; Mesyanzhinov, Vadim V; Miroshnikov, Konstantin A; Bernal, Ricardo A

    2016-04-05

    Chaperonins are ubiquitous, ATP-dependent protein-folding molecular machines that are essential for all forms of life. Bacteriophage φEL encodes its own chaperonin to presumably fold exceedingly large viral proteins via profoundly different nucleotide-binding conformations. Our structural investigations indicate that ATP likely binds to both rings simultaneously and that a misfolded substrate acts as the trigger for ATP hydrolysis. More importantly, the φEL complex dissociates into two single rings resulting from an evolutionarily altered residue in the highly conserved ATP-binding pocket. Conformational changes also more than double the volume of the single-ring internal chamber such that larger viral proteins are accommodated. This is illustrated by the fact that φEL is capable of folding β-galactosidase, a 116-kDa protein. Collectively, the architecture and protein-folding mechanism of the φEL chaperonin are significantly different from those observed in group I and II chaperonins.

  19. Functional Subunits of Eukaryotic Chaperonin CCT/TRiC in Protein Folding

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    M. Anaul Kabir

    2011-01-01

    Full Text Available Molecular chaperones are a class of proteins responsible for proper folding of a large number of polypeptides in both prokaryotic and eukaryotic cells. Newly synthesized polypeptides are prone to nonspecific interactions, and many of them make toxic aggregates in absence of chaperones. The eukaryotic chaperonin CCT is a large, multisubunit, cylindrical structure having two identical rings stacked back to back. Each ring is composed of eight different but similar subunits and each subunit has three distinct domains. CCT assists folding of actin, tubulin, and numerous other cellular proteins in an ATP-dependent manner. The catalytic cooperativity of ATP binding/hydrolysis in CCT occurs in a sequential manner different from concerted cooperativity as shown for GroEL. Unlike GroEL, CCT does not have GroES-like cofactor, rather it has a built-in lid structure responsible for closing the central cavity. The CCT complex recognizes its substrates through diverse mechanisms involving hydrophobic or electrostatic interactions. Upstream factors like Hsp70 and Hsp90 also work in a concerted manner to transfer the substrate to CCT. Moreover, prefoldin, phosducin-like proteins, and Bag3 protein interact with CCT and modulate its function for the fine-tuning of protein folding process. Any misregulation of protein folding process leads to the formation of misfolded proteins or toxic aggregates which are linked to multiple pathological disorders.

  20. Structural Mechanisms of Mutant Huntingtin Aggregation Suppression by the Synthetic Chaperonin-like CCT5 Complex Explained by Cryoelectron Tomography*

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    Darrow, Michele C.; Sergeeva, Oksana A.; Isas, Jose M.; Galaz-Montoya, Jesús G.; King, Jonathan A.; Langen, Ralf; Schmid, Michael F.; Chiu, Wah

    2015-01-01

    Huntington disease, a neurodegenerative disorder characterized by functional deficits and loss of striatal neurons, is linked to an expanded and unstable CAG trinucleotide repeat in the huntingtin gene (HTT). This DNA sequence translates to a polyglutamine repeat in the protein product, leading to mutant huntingtin (mHTT) protein aggregation. The aggregation of mHTT is inhibited in vitro and in vivo by the TCP-1 ring complex (TRiC) chaperonin. Recently, a novel complex comprised of a single type of TRiC subunit has been reported to inhibit mHTT aggregation. Specifically, the purified CCT5 homo-oligomer complex, when compared with TRiC, has a similar structure, ATP use, and substrate refolding activity, and, importantly, it also inhibits mHTT aggregation. Using an aggregation suppression assay and cryoelectron tomography coupled with a novel computational classification method, we uncover the interactions between the synthetic CCT5 complex (∼1 MDa) and aggregates of mutant huntingtin exon 1 containing 46 glutamines (mHTTQ46-Ex1). We find that, in a similar fashion to TRiC, synthetic CCT5 complex caps mHTT fibrils at their tips and encapsulates mHTT oligomers, providing a structural description of the inhibition of mHTTQ46-Ex1 by CCT5 complex and a shared mechanism of mHTT inhibition between TRiC chaperonin and the CCT5 complex: cap and contain. PMID:25995452

  1. Structural Mechanisms of Mutant Huntingtin Aggregation Suppression by the Synthetic Chaperonin-like CCT5 Complex Explained by Cryoelectron Tomography.

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    Darrow, Michele C; Sergeeva, Oksana A; Isas, Jose M; Galaz-Montoya, Jesús G; King, Jonathan A; Langen, Ralf; Schmid, Michael F; Chiu, Wah

    2015-07-10

    Huntington disease, a neurodegenerative disorder characterized by functional deficits and loss of striatal neurons, is linked to an expanded and unstable CAG trinucleotide repeat in the huntingtin gene (HTT). This DNA sequence translates to a polyglutamine repeat in the protein product, leading to mutant huntingtin (mHTT) protein aggregation. The aggregation of mHTT is inhibited in vitro and in vivo by the TCP-1 ring complex (TRiC) chaperonin. Recently, a novel complex comprised of a single type of TRiC subunit has been reported to inhibit mHTT aggregation. Specifically, the purified CCT5 homo-oligomer complex, when compared with TRiC, has a similar structure, ATP use, and substrate refolding activity, and, importantly, it also inhibits mHTT aggregation. Using an aggregation suppression assay and cryoelectron tomography coupled with a novel computational classification method, we uncover the interactions between the synthetic CCT5 complex (∼ 1 MDa) and aggregates of mutant huntingtin exon 1 containing 46 glutamines (mHTTQ46-Ex1). We find that, in a similar fashion to TRiC, synthetic CCT5 complex caps mHTT fibrils at their tips and encapsulates mHTT oligomers, providing a structural description of the inhibition of mHTTQ46-Ex1 by CCT5 complex and a shared mechanism of mHTT inhibition between TRiC chaperonin and the CCT5 complex: cap and contain.

  2. Chaperonin-Inspired pH Protection by Mesoporous Silica SBA-15 on Myoglobin and Lysozyme.

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    Lynch, Michele M; Liu, Jichuan; Nigra, Michael; Coppens, Marc-Olivier

    2016-09-20

    While enzymes are valuable tools in many fields of biotechnology, they are fragile and must be protected against denaturing conditions such as unfavorable solution pH. Within living organisms, chaperonins help enzymes fold into their native shape and protect them from damage. Inspired by this natural solution, mesoporous silica SBA-15 with different pore diameters is synthesized as a support material for immobilizing and protecting enzymes. In separate experiments, the model enzymes myoglobin and lysozyme are physically adsorbed to SBA-15 and exposed to a range of buffered pH conditions. The immobilized enzymes' biocatalytic activities are quantified and compared to the activities of nonimmobilized enzymes in the same solution conditions. It has been observed that myoglobin immobilized on SBA-15 is protected from acidic denaturation from pH 3.6 to 5.1, exhibiting relative activity of up to 350%. Immobilized lysozyme is protected from unfavorable conditions from pH 6.6 to 7.6, with relative activity of up to 200%. These results indicate that the protective effects conferred to enzymes immobilized by physical adsorption to SBA-15 are driven by the enzymes' electrostatic attraction to the material's surface. The pore diameter of SBA-15 affects the quality of protection given to immobilized enzymes, but the contribution of this effect at different pH values remains unclear.

  3. Molecular functions of chaperonin gene, containing tailless complex polypeptide 1 from Macrobrachium rosenbergii.

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    Arockiaraj, Jesu; Vanaraja, Puganeshwaran; Easwvaran, Sarasvathi; Singh, Arun; Othman, Rofina Yasmin; Bhassu, Subha

    2012-10-25

    Chaperonin (MrChap) was identified from a constructed transcriptome dataset of freshwater prawn Macrobrachium rosenbergii. The MrChap peptide contains a long chaperone super family domain between 11 and 525. Three chaperone tailless complex polypeptide (TCP-1) signatures are present in the MrChap peptide sequence at 36-48, 57-73 and 85-93. The gene expressions of MrChap in both healthy M. rosenbergii and those infected with infectious hypodermal and hematopoietic necrosis virus (IHHNV) were examined using qRT-PCR. To understand its biological activity, the recombinant MrChap gene was constructed and expressed in Escherichia coli BL21 (DE3). The results of ATPase assay showed that the recombinant MrChap protein exhibited apparent ATPase activity. Chaperone activity assay showed that the recombinant MrChap protein is an active chaperone. These results suggest that MrChap is potentially involved in the immune responses against viral infection in M. rosenbergii. These findings indicate that the recombinant MrChap protein may be used in immunotherapeutic approaches.

  4. Processing abstract language modulates motor system activity.

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    Glenberg, Arthur M; Sato, Marc; Cattaneo, Luigi; Riggio, Lucia; Palumbo, Daniele; Buccino, Giovanni

    2008-06-01

    Embodiment theory proposes that neural systems for perception and action are also engaged during language comprehension. Previous neuroimaging and neurophysiological studies have only been able to demonstrate modulation of action systems during comprehension of concrete language. We provide neurophysiological evidence for modulation of motor system activity during the comprehension of both concrete and abstract language. In Experiment 1, when the described direction of object transfer or information transfer (e.g., away from the reader to another) matched the literal direction of a hand movement used to make a response, speed of responding was faster than when the two directions mismatched (an action-sentence compatibility effect). In Experiment 2, we used single-pulse transcranial magnetic stimulation to study changes in the corticospinal motor pathways to hand muscles while reading the same sentences. Relative to sentences that do not describe transfer, there is greater modulation of activity in the hand muscles when reading sentences describing transfer of both concrete objects and abstract information. These findings are discussed in relation to the human mirror neuron system.

  5. Diversity of Archaea in Icelandic hot springs based on 16S rRNA and chaperonin genes.

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    Mirete, Salvador; de Figueras, Carolina G; González-Pastor, Jose E

    2011-07-01

    The diversity of archaeal communities growing in four hot springs (65-90 °C, pH 6.5) was assessed with 16S rRNA gene primers specific for the domain Archaea. Overall, mainly uncultured members of the Desulfurococcales, the Thermoproteales and the Korarchaeota, were identified. Based on this diversity, a set of chaperonin heat-shock protein (Hsp60) gene sequences from different archaeal species were aligned to design two degenerate primer sets for the amplification of the chaperonin gene: Ths and Kor (which can also detect the korarchaeotal chaperonin gene from one of the samples). A phylogenetic tree was constructed using the chaperonin sequences retrieved and other sequences from cultured representatives. The Alpha and Beta paralogs of the chaperonin gene were observed within the main clades and orthologs among them. Cultivated representatives from these clades were assigned to either paralog in the chaperonin tree. Uncultured representatives observed in the 16S rRNA gene analysis were found to be related to the Desulfurococcales. The topologies of the 16S rRNA gene and chaperonin phylogenetic trees were compared, and similar phylogenetic relationships were observed. Our results suggest that the chaperonin Hsp60 gene may be used as a phylogenetic marker for the clades found in this extreme environment.

  6. Folding of newly translated membrane protein CCR5 is assisted by the chaperonin GroEL-GroES

    Science.gov (United States)

    Chi, Haixia; Wang, Xiaoqiang; Li, Jiqiang; Ren, Hao; Huang, Fang

    2015-11-01

    The in vitro folding of newly translated human CC chemokine receptor type 5 (CCR5), which belongs to the physiologically important family of G protein-coupled receptors (GPCRs), has been studied in a cell-free system supplemented with the surfactant Brij-35. The freshly synthesized CCR5 can spontaneously fold into its biologically active state but only slowly and inefficiently. However, on addition of the GroEL-GroES molecular chaperone system, the folding of the nascent CCR5 was significantly enhanced, as was the structural stability and functional expression of the soluble form of CCR5. The chaperonin GroEL was partially effective on its own, but for maximum efficiency both the GroEL and its GroES lid were necessary. These results are direct evidence for chaperone-assisted membrane protein folding and therefore demonstrate that GroEL-GroES may be implicated in the folding of membrane proteins.

  7. 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.

  8. Bigelow Expandable Activity Module (BEAM) - ISS Inflatable Module Technology Demonstration

    Science.gov (United States)

    Dasgupta, Rajib; Munday, Steve; Valle, Gerard D.

    2014-01-01

    INNOVATION: BEAM is a pathway project demonstrating the design, fabrication, test, certification, integration, operation, on-orbit performance, and disposal of the first ever man-rated space inflatable structure. The groundwork laid through the BEAM project will support developing and launching a larger inflatable space structure with even greater mass per volume (M/V) advantages need for longer space missions. OVERVIEW: Inflatable structures have been shown to have much lower mass per volume ratios (M/V) when compared with conventional space structures. BEAM is an expandable structure, launched in a packed state, and then expanded once on orbit. It is a temporary experimental module to be used for gathering structural, thermal, and radiation data while on orbit. BEAM will be launched on Space X-8, be extracted from the dragon trunk, and will attach to ISS at Node 3- Aft. BEAM performance will be monitored over a two-year period and then BEAM will be jettison using the SSRMS.

  9. A single ring is sufficient for productive chaperonin-mediated folding in vivo.

    Science.gov (United States)

    Nielsen, K L; Cowan, N J

    1998-07-01

    Facilitated protein folding by the double toroidal bacterial chaperonin, GroEL/GroES, proceeds by a "two-stroke engine" mechanism in which an allosteric interaction between the two rings synchronizes the reaction cycle by controlling the binding and release of cochaperonin. Using chimeric chaperonin molecules assembled by fusing equatorial and apical domains derived from GroEL and its mammalian mitochondrial homolog, Hsp60, we show that productive folding by Hsp60 and its cognate cochaperonin, Hsp10, proceeds in vitro and in vivo without the formation of a two-ring structure. This simpler "one-stroke" engine works because Hsp60 has a different mechanism for the release of its cochaperonin cap and bound target protein.

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

    Directory of Open Access Journals (Sweden)

    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

  11. Insect Repellents: Modulators of Mosquito Odorant Receptor Activity

    Science.gov (United States)

    2010-08-01

    molecular pathways through allosteric regulation of various proteins including proteases [39,40], the cannabinoid receptor 1 (CB1) [41], the a7 nicotinic...41. Price MR, Baillie GL, Thomas A, Stevenson LA, Easson M, et al. (2005) Allosteric modulation of the cannabinoid CB1 receptor . Mol Pharmacol 68...Insect Repellents: Modulators of Mosquito Odorant Receptor Activity Jonathan D. Bohbot, Joseph C. Dickens* Invasive Insect Biocontrol and Behavior

  12. Modulation of motoneuron activity by serotonin.

    Science.gov (United States)

    Perrier, Jean-François

    2016-02-01

    Serotonin is a major neuromodulator in the central nervous system involved in most physiological functions including appetite regulation, sexual arousal, sleep regulation and motor control. The activity of neurons from the raphe spinal tract, which release serotonin on motoneurons, is positively correlated with motor behaviour. During moderate physical activity, serotonin is released from synaptic terminals onto the dendrites and cell bodies of motoneurons. Serotonin increases the excitability of motoneurons and thereby facilitate muscle contraction by acting on several parallel intracellular pathways. By activating 5-HT1A receptors, serotonin inhibits TWIK-related acid-sensitive potassium channels and small conductance calcium-activated potassium channels. In parallel, serotonin binds to 5-HT2 receptors, which promotes the low-threshold L-type Ca(2+) channels. During intense physical activity, more serotonin is released. The reuptake systems saturate and serotonin spills over to reach extrasynaptic 5-HT1A receptors located on the axon initial segment of motoneurons. This in turn induces the inhibition of the Na(+) channels responsible for the initiation of action potentials. Fewer nerve impulses are generated and muscle contraction becomes weaker. By decreasing the gain of motoneurons, serotonin triggers central fatigue.

  13. 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.

  14. 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.

  15. Eicosapentaenoic Acid Modulates Trichomonas vaginalis Activity.

    Science.gov (United States)

    Korosh, Travis; Jordan, Kelsey D; Wu, Ja-Shin; Yarlett, Nigel; Upmacis, Rita K

    2016-01-01

    Trichomonas vaginalis is a sexually transmitted parasite and, while it is often asymptomatic in males, the parasite is associated with disease in both sexes. Metronidazole is an effective treatment for trichomoniasis, but resistant strains have evolved and, thus, it has become necessary to investigate other possible therapies. In this study, we examined the effects of native and oxidized forms of the sodium salts of eicosapentaenoic, docosahexaenoic, and arachidonic acids on T. vaginalis activity. Eicosapentaenoic acid was the most toxic with 190 and 380 μM causing approximately 90% cell death in Casu2 and ATCC 50142 strains, respectively. In contrast, oxidized eicosapentaenoic acid was the least toxic, requiring > 3 mM to inhibit activity, while low levels (10 μM) were associated with increased parasite density. Mass spectrometric analysis of oxidized eicosapentaenoic acid revealed C20 products containing one to six additional oxygen atoms and various degrees of bond saturation. These results indicate that eicosapentaenoic acid has different effects on T. vaginalis survival, depending on whether it is present in the native or oxidized form. A better understanding of lipid metabolism in T. vaginalis may facilitate the design of synthetic fatty acids that are effective for the treatment of metronidazole-resistant T. vaginalis.

  16. Muscle metaboreceptor modulation of cutaneous active vasodilation

    Science.gov (United States)

    Crandall, C. G.; Stephens, D. P.; Johnson, J. M.

    1998-01-01

    PURPOSE: Isometric handgrip exercise in hyperthermia has been shown to reduce cutaneous vascular conductance (CVC) by inhibiting the cutaneous active vasodilator system. METHODS: To identify whether this response was initiated by muscle metaboreceptors, in seven subjects two 3-min bouts of isometric handgrip exercise in hyperthermia were performed, followed by 2 min of postexercise ischemia (PEI). An index of forearm skin blood flow (laser-Doppler flowmetry) was measured on the contralateral arm at an unblocked site and at a site at which adrenergic vasoconstrictor function was blocked via bretylium iontophoresis to reveal active cutaneous vasodilator function unambiguously. Sweat rate was measured via capacitance hygrometry, CVC was indexed from the ratio of skin blood flow to mean arterial pressure and was expressed as a percentage of maximal CVC at that site. In normothermia, neither isometric exercise nor PEI affected CVC (P > 0.05). RESULTS: The first bout of isometric handgrip exercise in hyperthermia reduced CVC at control sites and this reduction persisted through PEI (pre-exercise: 59.8 +/- 5.4, exercise: 49.8 +/- 4.9, PEI: 49.7 +/- 5.3% of maximum; both P vasodilator system, is primarily mediated by muscle metaboreceptors, whereas central command or muscle mechanoreceptors have less influence.

  17. 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.

  18. Translocation boost protein-folding efficiency of double-barreled chaperonins.

    Science.gov (United States)

    Coluzza, Ivan; van der Vies, Saskia M; Frenkel, Daan

    2006-05-15

    Incorrect folding of proteins in living cells may lead to malfunctioning of the cell machinery. To prevent such cellular disasters from happening, all cells contain molecular chaperones that assist nonnative proteins in folding into the correct native structure. One of the most studied chaperone complexes is the GroEL-GroES complex. The GroEL part has a "double-barrel" structure, which consists of two cylindrical chambers joined at the bottom in a symmetrical fashion. The hydrophobic rim of one of the GroEL chambers captures nonnative proteins. The GroES part acts as a lid that temporarily closes the filled chamber during the folding process. Several capture-folding-release cycles are required before the nonnative protein reaches its native state. Here we report molecular simulations that suggest that translocation of the nonnative protein through the equatorial plane of the complex boosts the efficiency of the chaperonin action. If the target protein is correctly folded after translocation, it is released. However, if it is still nonnative, it is likely to remain trapped in the second chamber, which then closes to start a reverse translocation process. This shuttling back and forth continues until the protein is correctly folded. Our model provides a natural explanation for the prevalence of double-barreled chaperonins. Moreover, we argue that internal folding is both more efficient and safer than a scenario where partially refolded proteins escape from the complex before being recaptured.

  19. 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...

  20. 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:  

  1. 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.

  2. Idefix insulator activity can be modulated by nearby regulatory elements

    OpenAIRE

    Brasset, E; Bantignies, F.; Court, F. (Franck); Cheresiz, S.; C. Conte; Vaury, C.

    2007-01-01

    Insulators play important roles in controlling gene activity and maintaining regulatory independence between neighbouring genes. In this article, we show that the enhancer-blocking activity of the insulator present within the LTR retrotransposon Idefix can be abolished if two copies of the region containing the insulator—specifically, the long terminal repeat (LTR)—are fused to the retrotransposon's 5′ untranslated region (5′ UTR). The presence of this combination of two [LTR-5′ UTR] modules ...

  3. Increased expression and purification of soluble iron-regulatory protein 1 from Escherichia coli co-expressing chaperonins GroES and GroEL

    Directory of Open Access Journals (Sweden)

    H. Carvalho

    2008-04-01

    Full Text Available Iron is an essential metal for all living organisms. However, iron homeostasis needs to be tightly controlled since iron can mediate the production of reactive oxygen species, which can damage cell components and compromise the integrity and/or cause DNA mutations, ultimately leading to cancer. In eukaryotes, iron-regulatory protein 1 (IRP1 plays a central role in the control of intracellular iron homeostasis. This occurs by interaction of IRP1 with iron-responsive element regions at 5' of ferritin mRNA and 3' of transferrin mRNA which, respectively, represses translation and increases mRNA stability. We have expressed IRP1 using the plasmid pT7-His-hIRP1, which codifies for human IRP1 attached to an NH2-terminal 6-His tag. IRP1 was expressed in Escherichia coli using the strategy of co-expressing chaperonins GroES and GroEL, in order to circumvent inclusion body formation and increase the yield of soluble protein. The protein co-expressed with these chaperonins was obtained mostly in the soluble form, which greatly increased the efficiency of protein purification. Metal affinity and FPLC ion exchange chromatography were used in order to obtain highly purified IRP1. Purified protein was biologically active, as assessed by electrophoretic mobility shift assay, and could be converted to the cytoplasmic aconitase form. These results corroborate previous studies, which suggest the use of folding catalysts as a powerful strategy to increase protein solubility when expressing heterologous proteins in E. coli.

  4. Surface plasmon polariton modulator with optimized active layer

    DEFF Research Database (Denmark)

    Babicheva, Viktoriia; Lavrinenko, Andrei

    2012-01-01

    A multilayered waveguide, which supports surface plasmon polaritons, is considered as an absorption modulator. The waveguide core consists of a silicon nitride layer and ultrathin layer with the varied carrier density embedded between two silver plates, which also serve as electrodes. Under...... 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...

  5. ISAR active jamming method based on sinusoidal modulation

    Institute of Scientific and Technical Information of China (English)

    Yu Zhang; Congfeng Liu; Yan Zhu

    2015-01-01

    It is potential y useful to perform deception or cover jamming using the rotating angular reflectors since they can form deception echoes along range and azimuth. Inspired by the cohe-rent jamming and micro-motion modulation, a novel active method is proposed for inverse synthetic aperture radar (ISAR). Radar pulses are sampled and frequency-modulated along azimuth by si-nusoidal signal, and then the jamming signals are retransmitted to the radar and the jamming images are induced after ISAR imaging. Therein, the jamming principle, key parameters and the jamming effect are discussed. The simulated data verify the effectiveness of the jamming method.

  6. 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...... losses and significantly better distribution of the power losses among the semiconductors of the Active-NPC inverter....

  7. Chaperonin GroEL/GroES over-expression promotes multi-drug resistance in E. coli following exposure to aminoglycoside antibiotics

    Directory of Open Access Journals (Sweden)

    Lise eGoltermann

    2016-01-01

    Full Text Available Antibiotic resistance is an increasing challenge to modern healthcare. Aminoglycoside antiobiotics cause translation corruption and protein misfolding and aggregation in Escherichia coli. We previously showed that chaperonin GroEL/GroES depletion and overexpression sensitize and promote short-term tolerance, respectively, to this drug class. Here we show that chaperonin GroEL/GroES over-expression accelerates acquisition of aminoglycoside resistance and multi-drug resistance following sub-lethal aminoglycoside antibiotic exposure. Chaperonin buffering could provide a novel mechanism for antibiotic resistance and multi-drug resistance development.

  8. Idefix insulator activity can be modulated by nearby regulatory elements.

    Science.gov (United States)

    Brasset, E; Bantignies, F; Court, F; Cheresiz, S; Conte, C; Vaury, C

    2007-01-01

    Insulators play important roles in controlling gene activity and maintaining regulatory independence between neighbouring genes. In this article, we show that the enhancer-blocking activity of the insulator present within the LTR retrotransposon Idefix can be abolished if two copies of the region containing the insulator--specifically, the long terminal repeat (LTR)--are fused to the retrotransposon's 5' untranslated region (5' UTR). The presence of this combination of two [LTR-5' UTR] modules is a prerequisite for the loss of enhancer-blocking activity. We further show that the 5' UTR causes flanking genomic sequences to be displaced to the nuclear periphery, which is not observed when two insulators are present by themselves. This study thus provides a functional link between insulators and independent genomic modules, which may cooperate to allow the specific regulation of defined genomic loci via nuclear repositioning. It further illustrates the complexity of genomic regulation within a chromatic environment with multiple functional elements.

  9. Generalized anxiety modulates frontal and limbic activation in major depression

    Directory of Open Access Journals (Sweden)

    Schlund Michael W

    2012-02-01

    Full Text Available Abstract Background Anxiety is relatively common in depression and capable of modifying the severity and course of depression. Yet our understanding of how anxiety modulates frontal and limbic activation in depression is limited. Methods We used functional magnetic resonance imaging and two emotional information processing tasks to examine frontal and limbic activation in ten patients with major depression and comorbid with preceding generalized anxiety (MDD/GAD and ten non-depressed controls. Results Consistent with prior studies on depression, MDD/GAD patients showed hypoactivation in medial and middle frontal regions, as well as in the anterior cingulate, cingulate and insula. However, heightened anxiety in MDD/GAD patients was associated with increased activation in middle frontal regions and the insula and the effects varied with the type of emotional information presented. Conclusions Our findings highlight frontal and limbic hypoactivation in patients with depression and comorbid anxiety and indicate that anxiety level may modulate frontal and limbic activation depending upon the emotional context. One implication of this finding is that divergent findings reported in the imaging literature on depression could reflect modulation of activation by anxiety level in response to different types of emotional information.

  10. Chaperonin containing T-complex polypeptide subunit eta (CCT-eta is a specific regulator of fibroblast motility and contractility.

    Directory of Open Access Journals (Sweden)

    Latha Satish

    Full Text Available Integumentary wounds in mammalian fetuses heal without scar; this scarless wound healing is intrinsic to fetal tissues and is notable for absence of the contraction seen in postnatal (adult wounds. The precise molecular signals determining the scarless phenotype remain unclear. We have previously reported that the eta subunit of the chaperonin containing T-complex polypeptide (CCT-eta is specifically reduced in healing fetal wounds in a rabbit model. In this study, we examine the role of CCT-eta in fibroblast motility and contractility, properties essential to wound healing and scar formation. We demonstrate that CCT-eta (but not CCT-beta is underexpressed in fetal fibroblasts compared to adult fibroblasts. An in vitro wound healing assay demonstrated that adult fibroblasts showed increased cell migration in response to epidermal growth factor (EGF and platelet derived growth factor (PDGF stimulation, whereas fetal fibroblasts were unresponsive. Downregulation of CCT-eta in adult fibroblasts with short inhibitory RNA (siRNA reduced cellular motility, both basal and growth factor-induced; in contrast, siRNA against CCT-beta had no such effect. Adult fibroblasts were more inherently contractile than fetal fibroblasts by cellular traction force microscopy; this contractility was increased by treatment with EGF and PDGF. CCT-eta siRNA inhibited the PDGF-induction of adult fibroblast contractility, whereas CCT-beta siRNA had no such effect. In each of these instances, the effect of downregulating CCT-eta was to modulate the behavior of adult fibroblasts so as to more closely approximate the characteristics of fetal fibroblasts. We next examined the effect of CCT-eta modulation on alpha-smooth muscle actin (alpha-SMA expression, a gene product well known to play a critical role in adult wound healing. Fetal fibroblasts were found to constitutively express less alpha-SMA than adult cells. Reduction of CCT-eta with siRNA had minimal effect on cellular

  11. Posttranslational modulation on the biological activities of molecular chaperones

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Molecular chaperones are a family of proteins that were first noticed to exist about 45 years ago from their increased transcription under heat shock conditions.As a result,the regulation of their encoding genes has been subject to extensive studies.Recent studies revealed that the biological activities of molecular chaperones can also be effectively modulated at the protein level.The ways of modulation so far elucidated include allosteric effect,covalent modification,protein-protein interaction,and con-formational alteration induced by such macro-environmental conditions as temperature and pH.These latter aspects were reviewed here.Emphasized here is the importance of such immediate structural alterations that lead to an immediate activity increase,providing the immediate protection needed for the cells to survive the stress conditions.

  12. Posttranslational modulation on the biological activities of molecular chaperones

    Institute of Scientific and Technical Information of China (English)

    CHANG ZengYi

    2009-01-01

    Molecular chaperones are a family of proteins that were first noticed to exist about 45 years ago from their increased transcription under heat shock conditions. As a result, the regulation of their encoding genes has been subject to extensive studies. Recent studies revealed that the biological activities of molecular chaperones can also be effectively modulated at the protein level. The ways of modulation so far elucidated include allosteric effect, covalent modification, protein-protein interaction, and con-formational alteration induced by such macro-environmental conditions as temperature and pH. These latter aspects were reviewed here. Emphasized here is the importance of such immediate structural alterations that lead to an immediate activity increase, providing the immediate protection needed for the cells to survive the stress conditions.

  13. Caenorhabditis elegans glia modulate neuronal activity and behavior

    OpenAIRE

    Randy F Stout; Alexei eVerkhratsky; Vladimir eParpura

    2014-01-01

    Glial cells of Caenorhabditis 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 spe...

  14. Chaperonin GroEL/GroES Over-Expression Promotes Aminoglycoside Resistance and Reduces Drug Susceptibilities in Escherichia coli Following Exposure to Sublethal Aminoglycoside Doses

    DEFF Research Database (Denmark)

    Goltermann, Lise; Sarusie, Menachem V; Bentin, Thomas

    2016-01-01

    Antibiotic resistance is an increasing challenge to modern healthcare. Aminoglycoside antibiotics cause translation corruption and protein misfolding and aggregation in Escherichia coli. We previously showed that chaperonin GroEL/GroES depletion and over-expression sensitize and promote short-ter...... mechanism for emergence of antibiotic resistance.......Antibiotic resistance is an increasing challenge to modern healthcare. Aminoglycoside antibiotics cause translation corruption and protein misfolding and aggregation in Escherichia coli. We previously showed that chaperonin GroEL/GroES depletion and over-expression sensitize and promote short......-term tolerance, respectively, to this drug class. Here, we show that chaperonin GroEL/GroES over-expression accelerates acquisition of streptomycin resistance and reduces susceptibility to several other antibiotics following sub-lethal streptomycin antibiotic exposure. Chaperonin buffering could provide a novel...

  15. Cost Effective System Modeling of Active Micro- Module Solar Tracker

    Directory of Open Access Journals (Sweden)

    Md. Faisal Shuvo

    2014-01-01

    Full Text Available The increasing interests in using renewable energies are coming from solar thermal energy and solar photovoltaic systems to the micro production of electricity. Usually we already have considered the solar tracking topology in large scale applications like power plants and satellite but most of small scale applications don’t have any solar tracker system, mainly because of its high cost and complex circuit design. From that aspect, this paper confab microcontroller based one dimensional active micro-module solar tracking system, in which inexpensive LDR is used to generate reference voltage to operate microcontroller for functioning the tracking system. This system provides a fast response of tracking system to the parameters like change of light intensity as well as temperature variations. This micro-module model of tracking system can be used for small scale applications like portable electronic devices and running vehicles.

  16. Functional modulation of AMP-activated protein kinase by cereblon.

    Science.gov (United States)

    Lee, Kwang Min; Jo, Sooyeon; Kim, Hyunyoung; Lee, Jongwon; Park, Chul-Seung

    2011-03-01

    Mutations in cereblon (CRBN), a substrate binding component of the E3 ubiquitin ligase complex, cause a form of mental retardation in humans. However, the cellular proteins that interact with CRBN remain largely unknown. Here, we report that CRBN directly interacts with the α1 subunit of AMP-activated protein kinase (AMPK α1) and inhibits the activation of AMPK activation. The ectopic expression of CRBN reduces phosphorylation of AMPK α1 and, thus, inhibits the enzyme in a nutrient-independent manner. Moreover, AMPK α1 can be potently activated by suppressing endogenous CRBN using CRBN-specific small hairpin RNAs. Thus, CRBN may act as a negative modulator of the AMPK signaling pathway in vivo.

  17. 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.

  18. Simulation of the shape of chaperonins using the small-angle x-ray scattering curves and torus form factor

    Energy Technology Data Exchange (ETDEWEB)

    Amarantov, S. V., E-mail: amarantov_s@mail.ru [Russian Academy of Sciences, Shubnikov Institute of Crystallography (Russian Federation); Naletova, I. N. [Moscow State University, Belozerskii Institute of Molecular Biology and Bioorganic Chemistry (Russian Federation); Kurochkina, L. P. [Russian Academy of Sciences, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry (Russian Federation)

    2011-08-15

    The inverse scattering problem has been solved for protein complexes whose surfaces can be described by a set of the simplest doubly connected surfaces in the uniform approximation (a scattering potential inside the molecule is a constant). Solutions of two proteins-well-known GroEL bacterial chaperonin and poor-studied bacteriophage chaperonin, which is a product of 146 gene (gp146)-were taken for the experiment. The shapes of protein complexes have been efficiently reconstructed from the experimental scattering curves. The shell method, the method of the rotation of amino acid sequences with the use of the form factor of an amino acid, and the method of seeking the model parameters of a protein complex with the preliminarily obtained form factor of the model have been used to reconstruct the shape of these particles.

  19. Improved Control Strategy for Active Bouncers used in Klystron Modulators

    CERN Document Server

    Aguglia, D; Benedetti, M; Garcia Retegui, R; Maestri, S; Nisbet, D

    2012-01-01

    This paper introduces a closed-loop control system for klystron modulators. The system is based on the discharge of a capacitor into a step-up voltage transformer and an active bouncer implemented with a multiphase buck converter. In order to obtain a constant Klystron voltage at the at-top, the active bouncer must compensate both the capacitor discharge and the pulse transformer characteristic. The proposed control includes an inner voltage regulation loop that controls the active bouncer output voltage and an outer one that controls the klystron voltage. The primary side current and main capacitor voltage are included in the regulation loops to simplify the controllers. Simulations demonstrate that the strategy adopted allows to obtain a precision better than 0:1% on a 110 kV klystron. Experimental tests have shown that the multiphase converter is able to track a high dynamics reference even under variable output voltage conditions.

  20. Visual experience modulates spatio-temporal dynamics of circuit activation

    Directory of Open Access Journals (Sweden)

    Lang eWang

    2011-06-01

    Full Text Available Persistent reduction in sensory drive in early development results in multiple plastic changes of different cortical synapses. How these experience-dependent modifications affect the spatio-temporal dynamics of signal propagation in neocortical circuits is poorly understood. Here we demonstrate that brief visual deprivation significantly affects the propagation of electrical signals in the primary visual cortex. The spatio-temporal spread of circuit activation upon direct stimulation of its input layer (Layer 4 is reduced, as is the activation of Layer 2/3 – the main recipient of the output from Layer 4. Our data suggest that the decrease in spatio-temporal activation of L2/3 depends on reduced L4 output, and is not intrinsically generated within L2/3. The data shown here suggest that changes in the synaptic components of the visual cortical circuit result not only in alteration of local integration of excitatory and inhibitory inputs, but also in a significant decrease in overall circuit activation. Furthermore, our data indicate a differential effect of visual deprivation on L4 and L2/3, suggesting that while feedforward activation of L2/3 is reduced, its activation by long range, within layer inputs is unaltered. Thus, brief visual deprivation induces experience-dependent circuit re-organization by modulating not only circuit excitability, but also the spatio-temporal patterns of cortical activation within and between layers.

  1. Endogenous epoxygenases are modulators of monocyte/macrophage activity.

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    Jonas Bystrom

    Full Text Available BACKGROUND: Arachidonic acid is metabolized through three major metabolic pathways, the cyclooxygenase, lipoxygenase and CYP450 enzyme systems. Unlike cyclooxygenase and lipoxygenases, the role of CYP450 epoxygenases in monocyte/macrophage-mediated responses is not known. METHODOLOGY/PRINCIPAL FINDINGS: When transfected in vitro, CYP2J2 is an efficient activator of anti-inflammatory pathways through the nuclear receptor peroxisome proliferator-activated receptor (PPAR α. Human monocytes and macrophages contain PPARα and here we show they express the epoxygenases CYP2J2 and CYP2C8. Inhibition of constitutive monocyte epoxygenases using the epoxygenase inhibitor SKF525A induces cyclooxygenase (COX-2 expression and activity, and the release of TNFα, and can be reversed by either add back of the endogenous epoxygenase products and PPARα ligand 11,12- epoxyeicosatrienoic acid (EET or the addition of the selective synthetic PPARα ligand GW7647. In alternatively activated (IL-4-treated monocytes, in contrast to classically activated cells, epoxygenase inhibition decreased TNFα release. Epoxygenases can be pro-inflammatory via superoxide anion production. The suppression of TNFα by SKF525A in the presence of IL-4 was associated with a reduction in superoxide anion generation and reproduced by the superoxide dismutase MnCl(2. Similar to these acute activation studies, in monocyte derived macrophages, epoxygenase inhibition elevates M1 macrophage TNFα mRNA and further decreases M2 macrophage TNFα. CONCLUSIONS/SIGNIFICANCE: In conclusion, epoxygenase activity represents an important endogenous pathway which limits monocyte activation. Moreover endogenous epoxygenases are immuno-modulators regulating monocyte/macrophage activation depending on the underlying activation state.

  2. Modulation of human motoneuron activity by a mental arithmetic task.

    Science.gov (United States)

    Bensoussan, Laurent; Duclos, Yann; Rossi-Durand, Christiane

    2012-10-01

    This study aimed to determine whether the performance of a mental task affects motoneuron activity. To this end, the tonic discharge pattern of wrist extensor motor units was analyzed in healthy subjects while they were required to maintain a steady wrist extension force and to concurrently perform a mental arithmetic (MA) task. A shortening of the mean inter-spike interval (ISI) and a decrease in ISI variability occurred when MA task was superimposed to the motor task. Aloud and silent MA affected equally the rate and variability of motoneuron discharge. Increases in surface EMG activity and force level were consistent with the modulation of the motor unit discharge rate. Trial-by-trial analysis of the characteristics of motor unit firing revealed that performing MA increases activation of wrist extensor SMU. It is suggested that increase in muscle spindle afferent activity, resulting from fusimotor drive activation by MA, may have contributed to the increase in synaptic inputs to motoneurons during the mental task performance, likely together with enhancement in the descending drive. The finding that a mental task affects motoneuron activity could have consequences in assessment of motor disabilities and in rehabilitation in motor pathologies.

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

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    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.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    Neural oscillations in different frequency bands have been observed in a range of sensorimotor tasks and have been linked to coupling of spatially distinct neurons. The goal of this study was to detect a general motor network that is activated during phasic and tonic movements and to study the task......-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...... connecting frontal, cerebellar and central motor regions, was consistently activated throughout the motor tasks. Quantification of observed spectral responses using dynamic causal modeling revealed strong coupling in the c-band (30–48 Hz) between frontal and central motor regions when a slow finger movement...

  5. Modulation of CD44 Activity by A6-Peptide

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    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.

  6. Longitudinal and geomagnetic activity modulation of the equatorial thermosphere anomaly

    Science.gov (United States)

    Lei, Jiuhou; Thayer, Jeffrey P.; Forbes, Jeffrey M.

    2010-08-01

    In this paper we examine the detailed similarities and differences between the equatorial thermosphere anomaly (ETA) and the equatorial ionization anomaly (EIA) from 20 March to 6 April 2002, when both the ETA and the EIA are distinct in the Challenging Minisatellite Payload (CHAMP) observations. The characteristics of the ETA and the EIA are obtained from the CHAMP accelerometer, in situ electron density measurements, and total electron content (TEC) above the CHAMP satellite. Our results show that the trough locations of the ETA and the EIA in latitude show a good agreement, and both correspond well with the dip magnetic equator, while the ETA crests are usually located poleward of the EIA. Meanwhile, the latitudinal locations of the ETA crests exhibit strong hemispheric asymmetry and large variability during our study interval. The longitudinal variations between the EIA and the ETA show significant differences. The EIA crests from the CHAMP observations show strong wave 4 structures, but the primary component in the ETA is wave 1. Moreover, the ETA densities show strong variations in response to geomagnetic activity, whereas CHAMP in situ electron densities and TEC at the EIA do not reflect such large day-to-day variability. Therefore, a simple EIA-ETA relationship cannot explain the dependence of the longitudinal and geomagnetic activity modulation of the ETA and the EIA. The meridional ion drag, which is significantly modulated by enhanced equatorward winds during elevated geomagnetic activity, is probably responsible for some of the observed features in the ETA, although no unambiguous explanation for ETA formation yet exists.

  7. Fingolimod modulates microglial activation to augment markers of remyelination

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    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. Bidirectional modulation of substantia nigra activity by motivational state.

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    Mark A Rossi

    Full Text Available A major output nucleus of the basal ganglia is the substantia nigra pars reticulata, which sends GABAergic projections to brainstem and thalamic nuclei. The GABAergic (GABA neurons are reciprocally connected with nearby dopaminergic neurons, which project mainly to the basal ganglia, a set of subcortical nuclei critical for goal-directed behaviors. Here we examined the impact of motivational states on the activity of GABA neurons in the substantia nigra pars reticulata and the neighboring dopaminergic (DA neurons in the pars compacta. Both types of neurons show short-latency bursts to a cue predicting a food reward. As mice became sated by repeated consumption of food pellets, one class of neurons reduced cue-elicited firing, whereas another class of neurons progressively increased firing. Extinction or pre-feeding just before the test session dramatically reduced the phasic responses and their motivational modulation. These results suggest that signals related to the current motivational state bidirectionally modulate behavior and the magnitude of phasic response of both DA and GABA neurons in the substantia nigra.

  9. Alteration of chaperonin60 and pancreatic enzyme in pancreatic acinar cell under pathological condition

    Institute of Scientific and Technical Information of China (English)

    Yong-Yu Li; Moise Bendayan

    2005-01-01

    AIM: To investigate the changes of chaperonin60 (Cpn60)and pancreatic enzymes in pancreatic acinar cells, and to explore their roles in the development of experimental diabetes and acute pancreatitis (AP).METHODS: Two different pathological models were replicated in Sprague-Dawley rats: streptozotocininduced diabetes and sodium deoxycholate-induced AP. The contents of Cpn60 and pancreatic enzymes in different compartments of the acinar cells were measured by quantitative immunocytochemistry.RESULTS: The levels of Cpn60 significantly increased in diabetes, but decreased in AP, especially in the zymogen granules of the pancreatic acinar cells. The elevation of Cpn60 was accompanied with the increased levels of pancreatic lipase and chymotrypsinogen in diabetes.However, a decreased Cpn60 level was accompanied by high levels of lipase and chymotrypsinogen in AP.The amylase level was markedly reduced in both the pathological conditions.CONCLUSION: The equilibrium between Cpn60 and pancreatic enzymes in the acinar cells breaks in AP, and Cpn60 content decreases, suggesting an insufficient chaperone capacity. This may promote the aggregation and autoactivation of the premature enzymes in the pancreatic acinar cells and play roles in the development of AP.

  10. Allosteric transitions of supramolecular systems explored by network models: application to chaperonin GroEL.

    Directory of Open Access Journals (Sweden)

    Zheng Yang

    2009-04-01

    Full Text Available Identification of pathways involved in the structural transitions of biomolecular systems is often complicated by the transient nature of the conformations visited across energy barriers and the multiplicity of paths accessible in the multidimensional energy landscape. This task becomes even more challenging in exploring molecular systems on the order of megadaltons. Coarse-grained models that lend themselves to analytical solutions appear to be the only possible means of approaching such cases. Motivated by the utility of elastic network models for describing the collective dynamics of biomolecular systems and by the growing theoretical and experimental evidence in support of the intrinsic accessibility of functional substates, we introduce a new method, adaptive anisotropic network model (aANM, for exploring functional transitions. Application to bacterial chaperonin GroEL and comparisons with experimental data, results from action minimization algorithm, and previous simulations support the utility of aANM as a computationally efficient, yet physically plausible, tool for unraveling potential transition pathways sampled by large complexes/assemblies. An important outcome is the assessment of the critical inter-residue interactions formed/broken near the transition state(s, most of which involve conserved residues.

  11. The chaperonin genes of jakobid and jakobid-like flagellates: implications for eukaryotic evolution.

    Science.gov (United States)

    Archibald, John M; O'Kelly, Charles J; Doolittle, W Ford

    2002-04-01

    The jakobids are free-living mitochondriate protists that share ultrastructural features with certain amitochondriate groups and possess the most bacterial-like mitochondrial genomes described thus far. Jakobids belong to a diverse group of mitochondriate and amitochondriate eukaryotes, the excavate taxa. The relationships among the various excavate taxa and their relationships to other putative deep-branching protist groups are largely unknown. With the hope of clarifying these issues, we have isolated the cytosolic chaperonin CCTalpha gene from the jakobid Reclinomonas americana (strains 50394 and 50283), the jakobid-like malawimonad Malawimonas jakobiformis, two heteroloboseans (Acrasis rosea and Naegleria gruberi), a euglenozoan (Trypanosoma brucei), and a parabasalid (Monocercomonas sp.). We also amplified the CCTdelta gene from M. jakobiformis. The Reclinomonas and Malawimonas sequences presented here are among the first nuclear protein-coding genes to be described from these organisms. Unlike other putative early diverging protist lineages, a high density of spliceosomal introns was found in the jakobid and malawimonad CCTs-similar to that observed in vertebrate protein-coding genes. An analysis of intron positions in CCT genes from protists, plants, animals, and fungi suggests that many of the intron-sparse or intron-lacking protist lineages may not be primitively so but have lost spliceosomal introns during their evolutionary history. In phylogenetic trees constructed from CCTalpha protein sequences, R. americana (but not M. jakobiformis) shows a weak but consistent affinity for the Heterolobosea and Euglenozoa.

  12. The htpAB operon of Legionella pneumophila cannot be deleted in the presence of the groE chaperonin operon of Escherichia coli.

    Science.gov (United States)

    Nasrallah, Gheyath K; Gagnon, Elizabeth; Orton, Dennis J; Garduño, Rafael A

    2011-11-01

    HtpB, the chaperonin of the intracellular bacterial pathogen Legionella pneumophila , displays several virulence-related functions in vitro. To confirm HtpB's role in vivo, host infections with an htpB deletion mutant would be required. However, we previously reported that the htpAB operon (encoding co-chaperonin and chaperonin) is essential. We attempted here to delete htpAB in a L. pneumophila strain carrying the groE operon (encoding the Escherichia coli co-chaperonin and chaperonin). The groE operon was inserted into the chromosome of L. pneumophila Lp02, and then allelic replacement of htpAB with a gentamicin resistance cassette was attempted. Although numerous potential postallelic replacement transformants showed a correct selection phenotype, we still detected htpAB by PCR and full-size HtpB by immunoblot. Southern blot and PCR analysis indicated that the gentamicin resistance cassette had apparently integrated in a duplicated htpAB region. However, we showed by Southern blot that strain Lp02, and the Lp02 derivative carrying the groE operon, have only one copy of htpAB. These results confirmed that the htpAB operon cannot be deleted, not even in the presence of the groE operon, and suggested that attempts to delete htpAB under strong phenotypic selection result in aberrant genetic recombinations that could involve duplication of the htpAB locus.

  13. Coco is a dual activity modulator of TGFβ signaling

    Science.gov (United States)

    Deglincerti, Alessia; Haremaki, Tomomi; Warmflash, Aryeh; Sorre, Benoit; Brivanlou, Ali H.

    2015-01-01

    The TGFβ signaling pathway is a crucial regulator of developmental processes and disease. The activity of TGFβ ligands is modulated by various families of soluble inhibitors that interfere with the interactions between ligands and receptors. In an unbiased, genome-wide RNAi screen to identify genes involved in ligand-dependent signaling, we unexpectedly identified the BMP/Activin/Nodal inhibitor Coco as an enhancer of TGFβ1 signaling. Coco synergizes with TGFβ1 in both cell culture and Xenopus explants. Molecularly, Coco binds to TGFβ1 and enhances TGFβ1 binding to its receptor Alk5. Thus, Coco acts as both an inhibitor and an enhancer of signaling depending on the ligand it binds. This finding raises the need for a global reconsideration of the molecular mechanisms regulating TGFβ signaling. PMID:26116664

  14. Workshop Physics Activity Guide, Module 4: Electricity and Magnetism

    Science.gov (United States)

    Laws, Priscilla W.

    2004-05-01

    The Workshop Physics Activity Guide is a set of student workbooks designed to serve as the foundation for a two-semester calculus-based introductory physics course. It consists of 28 units that interweave text materials with activities that include prediction, qualitative observation, explanation, equation derivation, mathematical modeling, quantitative experiments, and problem solving. Students use a powerful set of computer tools to record, display, and analyze data, as well as to develop mathematical models of physical phenomena. The design of many of the activities is based on the outcomes of physics education research. The Workshop Physics Activity Guide is supported by an Instructor's Website that: (1) describes the history and philosophy of the Workshop Physics Project; (2) provides advice on how to integrate the Guide into a variety of educational settings; (3) provides information on computer tools (hardware and software) and apparatus; and (4) includes suggested homework assignments for each unit. Log on to the Workshop Physics Project website at http://physics.dickinson.edu/ Workshop Physics is a component of the Physics Suite--a collection of materials created by a group of educational reformers known as the Activity Based Physics Group. The Physics Suite contains a broad array of curricular materials that are based on physics education research, including: Understanding Physics, by Cummings, Laws, Redish and Cooney (an introductory textbook based on the best-selling text by Halliday/Resnick/Walker) RealTime Physics Laboratory Modules Physics by Inquiry (intended for use in a workshop setting) Interactive Lecture Demonstration Tutorials in Introductory Physics Activity Based Tutorials (designed primarily for use in recitations)

  15. Auditory cortex basal activity modulates cochlear responses in chinchillas.

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    Alex León

    Full Text Available BACKGROUND: The auditory efferent system has unique neuroanatomical pathways that connect the cerebral cortex with sensory receptor cells. Pyramidal neurons located in layers V and VI of the primary auditory cortex constitute descending projections to the thalamus, inferior colliculus, and even directly to the superior olivary complex and to the cochlear nucleus. Efferent pathways are connected to the cochlear receptor by the olivocochlear system, which innervates outer hair cells and auditory nerve fibers. The functional role of the cortico-olivocochlear efferent system remains debated. We hypothesized that auditory cortex basal activity modulates cochlear and auditory-nerve afferent responses through the efferent system. METHODOLOGY/PRINCIPAL FINDINGS: Cochlear microphonics (CM, auditory-nerve compound action potentials (CAP and auditory cortex evoked potentials (ACEP were recorded in twenty anesthetized chinchillas, before, during and after auditory cortex deactivation by two methods: lidocaine microinjections or cortical cooling with cryoloops. Auditory cortex deactivation induced a transient reduction in ACEP amplitudes in fifteen animals (deactivation experiments and a permanent reduction in five chinchillas (lesion experiments. We found significant changes in the amplitude of CM in both types of experiments, being the most common effect a CM decrease found in fifteen animals. Concomitantly to CM amplitude changes, we found CAP increases in seven chinchillas and CAP reductions in thirteen animals. Although ACEP amplitudes were completely recovered after ninety minutes in deactivation experiments, only partial recovery was observed in the magnitudes of cochlear responses. CONCLUSIONS/SIGNIFICANCE: These results show that blocking ongoing auditory cortex activity modulates CM and CAP responses, demonstrating that cortico-olivocochlear circuits regulate auditory nerve and cochlear responses through a basal efferent tone. The diversity of the

  16. 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.

  17. Astrocytic Orosomucoid-2 Modulates Microglial Activation and Neuroinflammation.

    Science.gov (United States)

    Jo, Myungjin; Kim, Jong-Heon; Song, Gyun Jee; Seo, Minchul; Hwang, Eun Mi; Suk, Kyoungho

    2017-03-15

    Orosomucoid (ORM) is an acute-phase protein that belongs to the immunocalin subfamily, a group of small-molecule-binding proteins with immunomodulatory functions. Little is known about the role of ORM proteins in the CNS. The aim of the present study was to investigate the brain expression of ORM and its role in neuroinflammation. Expression of Orm2, but not Orm1 or Orm3, was highly induced in the mouse brain after systemic injection of lipopolysaccharide (LPS). Plasma levels of ORM2 were also significantly higher in patients with cognitive impairment than in normal subjects. RT-PCR, Western blot, and immunofluorescence analyses revealed that astrocytes are the major cellular sources of ORM2 in the inflamed mouse brain. Recombinant ORM2 protein treatment decreased microglial production of proinflammatory mediators and reduced microglia-mediated neurotoxicity in vitro LPS-induced microglial activation, proinflammatory cytokines in hippocampus, and neuroinflammation-associated cognitive deficits also decreased as a result of intracerebroventricular injection of recombinant ORM2 protein in vivo Moreover, lentiviral shRNA-mediated Orm2 knockdown enhanced LPS-induced proinflammatory cytokine gene expression and microglial activation in the hippocampus. Mechanistically, ORM2 inhibited C-C chemokine ligand 4 (CCL4)-induced microglial migration and activation by blocking the interaction of CCL4 with C-C chemokine receptor type 5. Together, the results from our cultured glial cells, mouse neuroinflammation model, and patient studies suggest that ORM2 is a novel mediator of astrocyte-microglial interaction. We also report that ORM2 exerts anti-inflammatory effects by modulating microglial activation and migration during brain inflammation. ORM2 can be exploited therapeutically for the treatment of neuroinflammatory diseases.SIGNIFICANCE STATEMENT Neural cell interactions are important for brain physiology and pathology. Particularly, the interaction between non

  18. Disease-associated mutations in the HSPD1 gene encoding the large subunit of the mitochondrial HSP60/HSP10 chaperonin complex

    Directory of Open Access Journals (Sweden)

    Peter Bross

    2016-08-01

    Full Text Available Heat shock protein 60 (HSP60 forms together with heat shock protein 10 (HSP10 double-barrel chaperonin complexes that are essential for folding to the native state of proteins in the mitochondrial matrix space. Two extremely rare monogenic disorders have been described that are caused by missense mutations in the HSPD1 gene that encodes the HSP60 subunit of the HSP60/HSP10 chaperonin complex. Investigations of the molecular mechanisms underlying these disorders have revealed that different degrees of reduced HSP60 function produce distinct neurological phenotypes. While mutations with deleterious or strong dominant negative effects are not compatible with life, HSPD1 gene variations found in the human population impair HSP60 function and depending on the mechanism and degree of HSP60 dys- and malfunction cause different phenotypes. We here summarize the knowledge on the effects of disturbances of the function of the HSP60/HSP10 chaperonin complex by disease-associated mutations.

  19. Cannabinoids modulate spontaneous synaptic activity in retinal ganglion cells.

    Science.gov (United States)

    Middleton, T P; Protti, D A

    2011-09-01

    The endocannabinoid (ECB) system has been found throughout the central nervous system and modulates cell excitability in various forms of short-term plasticity. ECBs and their receptors have also been localized to all retinal cells, and cannabinoid receptor activation has been shown to alter voltage-dependent conductances in several different retinal cell types, suggesting a possible role for cannabinoids in retinal processing. Their effects on synaptic transmission in the mammalian retina, however, have not been previously investigated. Here, we show that exogenous cannabinoids alter spontaneous synaptic transmission onto retinal ganglion cells (RGCs). Using whole-cell voltage-clamp recordings in whole-mount retinas, we measured spontaneous postsynaptic currents (SPSCs) in RGCs in adult and young (P14-P21) mice. We found that the addition of an exogenous cannabinoid agonist, WIN55212-2 (5 μM), caused a significant reversible reduction in the frequency of SPSCs. This change, however, did not alter the kinetics of the SPSCs, indicating a presynaptic locus of action. Using blockers to isolate inhibitory or excitatory currents, we found that cannabinoids significantly reduced the release probability of both GABA and glutamate, respectively. While the addition of cannabinoids reduced the frequency of both GABAergic and glutamatergic SPSCs in both young and adult mice, we found that the largest effect was on GABA-mediated currents in young mice. These results suggest that the ECB system may potentially be involved in the modulation of signal transmission in the retina. Furthermore, they suggest that it might play a role in the developmental maturation of synaptic circuits, and that exogenous cannabinoids are likely able to disrupt retinal processing and consequently alter vision.

  20. Micro-Stirling Active Cooling Module (MS/ACM) for DoD Electronics Systems

    Science.gov (United States)

    2012-03-01

    Micro- Stirling Active Cooling Module (MS/ACM) for DoD Electronics Systems Douglas S. Beck Beck Engineering, Inc. 1490 Lumsden Road, Port Orchard...refrigerator. We are developing for DARPA a cm-scale Micro- Stirling Active Cooling Module (MS/ACM) micro- refrigerator to benefit the DoD systems. Under...a DARPA contract, we are designing, building, and demonstrating a breadboard MS/ACM. Keywords: Stirling ; cooler; active cooling module; micro

  1. 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...

  2. Photo-Doped Active Electrically Controlled Terahertz Modulator

    Institute of Scientific and Technical Information of China (English)

    Bo Zhang; Liang Zhong; Ting He; Jing-Ling Shen

    2015-01-01

    We demonstrate an electric-controlled terahertz (THz) modulator which can be used to realize amplitude modulation of terahertz waves with slight photo-doping. The THz pulse transmission was efficiently modulated by electrically controlling the monolayer silicon-based device. The modulation depth reached 100% almost when the applied voltage was 7V at an external laser intensity of 0.6W/cm2. The saturation voltage reduced with the increase of the photo-excited intensity. In a THz continuous wave (CW) system, a significant fall in both THz transmission and reflection was also observed with the increase of applied voltage. This reduction in the THz transmission and reflection was induced by the absorption for electron injection. The results show that a high-efficiency and high modulation depth broadband electric-controlled terahertz modulator in a pure Si structure has been realized.

  3. 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.

  4. Rare earth activated yttrium aluminate phosphors with modulated luminescence.

    Science.gov (United States)

    Muresan, L E; Popovici, E J; Perhaita, I; Indrea, E; Oro, J; Casan Pastor, N

    2016-06-01

    Yttrium aluminate (Y3 A5 O12 ) was doped with different rare earth ions (i.e. Gd(3+) , Ce(3+) , Eu(3+) and/or Tb(3+) ) in order to obtain phosphors (YAG:RE) with general formula,Y3-x-a Gdx REa Al5 O12 (x = 0; 1.485; 2.97 and a = 0.03). The synthesis of the phosphor samples was done using the simultaneous addition of reagents technique. This study reveals new aspects regarding the influence of different activator ions on the morpho-structural and luminescent characteristics of garnet type phosphor. All YAG:RE phosphors are well crystallized powders containing a cubic-Y3 Al5 O12 phase as major component along with monoclinic-Y4 Al2 O9 and orthorhombic-YAlO3 phases as the impurity. The crystallites dimensions of YAG:RE phosphors vary between 38 nm and 88 nm, while the unit cell slowly increase as the ionic radius of the activator increases. Under UV excitation, YAG:Ce exhibits yellow emission due to electron transition in Ce(3+) from the 5d level to the ground state levels ((2) F5/2 , (2) F7/2 ). The emission intensity of Ce(3+) is enhanced in the presence of the Tb(3+) ions and is decreased in the presence of Eu(3+) ions due to some radiative or non-radiative processes that take place between activator ions. By varying the rare earth ions, the emission colour can be modulated from green to white and red. Copyright © 2015 John Wiley & Sons, Ltd.

  5. Modulation of RNase E activity by alternative RNA binding sites.

    Directory of Open Access Journals (Sweden)

    Daeyoung Kim

    Full Text Available Endoribonuclease E (RNase E affects the composition and balance of the RNA population in Escherichia coli via degradation and processing of RNAs. In this study, we investigated the regulatory effects of an RNA binding site between amino acid residues 25 and 36 (24LYDLDIESPGHEQK37 of RNase E. Tandem mass spectrometry analysis of the N-terminal catalytic domain of RNase E (N-Rne that was UV crosslinked with a 5'-32P-end-labeled, 13-nt oligoribonucleotide (p-BR13 containing the RNase E cleavage site of RNA I revealed that two amino acid residues, Y25 and Q36, were bound to the cytosine and adenine of BR13, respectively. Based on these results, the Y25A N-Rne mutant was constructed, and was found to be hypoactive in comparison to wild-type and hyperactive Q36R mutant proteins. Mass spectrometry analysis showed that Y25A and Q36R mutations abolished the RNA binding to the uncompetitive inhibition site of RNase E. The Y25A mutation increased the RNA binding to the multimer formation interface between amino acid residues 427 and 433 (427LIEEEALK433, whereas the Q36R mutation enhanced the RNA binding to the catalytic site of the enzyme (65HGFLPL*K71. Electrophoretic mobility shift assays showed that the stable RNA-protein complex formation was positively correlated with the extent of RNA binding to the catalytic site and ribonucleolytic activity of the N-Rne proteins. These mutations exerted similar effects on the ribonucleolytic activity of the full-length RNase E in vivo. Our findings indicate that RNase E has two alternative RNA binding sites for modulating RNA binding to the catalytic site and the formation of a functional catalytic unit.

  6. Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy.

    Science.gov (United States)

    Hapgood, Janet P; Avenant, Chanel; Moliki, Johnson M

    2016-09-01

    Pharmacological doses of glucocorticoids (GCs), acting via the glucocorticoid receptor (GR) to repress inflammation and immune function, remain the most effective therapy in the treatment of inflammatory and immune diseases. Since many patients on GC therapy exhibit GC resistance and severe side-effects, much research is focused on developing more selective GCs and combination therapies, with greater anti-inflammatory potency. GCs mediate their classical genomic transcriptional effects by binding to the cytoplasmic GR, followed by nuclear translocation and modulation of transcription of target genes by direct DNA binding of the GR or its tethering to other transcription factors. Recent evidence suggests, however, that the responses mediated by the GR are much more complex and involve multiple parallel mechanisms integrating simultaneous signals from other receptors, both in the absence and presence of GCs, to shift the sensitivity of a target cell to GCs. The level of cellular stress, immune activation status, or the cell cycle phase may be crucial for determining GC sensitivity and GC responsiveness as well as subcellular localization of the GR and GR levels. Central to the development of new drugs that target GR signaling alone or as add-on therapies, is an in-depth understanding of the molecular mechanisms of GC-independent GR desensitization, priming and activation of the unliganded GR, as well as synergy and cross-talk with other signaling pathways. This review will discuss the information currently available on these topics and their relevance to immunotherapy, as well as identify unanswered questions and future areas of research.

  7. 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. PMID:27445696

  8. Unified active and reactive power modulation of HVDC transmission systems

    Science.gov (United States)

    Grund, C. E.; Pohl, R. V.

    1981-11-01

    The power modulation of a high voltage direct current (HVDC) system for stabilization of an ac/dc network was investigated. It was found that simultaneous modulation of both dc current and voltage was more effective than just current modulation by itself, since the dc voltage modulation could be used to minimize the reactive power changes resulting from a change of the dc current. This helps stabilize the ac busbar voltages at the converters, which reduces undesirable load flow changes to voltage dependent ac loads, thus improving the effectiveness of the dc power modulation. This unified modulation control concept was evaluated by means of digital computer studies as well as a special purpose HVDC simulator. Several combined ac/dc power transmission systems were synthesized for testing of different modulation controller concepts. An optimum controller design incorporating a linear quadratic control algorithm with full state feedback was first studied. This provided a basis for comparison of suboptimal controller designs utilizing reduced state feedback and a Kalman filter state reconstruction technique.

  9. Activity of catalytic silver nanoparticles modulated by capping agent hydrophobicity.

    Science.gov (United States)

    Janani, Seralathan; Stevenson, Priscilla; Veerappan, Anbazhagan

    2014-05-01

    In this paper, a facile in situ method is reported for the preparation of catalytic silver nanoparticles (AgNPs) using N-acyl tyramine (NATA) with variable hydrophobic acyl length. Scanning electron microscopic analysis shows that NATA exists initially as larger aggregates in alkaline aqueous solution. The addition of AgNO3 dissociates these larger aggregate and subsequently promotes the formation of self-assembled NATA and AgNPs. Characterization of AgNPs using UV-vis spectroscopy, scanning electron microscope and transmission electron microscope revealed that the hydrophobic acyl chain length of NATA does not influence the particle size, shape and morphology. All NATA-AgNPs yielded relatively identical values in full width at half-maximum (FWHM) analysis, indicating that the AgNPs prepared with NATA are relatively polydispersed at all tested acyl chain lengths. These nanoparticles are able to efficiently catalyze the reduction of 4-nitro phenol to 4-amino phenol, 2-nitro aniline to 1,2-diamino benzene, 2,4,6-trinitro phenol to 2,4,6-triamino phenol by NaBH4 in an aqueous environment. The reduction reaction rate is determined to be pseudo-first order and the apparent rate constant is linearly dependent on the hydrophobic acyl chain length of the NATA. All reaction kinetics presented an induction period, which is dependent on the N-acyl chain length, indicating that the hydrophobic effects play a critical role in bringing the substrate to the metal nanoparticle surface to induce the catalytic reaction. In this study, however, the five catalytic systems have similar size and polydispersity, differing only in terms of capping agent hydrophobicity, and shows different catalytic activity with respect to the alkyl chain length of the capping agent. As discussed, the ability to modulate the metal nanoparticles catalytic property, by modifying the capping agent hydrophobicity represents a promising future for developing an efficient nanocatalyst without altering the size

  10. Modulation of neuronal microcircuit activities within the medial prefrontal cortex by mGluR5 positive allosteric modulator.

    Science.gov (United States)

    Pollard, Marie; Bartolome, Jose Manuel; Conn, P Jeffrey; Steckler, Thomas; Shaban, Hamdy

    2014-10-01

    Suppressing anxiety and fear memory relies on bidirectional projections between the medial prefrontal cortex and the amygdala. Positive allosteric modulators of mGluR5 improve cognition in animal models of schizophrenia and retrieval of newly formed associations such as extinction of fear-conditioned behaviour. The increase in neuronal network activities of the medial prefrontal cortex is influenced by both mGluR1 and mGluR5; however, it is not well understood how they modulate network activities and downstream information processing. To map mGluR5-mediated network activity in relation to its emergence as a viable cognitive enhancer, we tested group I mGluR compounds on medial prefrontal cortex network activity via multi-electrode array neuronal spiking and whole-cell patch clamp recordings. Results indicate that mGluR5 activation promotes feed-forward inhibition that depends on recruitment of neuronal activity by carbachol-evoked up states. The rate of neuronal spiking activity under the influence of carbachol was reduced by the mGluR5 positive allosteric modulator, N-(1,3-Diphenyl-1H-pyrazolo-5-yl)-4-nitrobenzamide (VU-29), and enhanced by the mGluR5 negative allosteric modulator, 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP). Spontaneous inhibitory post-synaptic currents were increased upon application of carbachol and in combination with VU-29. These results emphasize a bias towards tonic mGluR5-mediated inhibition that might serve as a signal-to-noise enhancer of sensory inputs projected from associated limbic areas onto the medial prefrontal cortex neuronal microcircuit.

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. The study of disk resonators diode modules, solid-state generators active

    Directory of Open Access Journals (Sweden)

    B. A. Kotserzhinskii

    1987-12-01

    Full Text Available The results of an experimental study of disk resonators diode modules, solid-state active microwave generators. The effect of current leads, as well as errors in the manufacture of resonators their characteristics.

  17. Identification of Post-Transcriptional Modulators of Breast Cancer Transcription Factor Activity Using MINDy

    Science.gov (United States)

    Campbell, Thomas M.; Castro, Mauro A. A.; Ponder, Bruce A. J.

    2016-01-01

    We have recently identified transcription factors (TFs) that are key drivers of breast cancer risk. To better understand the pathways or sub-networks in which these TFs mediate their function we sought to identify upstream modulators of their activity. We applied the MINDy (Modulator Inference by Network Dynamics) algorithm to four TFs (ESR1, FOXA1, GATA3 and SPDEF) that are key drivers of estrogen receptor-positive (ER+) breast cancer risk, as well as cancer progression. Our computational analysis identified over 500 potential modulators. We assayed 189 of these and identified 55 genes with functional characteristics that were consistent with a role as TF modulators. In the future, the identified modulators may be tested as potential therapeutic targets, able to alter the activity of TFs that are critical in the development of breast cancer. PMID:27997592

  18. [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.

  19. Muscarinic modulation of sodium current by activation of protein kinase C in rat hippocampal neurons.

    Science.gov (United States)

    Cantrell, A R; Ma, J Y; Scheuer, T; Catterall, W A

    1996-05-01

    Phosphorylation of brain Na+ channels by protein kinase C (PKC) decreases peak Na+ current and slows macroscopic inactivation, but receptor-activated modulation of Na+ currents via the PKC pathway has not been demonstrated. We have examined modulation of Na+ channels by activation of muscarinic receptors in acutely-isolated hippocampal neurons using whole-cell voltage-clamp recording. Application of the muscarinic agonist carbachol reduced peak Na+ current and slowed macroscopic inactivation at all potentials, without changing the voltage-dependent properties of the channel. These effects were mediated by PKC, since they were eliminated when the specific PKC inhibitor (PKCI19-36) was included in the pipette solution and mimicked by the extracellular application of the PKC activator, OAG. Thus, activation of endogenous muscarinic receptors on hippocampal neurons strongly modulates Na+ channel activity by activation of PKC. Cholinergic input from basal forebrain neurons may have this effect in the hippocampus in vivo.

  20. Magnesium Modulates Doxorubicin Activity through Drug Lysosomal Sequestration and Trafficking.

    Science.gov (United States)

    Trapani, Valentina; Luongo, Francesca; Arduini, Daniela; Wolf, Federica I

    2016-03-21

    Magnesium is directly involved in the control of cell growth and survival, but its role in cancer biology and therapy is multifaceted; in particular, it is highly controversial whether magnesium levels can affect therapy outcomes. Here we investigated whether magnesium availability can modulate cellular responses to the widely used chemotherapeutic doxorubicin. We used an in vitro model consisting of mammary epithelial HC11 cells and found that high magnesium availability was correlated with diminished sensitivity both in cells chronically adapted to high magnesium concentrations and in acutely magnesium-supplemented cells. This decrease in sensitivity resulted from reduced intracellular doxorubicin accumulation in the face of a similar drug uptake rate. We observed that high-magnesium conditions caused a decrease in intracellular drug retention by altering drug lysosomal sequestration and trafficking. In our model, magnesium supplementation correspondingly modulated expression of the TRPM7 channel, which is known to control cytoskeletal organization and dynamics and may be involved in the proposed mechanism. Our findings suggest that magnesium supplementation in hypomagnesemic cancer patients may hinder response to therapy.

  1. Pre-stimulus BOLD-network activation modulates EEG spectral activity during working memory retention

    Directory of Open Access Journals (Sweden)

    Mara eKottlow

    2015-05-01

    Full Text Available Working memory (WM processes depend on our momentary mental state and therefore exhibit considerable fluctuations. Here, we investigate the interplay of task-preparatory and task-related brain activity as represented by pre-stimulus BOLD-fluctuations and spectral EEG from the retention periods of a visual WM task. Visual WM is used to maintain sensory information in the brain enabling the performance of cognitive operations and is associated with mental health.We tested 22 subjects simultaneously with EEG and fMRI while performing a visuo-verbal Sternberg task with two different loads, allowing for the temporal separation of preparation, encoding, retention and retrieval periods.Four temporally coherent networks - the default mode network (DMN, the dorsal attention, the right and the left WM network - were extracted from the continuous BOLD data by means of a group ICA. Subsequently, the modulatory effect of these networks’ pre-stimulus activation upon retention-related EEG activity in the theta, alpha and beta frequencies was analyzed. The obtained results are informative in the context of state-dependent information processing.We were able to replicate two well-known load-dependent effects: the frontal-midline theta increase during the task and the decrease of pre-stimulus DMN activity. As our main finding, these two measures seem to depend on each other as the significant negative correlations at frontal-midline channels suggested. Thus, suppressed pre-stimulus DMN levels facilitated later task related frontal midline theta increases. In general, based on previous findings that neuronal coupling in different frequency bands may underlie distinct functions in WM retention, our results suggest that processes reflected by spectral oscillations during retention seem not only to be online synchronized with activity in different attention-related networks but are also modulated by activity in these networks during preparation intervals.

  2. Modulating the Anticancer Activity of Ruthenium(II)-Arene Complexes.

    Science.gov (United States)

    Clavel, Catherine M; Păunescu, Emilia; Nowak-Sliwinska, Patrycja; Griffioen, Arjan W; Scopelliti, Rosario; Dyson, Paul J

    2015-04-23

    Following the identification of [Ru(η(6)-p-cymene)Cl2(1H,1H,2H,2H-perfluorodecyl-3-(pyridin-3-yl)propanoate)], a ruthenium(II)-arene complex with a perfluoroalkyl-modified ligand that displays remarkable in vitro cancer cell selectivity, a series of structurally related compounds were designed. In the new derivatives, the p-cymene ring and/or the chloride ligands are substituted by other ligands to modulate the steric bulk or aquation kinetics. The new compounds were evaluated in both in vitro (cytotoxicity and migration assays) and in vivo (chicken chorioallantoic membrane) models and were found to exhibit potent antivascular effects.

  3. The modulation of pancreatic lipase activity by alginates

    OpenAIRE

    Wilcox, Matthew D.; Brownlee, Iain A.; Richardson, J. Craig; Dettmar, Peter W.; Jeffrey P. Pearson

    2014-01-01

    Alginates are comprised of mannuronic (M) and guluronic acid (G) and have been shown to inhibit enzyme activity. Pancreatic lipase is important in dietary triacylglycerol breakdown; reducing pancreatic lipase activity would reduce triacylglycerol breakdown resulting in lower amounts being absorbed by the body. Lipase activity in the presence of biopolymers was assessed by enzymatic assay using natural and synthetic substrates. Alginate inhibited pancreatic lipase by a maximum of 72.2% (±4.1) ...

  4. 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.

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

    DEFF Research Database (Denmark)

    Babicheva, Viktoriia; Lavrinenko, Andrei

    2012-01-01

    We study an ultra-compact plasmonic modulator that can be applied in photonic integrated circuits. The modulator is a metal-insulator-metal waveguide with an additional ultra-thin layer of indium tin oxide (ITO). Bias is applied to the multilayer core by means of metal plates that serve...... several optimizations. We examine influence of the ITO permittivity on the modulator's performance and point out appropriate values. We analyze eigenmodes of the waveguide structure and specify the range for its efficient operation. We show that substituting the continuous active layer by a one......-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...

  6. 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.

  7. 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

  8. UHF wearable battery free sensor module for activity and falling detection.

    Science.gov (United States)

    Nam Trung Dang; Thang Viet Tran; Wan-Young Chung

    2016-08-01

    Falling is one of the most serious medical and social problems in aging population. Therefore taking care of the elderly by detecting activity and falling for preventing and mitigating the injuries caused by falls needs to be concerned. This study proposes a wearable, wireless, battery free ultra-high frequency (UHF) smart sensor tag module for falling and activity detection. The proposed tag is powered by UHF RF wave from reader and read by a standard UHF Electronic Product Code (EPC) Class-1 Generation-2 reader. The battery free sensor module could improve the wearability of the wireless device. The combination of accelerometer signal and received signal strength indication (RSSI) from a reader in the passive smart sensor tag detect the activity and falling of the elderly very successfully. The fabricated smart sensor tag module has an operating range of up to 2.5m and conducting in real-time activity and falling detection.

  9. Social status modulates neural activity in the mentalizing network.

    Science.gov (United States)

    Muscatell, Keely A; Morelli, Sylvia A; Falk, Emily B; Way, Baldwin M; Pfeifer, Jennifer H; Galinsky, Adam D; Lieberman, Matthew D; Dapretto, Mirella; Eisenberger, Naomi I

    2012-04-15

    The current research explored the neural mechanisms linking social status to perceptions of the social world. Two fMRI studies provide converging evidence that individuals lower in social status are more likely to engage neural circuitry often involved in 'mentalizing' or thinking about others' thoughts and feelings. Study 1 found that college students' perception of their social status in the university community was related to neural activity in the mentalizing network (e.g., DMPFC, MPFC, precuneus/PCC) while encoding social information, with lower social status predicting greater neural activity in this network. Study 2 demonstrated that socioeconomic status, an objective indicator of global standing, predicted adolescents' neural activity during the processing of threatening faces, with individuals lower in social status displaying greater activity in the DMPFC, previously associated with mentalizing, and the amygdala, previously associated with emotion/salience processing. These studies demonstrate that social status is fundamentally and neurocognitively linked to how people process and navigate their social worlds.

  10. 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.

  11. 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....

  12. 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…

  13. 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.

  14. Modulation of NADPH oxidase activity by known uraemic retention solutes

    DEFF Research Database (Denmark)

    Schulz, Anna Marta; Terne, Cindy; Jankowski, Vera

    2014-01-01

    as the strongest inhibitor of NADPH oxidase (90% of DPI inhibition). Surprisingly, none of the uraemic retention solutes we investigated was found to increase NADPH oxidase activity. Furthermore, plasma from patients with CKD-5D before dialysis caused significantly higher inhibitory effect on NADPH oxidase...... inhibitory effect on NADPH oxidase activity in the presence of plasma from patients with CKD-5D after dialysis compared with before dialysis, we investigated the effect of 48 known and commercially available uraemic retention solutes on the enzymatic activity of NADPH oxidase. METHODS: Mononuclear leucocytes...... isolated from buffy coats of healthy volunteers were isolated, lysed and incubated with NADH in the presence of plasma from healthy controls and patients with CKD-5D. Furthermore, the leucocytes were lysed and incubated in the presence of uraemic retention solute of interest and diphenyleneiodonium...

  15. 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

  16. 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.

  17. 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.

  18. Etk/Bmx activation modulates barrier function in epithelial cells.

    Science.gov (United States)

    Hamm-Alvarez, S F; Chang, A; Wang, Y; Jerdeva, G; Lin, H H; Kim, K J; Ann, D K

    2001-06-01

    Etk/Bmx is a member of the Tec family of cytoplasmic non-receptor tyrosine kinases known to express in epithelial cells. We demonstrate herein that Etk activation in stably Etk-transfected epithelial Pa-4 cells resulted in a consistently increased transepithelial resistance (TER). After 24 h of hypoxic (1% O(2)) exposure, the TER and equivalent active ion transport rate (I(eq)) were reduced to <5% of the normoxia control in Pa-4 cells, whereas both TER and I(eq) were maintained at comparable and 60% levels, respectively, relative to their normoxic controls in cells with Etk activation. Moreover, Pa-4 cells exhibited an abundant actin stress fiber network with a diffuse distribution of beta-catenin at the cell periphery. By contrast, Etk-activated cells displayed a redistribution of actin to an exclusively peripheral network, with a discrete band of beta-catenin also concentrated at the cell periphery, and an altered occludin distribution profile. On the basis of these findings, we propose that Etk may be a novel regulator of epithelial junctions during physiological and pathophysiological conditions.

  19. CYLD regulates RhoA activity by modulating LARG ubiquitination.

    Directory of Open Access Journals (Sweden)

    Yunfan Yang

    Full Text Available Rho family guanosine triphosphatases (GTPases, such as RhoA, Cdc42, and Rac1, play a fundamental role in various cellular processes. The activation of Rho proteins is catalyzed by guanine nucleotide-exchange factors (GEFs, which promote the exchange of GDP for GTP. The precise mechanisms regulating the activation of Rho proteins are not fully understood. Herein, we demonstrate that RhoA activity is regulated by cylindromatosis (CYLD, a deubiquitinase harboring multiple functions. In addition, we find that RhoA-mediated cytoskeletal rearrangement, chromosome separation, and cell polarization are altered in CYLD-depleted cells. Mechanistically, CYLD does not interact with RhoA; instead, it interacts with and deubiquitinates leukemia-associated RhoGEF (LARG. Our data further show that CYLD-mediated deubiquitination of LARG enhances its ability to stimulate the GDP/GTP exchange on RhoA. These data thus identify LARG as a new substrate of CYLD and provide novel insights into the regulation of RhoA activation. Our results also suggest that the LARG-RhoA signaling pathway may play a role in diverse CYLD-mediated cellular events.

  20. CYLD regulates RhoA activity by modulating LARG ubiquitination.

    Science.gov (United States)

    Yang, Yunfan; Sun, Lei; Tala; Gao, Jinmin; Li, Dengwen; Zhou, Jun; Liu, Min

    2013-01-01

    Rho family guanosine triphosphatases (GTPases), such as RhoA, Cdc42, and Rac1, play a fundamental role in various cellular processes. The activation of Rho proteins is catalyzed by guanine nucleotide-exchange factors (GEFs), which promote the exchange of GDP for GTP. The precise mechanisms regulating the activation of Rho proteins are not fully understood. Herein, we demonstrate that RhoA activity is regulated by cylindromatosis (CYLD), a deubiquitinase harboring multiple functions. In addition, we find that RhoA-mediated cytoskeletal rearrangement, chromosome separation, and cell polarization are altered in CYLD-depleted cells. Mechanistically, CYLD does not interact with RhoA; instead, it interacts with and deubiquitinates leukemia-associated RhoGEF (LARG). Our data further show that CYLD-mediated deubiquitination of LARG enhances its ability to stimulate the GDP/GTP exchange on RhoA. These data thus identify LARG as a new substrate of CYLD and provide novel insights into the regulation of RhoA activation. Our results also suggest that the LARG-RhoA signaling pathway may play a role in diverse CYLD-mediated cellular events.

  1. 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.

  2. Plastid chaperonin proteins Cpn60α and Cpn60β are required for plastid division in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Osteryoung Katherine W

    2009-04-01

    Full Text Available Abstract Background Plastids arose from a free-living cyanobacterial endosymbiont and multiply by binary division as do cyanobacteria. Plastid division involves nucleus-encoded homologs of cyanobacterial division proteins such as FtsZ, MinD, MinE, and ARC6. However, homologs of many other cyanobacterial division genes are missing in plant genomes and proteins of host eukaryotic origin, such as a dynamin-related protein, PDV1 and PDV2 are involved in the division process. Recent identification of plastid division proteins has started to elucidate the similarities and differences between plastid division and cyanobacterial cell division. To further identify new proteins that are required for plastid division, we characterized previously and newly isolated plastid division mutants of Arabidopsis thaliana. Results Leaf cells of two mutants, br04 and arc2, contain fewer, larger chloroplasts than those of wild type. We found that ARC2 and BR04 are identical to nuclear genes encoding the plastid chaperonin 60α (ptCpn60α and chaperonin 60β (ptCpn60β proteins, respectively. In both mutants, plastid division FtsZ ring formation was partially perturbed though the level of FtsZ2-1 protein in plastids of ptcpn60β mutants was similar to that in wild type. Phylogenetic analyses showed that both ptCpn60 proteins are derived from ancestral cyanobacterial proteins. The A. thaliana genome encodes two members of ptCpn60α family and four members of ptCpn60β family respectively. We found that a null mutation in ptCpn60α abolished greening of plastids and resulted in an albino phenotype while a weaker mutation impairs plastid division and reduced chlorophyll levels. The functions of at least two ptCpn60β proteins are redundant and the appearance of chloroplast division defects is dependent on the number of mutant alleles. Conclusion Our results suggest that both ptCpn60α and ptCpn60β are required for the formation of a normal plastid division apparatus, as

  3. Cloning, characterization and sub-cellular localization of gamma subunit of T-complex protein-1 (chaperonin) from Leishmania donovani

    Energy Technology Data Exchange (ETDEWEB)

    Bhaskar,; Kumari, Neeti [Division of Biochemistry, CSIR-Central Drug Research Institute, Chattar Manzil Palace, PO Box 173, Lucknow (India); Goyal, Neena, E-mail: neenacdri@yahoo.com [Division of Biochemistry, CSIR-Central Drug Research Institute, Chattar Manzil Palace, PO Box 173, Lucknow (India)

    2012-12-07

    Highlights: Black-Right-Pointing-Pointer The study presents cloning and characterization of TCP1{gamma} gene from L. donovani. Black-Right-Pointing-Pointer TCP1{gamma} is a subunit of T-complex protein-1 (TCP1), a chaperonin class of protein. Black-Right-Pointing-Pointer LdTCP{gamma} exhibited differential expression in different stages of promastigotes. Black-Right-Pointing-Pointer LdTCP{gamma} co-localized with actin, a cytoskeleton protein. Black-Right-Pointing-Pointer The data suggests that this gene may have a role in differentiation/biogenesis. Black-Right-Pointing-Pointer First report on this chapronin in Leishmania. -- Abstract: T-complex protein-1 (TCP1) complex, a chaperonin class of protein, ubiquitous in all genera of life, is involved in intracellular assembly and folding of various proteins. The gamma subunit of TCP1 complex (TCP1{gamma}), plays a pivotal role in the folding and assembly of cytoskeleton protein(s) as an individual or complexed with other subunits. Here, we report for the first time cloning, characterization and expression of the TCP1{gamma} of Leishmania donovani (LdTCP1{gamma}), the causative agent of Indian Kala-azar. Primary sequence analysis of LdTCP1{gamma} revealed the presence of all the characteristic features of TCP1{gamma}. However, leishmanial TCP1{gamma} represents a distinct kinetoplastid group, clustered in a separate branch of the phylogenic tree. LdTCP1{gamma} exhibited differential expression in different stages of promastigotes. The non-dividing stationary phase promastigotes exhibited 2.5-fold less expression of LdTCP1{gamma} as compared to rapidly dividing log phase parasites. The sub-cellular distribution of LdTCP1{gamma} was studied in log phase promastigotes by employing indirect immunofluorescence microscopy. The protein was present not only in cytoplasm but it was also localized in nucleus, peri-nuclear region, flagella, flagellar pocket and apical region. Co-localization of LdTCP1{gamma} with actin suggests

  4. The modulation of pancreatic lipase activity by alginates.

    Science.gov (United States)

    Wilcox, Matthew D; Brownlee, Iain A; Richardson, J Craig; Dettmar, Peter W; Pearson, Jeffrey P

    2014-03-01

    Alginates are comprised of mannuronic (M) and guluronic acid (G) and have been shown to inhibit enzyme activity. Pancreatic lipase is important in dietary triacylglycerol breakdown; reducing pancreatic lipase activity would reduce triacylglycerol breakdown resulting in lower amounts being absorbed by the body. Lipase activity in the presence of biopolymers was assessed by enzymatic assay using natural and synthetic substrates. Alginate inhibited pancreatic lipase by a maximum of 72.2% (±4.1) with synthetic substrate (DGGR) and 58.0% (±9.7) with natural substrate. High-G alginates from Laminaria hyperborea seaweed inhibited pancreatic lipase to a significantly higher degree than High-M alginates from Lessonia nigrescens, showing that inhibition was related to alginate structure. High-G alginates are effective inhibitors of pancreatic lipase and are used in the food industry at low levels. They could be included at higher levels in foods without altering organoleptic qualities, potentially reduce the uptake of dietary triacylglycerol aiding in weight management.

  5. 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.

  6. Dopamine Transporter Activity Is Modulated by α-Synuclein.

    Science.gov (United States)

    Butler, Brittany; Saha, Kaustuv; Rana, Tanu; Becker, Jonas P; Sambo, Danielle; Davari, Paran; Goodwin, J Shawn; Khoshbouei, Habibeh

    2015-12-04

    The duration and strength of the dopaminergic signal are regulated by the dopamine transporter (DAT). Drug addiction and neurodegenerative and neuropsychiatric diseases have all been associated with altered DAT activity. The membrane localization and the activity of DAT are regulated by a number of intracellular proteins. α-Synuclein, a protein partner of DAT, is implicated in neurodegenerative disease and drug addiction. Little is known about the regulatory mechanisms of the interaction between DAT and α-synuclein, the cellular location of this interaction, and the functional consequences of this interaction on the basal, amphetamine-induced DAT-mediated dopamine efflux, and membrane microdomain distribution of the transporter. Here, we found that the majority of DAT·α-synuclein protein complexes are found at the plasma membrane of dopaminergic neurons or mammalian cells and that the amphetamine-mediated increase in DAT activity enhances the association of these proteins at the plasma membrane. Further examination of the interaction of DAT and α-synuclein revealed a transient interaction between these two proteins at the plasma membrane. Additionally, we found DAT-induced membrane depolarization enhances plasma membrane localization of α-synuclein, which in turn increases dopamine efflux and enhances DAT localization in cholesterol-rich membrane microdomains.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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...... hyperalgesia. Direct contrasts between control and hypnotic hypoalgesia conditions demonstrated significant decreases in right posterior insula and BA21, as well as left BA40 during hypoalgesia. These findings are the first to describe hypnotic modulation of brain activity associated with nociceptive...

  12. Serotonergic modulation of astrocytic activity in the hamster suprachiasmatic nucleus.

    Science.gov (United States)

    Glass, J D; Chen, L

    1999-01-01

    The present study was undertaken to explore the effects of central serotonin receptor activation on the expression of glial fibrillary acidic protein in the suprachiasmatic nucleus of Syrian hamsters. Immunoblot and immunohistochemical procedures were used to examine the effects of systemic application of the serotonin-1A and serotonin-7 receptor agonist, (+/-)-2-dipropyl-amino-8-hydroxyl-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT; 3.75 mg/kg) on the contents and distribution of glial fibrillary acidic protein in the suprachiasmatic nucleus. Administration of 8-OH-DPAT at midday caused a significant reduction in immunoreactive glial fibrillary acidic protein content within 1 h of injection, compared to vehicle controls. This effect was not evident 3 h after drug injection. Treatment with 8-OH-DPAT during the late dark phase had little effect on glial fibrillary acidic protein content. The 8-OH-DPAT-induced reduction in glial fibrillary acidic protein content seen at midday was blocked partially by pretreatment with the serotonin-2 and serotonin-7 receptor antagonist, ritanserin, and more substantially by pretreatment with the serotonin-1A receptor antagonist, NAN-190. Treatment with 8-OH-DPAT also caused a significant redistribution of immunoreactive glial fibrillary acidic protein, such that the dense mesh-like appearance seen in vehicle controls was significantly reduced. The 8-OH-DPAT treatment also significantly decreased expression of polysialic acid, a cell-surface molecule associated with neural plasticity. Immunoblot assessments of glial fibrillary acidic protein contents 2 h before and 1 h after lights off revealed a significant time-of-day difference in glial fibrillary acidic protein expression, with lowest levels occurring at the latter time-point, associated with maximal endogenous serotonin release in the suprachiasmatic nucleus. Collectively, these results indicate that acute plastic changes in glial fibrillary acidic protein

  13. 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.  

  14. Can lactoferrin modulate the immunostimulant activity of levamisole in rats

    Directory of Open Access Journals (Sweden)

    Wafaa Abdou Mohamed Mohamed

    2014-03-01

    Full Text Available Objective: The aim of this study was to study the immunomodulatory activity improvement of levamisole by using lactoferrin when applied to immunosuppressed rat model. Methods: The study was designed as follows, 140 male albino rats (250-280 g 14 weeks old were used in our work. Rats were randomly divided into seven groups, 20 in each. The group I was kept as a control, group II was given cyclophosphamide (CYP at a single intraperitoneal dose of (250 mg/kg body weight, group III CYP and lactoferrin (Lac treated group, group IV orally administrated Lac only (0.5% in drinking water, group V treated with CYP and levamisole, group VI administrated levamisole orally at a dose of (2.5 mg/kg body weight and group VII was given CYP, Lac and levamisole. Animals were sacrificed and two separate blood samples were collected after 21 days from the beginning of the experiment for measuring the total and differential leukocyte count, serum total proteins, albumin, alpha globulin, beta globulin and gamma globulin, Nitric oxide (NO production and lysozyme activity. Results: CYP group showed significant decrease in the above mentioned parameters, which were improved after administration of both lactoferrin and levamisole. Conclusion: Our study concluded that lactoferrin improve the immunostimulant effect of levamisole in CYP- immunosuppressed rats. J Clin Exp Invest 2014; 5 (1: 48-53

  15. 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.

  16. Surround modulation characteristics of local field potential and spiking activity in primary visual cortex of cat.

    Directory of Open Access Journals (Sweden)

    Li Zhang

    Full Text Available In primary visual cortex, spiking activity that evoked by stimulus confined in receptive field can be modulated by surround stimulus. This center-surround interaction is hypothesized to be the basis of visual feature integration and segregation. Spiking output has been extensively reported to be surround suppressive. However, less is known about the modulation properties of the local field potential (LFP, which generally reflects synaptic inputs. We simultaneously recorded spiking activity and LFP in the area 17 of anesthetized cats to examine and compare their modulation characteristics. When the stimulus went beyond the classical receptive field, LFP exhibited decreased power along the gamma band (30-100 Hz in most of our recording sites. Further investigation revealed that suppression of the LFP gamma mean power (gLFP depended on the angle between the center and surround orientations. The strongest suppression was induced when center and surround orientations were parallel. Moreover, the surround influence of the gLFP exhibited an asymmetric spatial organization. These results demonstrate that the gLFP has similar but not identical surround modulation properties, as compared to the spiking activity. The spatiotemporal integration of LFP implies that the oscillation and synchronization of local synaptic inputs may have important functions in surround modulation.

  17. 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.

  18. 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.

  19. 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

  20. Local atomic structure modulations activate metal oxide as electrocatalyst for hydrogen evolution in acidic water.

    Science.gov (United States)

    Li, Yu Hang; Liu, Peng Fei; Pan, Lin Feng; Wang, Hai Feng; Yang, Zhen Zhong; Zheng, Li Rong; Hu, P; Zhao, Hui Jun; Gu, Lin; Yang, Hua Gui

    2015-08-19

    Modifications of local structure at atomic level could precisely and effectively tune the capacity of materials, enabling enhancement in the catalytic activity. Here we modulate the local atomic structure of a classical but inert transition metal oxide, tungsten trioxide, to be an efficient electrocatalyst for hydrogen evolution in acidic water, which has shown promise as an alternative to platinum. Structural analyses and theoretical calculations together indicate that the origin of the enhanced activity could be attributed to the tailored electronic structure by means of the local atomic structure modulations. We anticipate that suitable structure modulations might be applied on other transition metal oxides to meet the optimal thermodynamic and kinetic requirements, which may pave the way to unlock the potential of other promising candidates as cost-effective electrocatalysts for hydrogen evolution in industry.

  1. 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)

  2. Modulation of anticipatory postural activity for multiple conditions of a whole-body pointing task.

    Science.gov (United States)

    Tolambiya, A; Chiovetto, E; Pozzo, T; Thomas, E

    2012-05-17

    This is a study on associated postural activities during the anticipatory segments of a multijoint movement. Several previous studies have shown that they are task dependant. The previous studies, however, have mostly been limited in demonstrating the presence of modulation for one task condition, that is, one aspect such as the distance of the target or the direction of reaching. Real-life activities like whole-body pointing, however, can vary in several ways. How specific is the adaptation of the postural activities for the diverse possibilities of a whole-body pointing task? We used a classification paradigm to answer this question. We examined the anticipatory postural electromyograms for four different types of whole-body pointing tasks. The presence of task-dependent modulations in these signals was probed by performing four-way classification tests using a support vector machine (SVM). The SVM was able to achieve significantly higher than chance performance in correctly predicting the movements at hand (Chance performance 25%). Using only anticipatory postural muscle activity, the correct movement at hand was predicted with a mean rate of 62%. Because this is 37% above chance performance, it suggests the presence of postural modulation for diverse conditions. The anticipatory activities consisted of both activations and deactivations. Movement prediction with the use of the activating muscles was significantly better than that obtained with the deactivating muscles. This suggests that more specific modulations for the movement at hand take place through activation, whereas the deactivation is more general. The study introduces a new method for investigating adaptations in motor control. It also sheds new light on the quantity and quality of information available in the feedforward segments of a voluntary multijoint motor activity.

  3. 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

  4. 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.

  5. Modulation of muscle activity and force fluctuations in the plantarflexors after bedrest depends on knee position.

    Science.gov (United States)

    Yoshitake, Yasuhide; Kouzaki, Motoki; Fukuoka, Hideoki; Fukunaga, Tetsuo; Shinohara, Minoru

    2007-06-01

    Force fluctuations in leg muscles increase after bedrest, perhaps due to modulation of the neural strategy that is specific to a muscle or common to agonist muscles. The purpose of this study was to examine the modulation of muscle activity and force fluctuations during steady contractions with variable involvement of plantarflexor muscles after bedrest at knee-flexed (FLX) and extended (EXT) positions. Before and after 20-day bedrest, plantarflexion force and surface electromyogram (EMG) in the medial gastrocnemius (MG), lateral gastrocnemius, and soleus muscles were measured during steady isometric contractions in five young men. In EXT, power EMG of MG increased significantly after bedrest. This low-frequency modulation of muscle activity in MG accompanied a 29% increase in the standard deviation of force. There was no change in EMG in other muscles. In FLX, there was no adjustment in EMG or force fluctuations. These results suggest that low-frequency modulation of MG plays a role in increasing force fluctuations during steady plantarflexion in EXT after bedrest. The findings indicate task/muscle specificity in the modulation of neural strategy during steady contractions after bedrest and underscore the importance of designing a specific training regimen targeted to particular tasks/muscles with regard to force fluctuations in multiple-agonist systems.

  6. 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.

  7. 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.

  8. Influence of excipients on drug absorption via modulation of intestinal transporters activity

    Directory of Open Access Journals (Sweden)

    Hetal P Thakkar

    2015-01-01

    Full Text Available One of the major factors affecting oral drug bioavailability is the activity of intestinal transport proteins, particularly for the drugs that undergo absorption by active transport mechanism. Many of the active pharmacological agents and the excipients used in their formulation are reported to modulate the activity of these transporters thereby either enhancing or decreasing the drug absorption and its systemic availability. These excipients are considered pharmacologically "inert" and have been used since years in pharmaceutical formulations. Appreciable interest is developing on the data demonstrating the role of excipients in altering the drug absorption across the intestine. Careful selection of the excipients thus is very important. A correctly chosen excipient can enhance the drug bioavailability and thus its therapeutic efficacy without increasing its dose. For locally acting drugs having systemic side effects, a proper excipient could lead to a decrease in its systemic absorption, thus reducing its side effects. This review focuses on the current findings of the excipients identified to modulate the activity of transporters, their mechanism of modulating the transporter′s activity and various formulation strategies using these excipients to enhance drug absorption.

  9. 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...... subtypes of SK channels (SK1, SK2, and SK3) in Xenopus laevis oocytes. SK channels were activated by intracellular injection of Cd2+. Subsequent activation of 5-HT1A receptors by 8-OH-DPAT always produced an inhibition of the SK current, showing the existence of a specific pathway between the receptor...

  10. β-noradrenergic receptor activation specifically modulates the generation of sighs in vivo and in vitro

    Directory of Open Access Journals (Sweden)

    Jean-Charles eViemari

    2013-11-01

    Full Text Available The pre-Bötzinger complex (preBötC, an area that is critical for generating breathing (eupnea, gasps and sighs is continuously modulated by catecholamines. These amines and the generation of sighs have also been implicated in the regulation of arousal. Here we studied the catecholaminergic modulation of sighs not only in anesthetized freely breathing mice (in vivo, but also in medullary slice preparations that contain the preBötC and that generate fictive eupneic and sigh rhythms in vitro. We demonstrate that activating -noradrenergic receptors (B-NR specifically increases the frequency of sighs, while eupnea remains unaffected both in vitro and in vivo. B-NR activation specifically increased the frequency of intrinsically bursting pacemaker neurons that rely on persistent sodium current (INap. By contrast, all parameters of bursting pacemakers that rely on the non-specific cation current (ICAN remained unaffected. Moreover, riluzole, which blocks bursting in INap pacemakers abolished sighs altogether, while flufenamic acid which blocks the ICAN current did not alter the sigh-increasing effect caused by B-NR. Our results suggest that the selective B-NR action of sighs may result from the modulation of INap pacemaker activity and that disturbances in noradrenergic system may contribute to abnormal arousal response. The B-NR action on the preBötC may be an important mechanism in modulating behaviors that are specifically associated with sighs, such as the regulation of the early events leading to the arousal response.

  11. Elevated blood Hsp60, its structural similarities and cross-reactivity with thyroid molecules, and its presence on the plasma membrane of oncocytes point to the chaperonin as an immunopathogenic factor in Hashimoto's thyroiditis.

    Science.gov (United States)

    Marino Gammazza, Antonella; Rizzo, Manfredi; Citarrella, Roberto; Rappa, Francesca; Campanella, Claudia; Bucchieri, Fabio; Patti, Angelo; Nikolic, Dragana; Cabibi, Daniela; Amico, Giandomenico; Conaldi, Pier Giulio; San Biagio, Pier Luigi; Montalto, Giuseppe; Farina, Felicia; Zummo, Giovanni; Conway de Macario, Everly; Macario, Alberto J L; Cappello, Francesco

    2014-05-01

    The role Hsp60 might play in various inflammatory and autoimmune diseases is under investigation, but little information exists pertaining to Hashimoto's thyroiditis (HT). With the aim to fill this gap, in the present work, we directed our attention to Hsp60 participation in HT pathogenesis. We found Hsp60 levels increased in the blood of HT patients compared to controls. The chaperonin was immunolocalized in thyroid tissue specimens from patients with HT, both in thyrocytes and oncocytes (Hurthle cells) with higher levels compared to controls (goiter). In oncocytes, we found Hsp60 not only in the cytoplasm but also on the plasma membrane, as shown by double immunofluorescence performed on fine needle aspiration cytology. By bioinformatics, we found regions in the Hsp60 molecule with remarkable structural similarity with the thyroglobulin (TG) and thyroid peroxidase (TPO) molecules, which supports the notion that autoantibodies against TG and TPO are likely to recognize Hsp60 on the plasma membrane of oncocytes. This was also supported by data obtained by ELISA, showing that anti-TG and anti-TPO antibodies cross-react with human recombinant Hsp60. Antibody-antigen (Hsp60) reaction on the cell surface could very well mediate thyroid cell damage and destruction, perpetuating inflammation. Experiments with recombinant Hsp60 did not show stimulation of cytokine production by peripheral blood mononuclear cells from HT patients. All together, these results led us to hypothesize that Hsp60 may be an active player in HT pathogenesis via an antibody-mediated immune mechanism.

  12. Modulation of the antibiotic activity against multidrug resistant strains of coumarins isolated from Rutaceae species.

    Science.gov (United States)

    Madeiro, Sara A L; Borges, Nathalie H P B; Souto, Augusto L; de Figueiredo, Pedro T R; Siqueira-Junior, José P; Tavares, Josean F

    2017-03-01

    The first occurrences and dissemination of resistant microorganisms led to the inefficacy of many antibiotics, available in the market nowadays, therefore, the search for new substances with antimicrobial activity from natural sources has gained a great importance. The purpose of this work is to evaluate the antibacterial activity and modulation of drug resistance in Staphylococcus aureus by coumarins such as bergapten, xantotoxin, isopimpinellin and imperatorin obtained from two Rutaceae species (Metrodorea mollis and Pilocarpus spicatus). The antimicrobial activity was assessed based on the minimum inhibitory concentration (MIC), using the microdilution method. The MIC was >256 g/mL for all coumarins tested. Regarding the modulation of drug resistance assay, the isopimpinellin reducted the MIC of erytromicin by 4 times, whereas imperatorin exhibited the best result, reducing the MIC of tetracycline (2 times), erytomicin (4 times) and norfloxacin (4 times). By reducing the MIC of ethidium bromide, the imperatorin is consider in fact, as a putative efflux pump inhibitor of bacteria.

  13. 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.

  14. Category expectation modulates baseline and stimulus-evoked activity in human inferotemporal cortex.

    Science.gov (United States)

    Puri, Amrita M; Wojciulik, Ewa; Ranganath, Charan

    2009-12-08

    Expectation of locations and low-level features increases activity in extrastriate visual areas even in the absence of a stimulus, but it is unclear whether or how expectation of higher-level stimulus properties affects visual responses. Here, we used event-related functional magnetic resonance imaging (fMRI) to test whether category expectation affects baseline and stimulus-evoked activity in higher-level, category-selective inferotemporal (IT) visual areas. Word cues indicating an image category (FACE or HOUSE) were followed by a delay, then a briefly presented image of a face or a house. On most trials, the cue correctly predicted the upcoming stimulus. Baseline activity in regions within the fusiform face area (FFA) and parahippocampal place area (PPA) was modulated such that activity was higher during expectation of the preferred (e.g., FACE for FFA) vs. non-preferred category. Stimulus-evoked responses reflected an initial bias (higher overall activity) followed by increased selectivity (greater difference between activity to a preferred vs. non-preferred stimulus) after expectation of the preferred vs. non-preferred category. Consistent with the putative role of a frontoparietal network in top-down modulation of activity in sensory cortex, expectation-related activity in several frontal and parietal areas correlated with the magnitude of baseline shifts in the FFA and PPA across subjects. Furthermore, expectation-related activity in lateral prefrontal cortex also correlated with the magnitude of expectation-based increases in stimulus selectivity in IT areas. These findings demonstrate that category expectation influences both baseline and stimulus-evoked activity in category-selective inferotemporal visual areas, and that these modulations may be driven by a frontoparietal attentional control network.

  15. 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.

  16. Sympathetic Neurotransmitters Modulate Osteoclastogenesis and Osteoclast Activity in the Context of Collagen-Induced Arthritis.

    Directory of Open Access Journals (Sweden)

    Dominique Muschter

    Full Text Available Excessive synovial osteoclastogenesis is a hallmark of rheumatoid arthritis (RA. Concomitantly, local synovial changes comprise neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze if collagen-induced arthritis (CIA alters bone marrow-derived macrophage (BMM osteoclastogenesis and osteoclast activity, and how sympathetic neurotransmitters participate in this process. Therefore, BMMs from Dark Agouti rats at different CIA stages were differentiated into osteoclasts in vitro and osteoclast number, cathepsin K activity, matrix resorption and apoptosis were analyzed in the presence of acetylcholine (ACh, noradrenaline (NA vasoactive intestinal peptide (VIP and assay-dependent, adenylyl cyclase activator NKH477. We observed modulation of neurotransmitter receptor mRNA expression in CIA osteoclasts without affecting protein level. CIA stage-dependently altered marker gene expression associated with osteoclast differentiation and activity without affecting osteoclast number or activity. Neurotransmitter stimulation modulated osteoclast differentiation, apoptosis and activity. VIP, NA and adenylyl cyclase activator NKH477 inhibited cathepsin K activity and osteoclastogenesis (NKH477, 10(-6 M NA whereas ACh mostly acted pro-osteoclastogenic. We conclude that CIA alone does not affect metabolism of in vitro generated osteoclasts whereas stimulation with NA, VIP plus specific activation of adenylyl cyclase induced anti-resorptive effects probably mediated via cAMP signaling. Contrary, we suggest pro-osteoclastogenic and pro-resorptive properties of ACh mediated via muscarinic receptors.

  17. 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.

  18. 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.

  19. Molecular diagnostic tools for detection and differentiation of phytoplasmas based on chaperonin-60 reveal differences in host plant infection patterns.

    Directory of Open Access Journals (Sweden)

    Tim J Dumonceaux

    Full Text Available Phytoplasmas ('Candidatus Phytoplasma' spp. are insect-vectored bacteria that infect a wide variety of plants, including many agriculturally important species. The infections can cause devastating yield losses by inducing morphological changes that dramatically alter inflorescence development. Detection of phytoplasma infection typically utilizes sequences located within the 16S-23S rRNA-encoding locus, and these sequences are necessary for strain identification by currently accepted standards for phytoplasma classification. However, these methods can generate PCR products >1400 bp that are less divergent in sequence than protein-encoding genes, limiting strain resolution in certain cases. We describe a method for accessing the chaperonin-60 (cpn60 gene sequence from a diverse array of 'Ca.Phytoplasma' spp. Two degenerate primer sets were designed based on the known sequence diversity of cpn60 from 'Ca.Phytoplasma' spp. and used to amplify cpn60 gene fragments from various reference samples and infected plant tissues. Forty three cpn60 sequences were thereby determined. The cpn60 PCR-gel electrophoresis method was highly sensitive compared to 16S-23S-targeted PCR-gel electrophoresis. The topology of a phylogenetic tree generated using cpn60 sequences was congruent with that reported for 16S rRNA-encoding genes. The cpn60 sequences were used to design a hybridization array using oligonucleotide-coupled fluorescent microspheres, providing rapid diagnosis and typing of phytoplasma infections. The oligonucleotide-coupled fluorescent microsphere assay revealed samples that were infected simultaneously with two subtypes of phytoplasma. These tools were applied to show that two host plants, Brassica napus and Camelina sativa, displayed different phytoplasma infection patterns.

  20. Chaperonin GroEL a Brucella immunodominant antigen identified using Nanobody and MALDI-TOF-MS technologies.

    Science.gov (United States)

    Abbady, A Q; Al-Daoude, A; Al-Mariri, A; Zarkawi, M; Muyldermans, S

    2012-05-15

    The deployment of today's antibodies that are able to distinguish Brucella from the closely similar pathogens, such as Yersinia, is still considered a great challenge since both pathogens share identical LPS (lipopolysaccharide) O-ring epitopes. In addition, because of the great impact of Brucella on health and economy in many countries including Syria, much effort is going to the development of next generation vaccines, mainly on the identification of new immunogenic proteins of this pathogen. In this context, Brucella-specific nanobodies (Nbs), camel genetic engineered heavy-chain antibody fragments, could be of great value. Previously, a large Nb library was constructed from a camel immunized with heat-killed Brucella. Phage display panning of this 'immune' library with Brucella total lysate resulted in a remarkable fast enrichment for a Nb referred to as NbBruc02. In the present work, we investigated the main characteristics of this Nb that can efficiently distinguish under well-defined conditions the Brucella from other bacteria including Yersinia. NbBruc02 showed a strong and specific interaction with its antigen within the crude lysate as tested by a surface plasmon resonance (SPR) biosensor and it was also able to pull down its cognate antigen from such lysate by immuno-capturing. Using matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), NbBruc02 specific antigen was identified as chaperonin GroEL, also known as heat shock protein of 60 kDa (HSP-60), which represents a Brucella immunodominant antigen responsible of maintaining proteins folding during stress conditions. Interestingly, the antigen recognition by NbBruc02 was found to be affected by the state of GroEL folding. Thus, the Nb technology applied in the field of infectious diseases, e.g. brucellosis, yields two outcomes: (1) it generates specific binders that can be used for diagnosis, and perhaps treatment, and (2) it identifies the immunogenic candidate

  1. Predicting relatedness of bacterial genomes using the chaperonin-60 universal target (cpn60 UT): application to Thermoanaerobacter species.

    Science.gov (United States)

    Verbeke, Tobin J; Sparling, Richard; Hill, Janet E; Links, Matthew G; Levin, David; Dumonceaux, Tim J

    2011-05-01

    D.R. Zeigler determined that the sequence identity of bacterial genomes can be predicted accurately using the sequence identities of a corresponding set of genes that meet certain criteria [32]. This three-gene model for comparing bacterial genome pairs requires the determination of the sequence identities for recN, thdF, and rpoA. This involves the generation of approximately 4.2kb of genomic DNA sequence from each organism to be compared, and also normally requires that oligonucleotide primers be designed for amplification and sequencing based on the sequences of closely related organisms. However, we have developed an analogous mathematical model for predicting the sequence identity of whole genomes based on the sequence identity of the 542-567 base pair chaperonin-60 universal target (cpn60 UT). The cpn60 UT is accessible in nearly all bacterial genomes with a single set of universal primers, and its length is such that it can be completely sequenced in one pair of overlapping sequencing reads via di-deoxy sequencing. These mathematical models were applied to a set of Thermoanaerobacter isolates from a wood chip compost pile and it was shown that both the one-gene cpn60 UT-based model and the three-gene model based on recN, rpoA, and thdF predicted that these isolates could be classified as Thermoanaerobacter thermohydrosulfuricus. Furthermore, it was found that the genomic prediction model using cpn60 UT gave similar results to whole-genome sequence alignments over a broad range of taxa, suggesting that this method may have general utility for screening isolates and predicting their taxonomic affiliations.

  2. Lateral entorhinal modulation of piriform cortical activity and fine odor discrimination.

    Science.gov (United States)

    Chapuis, Julie; Cohen, Yaniv; He, Xiaobin; Zhang, Zhijan; Jin, Sen; Xu, Fuqiang; Wilson, Donald A

    2013-08-14

    The lateral entorhinal cortex (LEC) receives direct input from olfactory bulb mitral cells and piriform cortical pyramidal cells and is the gateway for olfactory input to the hippocampus. However, the LEC also projects back to the piriform cortex and olfactory bulb. Activity in the LEC is shaped by input from the perirhinal cortices, hippocampus, and amygdala, and thus could provide a rich contextual modulation of cortical odor processing. The present study further explored LEC feedback to anterior piriform cortex by examining how LEC top-down input modulates anterior piriform cortex odor evoked activity in rats. Retrograde viral tracing confirmed rich LEC projections to both the olfactory bulb and piriform cortices. In anesthetized rats, reversible lesions of the ipsilateral LEC increased anterior piriform cortical single-unit spontaneous activity. In awake animals performing an odor discrimination task, unilateral LEC reversible lesions enhanced ipsilateral piriform cortical local field potential oscillations during odor sampling, with minimal impact on contralateral activity. Bilateral LEC reversible lesions impaired discrimination performance on a well learned, difficult odor discrimination task, but had no impact on a well learned simple odor discrimination task. The simple discrimination task was impaired by bilateral reversible lesions of the anterior piriform cortex. Given the known function of LEC in working memory and multisensory integration, these results suggest it may serve as a powerful top-down modulator of olfactory cortical function and odor perception. Furthermore, the results provide potential insight into how neuropathology in the entorhinal cortex could contribute to early olfactory deficits seen in Alzheimer's disease.

  3. Functional insights into modulation of BKCa channel activity to alter myometrial contractility

    Directory of Open Access Journals (Sweden)

    Ramón A Lorca

    2014-07-01

    Full Text Available The large-conductance voltage- and Ca2+-activated K+ channel (BKCa is an important regulator of membrane excitability in a wide variety of cells and tissues. In myometrial smooth muscle, activation of BKCa plays essential roles in buffering contractility to maintain uterine quiescence during pregnancy and in the transition to a more contractile state at the onset of labor. Multiple mechanisms of modulation have been described to alter BKCa channel activity, expression, and cellular localization. In the myometrium, BKCa is regulated by alternative splicing, protein targeting to the plasma membrane, compartmentation in membrane microdomains, and posttranslational modifications. In addition, interaction with auxiliary proteins (i.e., β1- and β2-subunits, association with G-protein coupled receptor signaling pathways, such as those activated by adrenergic and oxytocin receptors, and hormonal regulation provide further mechanisms of variable modulation of BKCa channel function in myometrial smooth muscle. Here, we provide an overview of these mechanisms of BKCa channel modulation and provide a context for them in relation to myometrial function.

  4. Modulation of oncogenic DBL activity by phosphoinositol phosphate binding to pleckstrin homology domain.

    Science.gov (United States)

    Russo, C; Gao, Y; Mancini, P; Vanni, C; Porotto, M; Falasca, M; Torrisi, M R; Zheng, Y; Eva, A

    2001-06-01

    The Dbl family guanine nucleotide exchange factors (GEFs) contain a region of sequence similarity consisting of a catalytic Dbl homology (DH) domain in tandem with a pleckstrin homology (PH) domain. PH domains are involved in the regulated targeting of signaling molecules to plasma membranes by protein-protein and/or protein-lipid interactions. Here we show that Dbl PH domain binding to phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-triphosphate results in the inhibition of Dbl GEF activity on Rho family GTPase Cdc42. Phosphatidylinositol 4,5-bisphosphate binding to the PH domain significantly inhibits the Cdc42 interactive activity of the DH domain suggesting that the DH domain is subjected to the PH domain modulation under the influence of phosphoinositides (PIPs). We generated Dbl mutants unable to interact with PIPs. These mutants retained GEF activity on Cdc42 in the presence of PIPs and showed a markedly enhanced activating potential for both Cdc42 and RhoA in vivo while displaying decreased cellular transforming activity. Immunofluorescence analysis of NIH3T3 transfectants revealed that whereas the PH domain localizes to actin stress fibers and plasma membrane, the PH mutants are no longer detectable on the plasma membrane. These results suggest that modulation of PIPs in both the GEF catalytic activity and the targeting to plasma membrane determines the outcome of the biologic activity of Dbl.

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

    CERN Document Server

    INSPIRE-00219560; 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 $5\\times 10^{15}$ \

  6. 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.

  7. Phenolic composition and antioxidant activity in sparkling wines: modulation by the ageing on lees.

    Science.gov (United States)

    Stefenon, C A; Bonesi, C De M; Marzarotto, V; Barnabé, D; Spinelli, F R; Webber, V; Vanderlinde, R

    2014-02-15

    Sparkling wines (SW) have a special biological ageing on lees that is performed using two distinct methods: in the bottle (Champenoise) or in isobaric tanks (Charmat method). The objective of this study was to compare the levels of phenolic compounds, β-Glucosidase and antioxidant activity during the ageing on lees, in samples of SW produced at industrial scale by both methods. The β-Glucosidase activity has been constant over time, showing a close relationship with all the polyphenols studied (resveratrol, piceid, tyrosol, gallic, caffeic and ferulic acids), which were affected by the sur lie time. With these cross-reactions, the biological properties of the SW were also modulated. The results showed that the long period of ageing decreased the antioxidant potential in all samples. This work demonstrates that the sur lie is more important than the production method itself, due to its ability to modulate the necessary changes to achieve the specific objective.

  8. A Novel Active Bouncer System for Klystron Modulators with Constant AC Power Consumption

    CERN Document Server

    Cabaleiro Magallanes, F; Viarouge, P; Cros, J; De Almeida Martins, C

    2014-01-01

    This paper presents the principles and design methodologies of a novel active bouncer system, to be implemented in a transformer-based klystron modulator, which is able to meet two different objectives: 1. Regulate the output pulse voltage flattop, and 2. Attenuate the power fluctuation withdrawn from the AC network. This solution allows the utilization of a standard constant voltage / constant current power supply as a capacitor charger. The solution consists of a 4-quadrant switching converter placed in series with the main capacitor bank (forming a unique element in parallel with the capacitor charger), controlled with specific feed-back loops to achieve the two objectives. The complete design method, including a numerical optimization, of the whole system, is presented in the paper. Analyses of the compromises between the active bouncer specifications and the other modulator sub-components design is presented as well.

  9. Kainate-type glutamate receptors modulating network activity in developing hippocampus

    OpenAIRE

    Juuri, Juuso

    2015-01-01

    Kainate-type of ionotropic glutamate (KA) receptors are associated with the modulation of neuronal excitability, synaptic transmission, and activity of neuronal networks. They are believed to have an important role in the development of neuronal connections. In this thesis, the role of KA receptors in the early brain development was assessed by conducting in vitro electrophysiological recordings from individual neurons at CA3 region in acute slices of neonatal rodent hippocampi. It was f...

  10. Memory Self-Efficacy Beliefs Modulate Brain Activity when Encoding Real-World Future Intentions

    OpenAIRE

    2013-01-01

    Background: While the use of different cognitive strategies when encoding episodic memory information has been extensively investigated, modulation of brain activity by memory self-efficacy beliefs has not been studied yet. Methodology/Principal Findings: Sixteen young adults completed the prospective and retrospective metamemory questionnaire, providing individual subjective judgments of everyday memory function. The day after, using functional magnetic resonance imaging, the participants ha...

  11. Lateral Entorhinal Modulation of Piriform Cortical Activity and Fine Odor Discrimination

    OpenAIRE

    Chapuis, Julie; Cohen, Yaniv; He, Xiaobin; Zhang, Zhijan; Jin, Sen; Xu, Fuqiang; Wilson, Donald A.

    2013-01-01

    The lateral entorhinal cortex (LEC) receives direct input from olfactory bulb mitral cells and piriform cortical pyramidal cells and is the gateway for olfactory input to the hippocampus. However, the LEC also projects back to the piriform cortex and olfactory bulb. Activity in the LEC is shaped by input from the perirhinal cortices, hippocampus, and amygdala, and thus could provide a rich contextual modulation of cortical odor processing. The present study further explored LEC feedback to an...

  12. Peroxidase activity of bacterial cytochrome P450 enzymes: modulation by fatty acids and organic solvents.

    Science.gov (United States)

    Rabe, Kersten S; Erkelenz, Michael; Kiko, Kathrin; Niemeyer, Christof M

    2010-08-01

    The modulation of peroxidase activity by fatty acid additives and organic cosolvents was determined and compared for four bacterial cytochrome P450 enzymes, thermostable P450 CYP119A1, the P450 domain of CYP102A1 (BMP), CYP152A1 (P450(bsbeta)), and CYP101A1 (P450(cam)). Utilizing a high-throughput microplate assay, we were able to readily screen more than 100 combinations of enzymes, additives and cosolvents in a convenient and highly reproducible assay format. We found that, in general, CYP119A1 and BMP showed an increase in peroxidative activity in the presence of fatty acids, whereas CYP152A1 revealed a decrease in activity and CYP101A1 was only slightly affected. In particular, we observed that the conversion of the fluorogenic peroxidase substrate Amplex Red by CYP119A1 and BMP was increased by a factor of 38 or 11, respectively, when isopropanol and lauric acid were present in the reaction mixture. The activity of CYP119A1 could thus be modulated to reach more than 90% of the activity of CYP152A1 without effectors, which is the system with the highest peroxidative activity. For all P450s investigated we found distinctive reactivity patterns, which suggest similarities in the binding site of CYP119A1 and BMP in contrast with the other two proteins studied. Therefore, this study points towards a role of fatty acids as activators for CYP enzymes in addition to being mere substrates. In general, our detailed description of fatty acid- and organic solvent-effects is of practical interest because it illustrates that optimization of modulators and cosolvents can lead to significantly increased yields in biocatalysis.

  13. Sensory modulation of voluntary and TMS-induced activation in hand muscles.

    Science.gov (United States)

    Kofler, Markus; Valls-Solé, Josep; Fuhr, Peter; Schindler, Christian; Zaccaria, Barbara R; Saltuari, Leopold

    2008-07-01

    Nociceptive suppression of tonic voluntary electromyographic (EMG) activity in human hand muscles (cutaneous silent period, CSP) is in its functional organization consistent with a spinal protective reflex. Motoneuronal excitability and its modulation may also be investigated by conditioned motor evoked potentials (MEPs). To date, effects of exteroceptive stimuli on tonic EMG and on MEPs have been compared mainly using innocuous stimuli, while noxious stimuli have not been studied in great detail. In ten subjects, we recorded CSPs induced in volitionally activated flexor pollicis brevis muscle (FPB) by noxious digit II (D2) stimulation, and in first dorsal interosseous muscle (FDI) following noxious D2 and digit V (D5) stimulation. Then, transcranial magnetic stimulation (TMS) was used to evoke MEPs in the same hand muscles at rest--conditioned by equal noxious D2 or D5 stimulation and individually delayed--so that the MEPs occurred at times corresponding to immediately before, during, and immediately after the CSP in each subject. Immediately before the CSP, there was no significant difference between nociceptive MEP modulation and tonic EMG modulation in any muscle-finger-combination. In the middle of the CSP, noxious finger stimulation exerted suppression of TMS-induced MEPs in all the three muscle-finger-combinations, but less so as compared to corresponding tonic EMG levels. After the CSP, MEPs remained suppressed when corresponding tonic EMG levels were significantly enhanced. Notably, MEPs were also suppressed in cases when occurring at times corresponding to the excitatory long-loop reflex. Incomplete MEP suppression during the CSP may allow for an "emergency grip" even during noxious stimulation. MEP suppression outlasting the CSP is compatible with a "passive" re-synchronization of volitionally activated motor units rather than an "active" reflex involving recruitment of corticospinal motoneurons. The differences in tonic EMG and MEP modulation favors an

  14. Modulation of tibialis anterior muscle activity changes with upright stance width.

    Science.gov (United States)

    Lemos, Thiago; Imbiriba, Luís A; Vargas, Claudia D; Vieira, Taian M

    2015-02-01

    When individuals stand with their feet apart, activation of tibialis anterior (TA) muscle seems to slightly exceed rest levels. In narrow stances, conversely, the stabilization of body lateral sways may impose marked, active demand on ankle inversors/eversors. In this study we investigate how much the modulation in TA activity, associated to center of pressure (COP) lateral sways, changes when stance width reduces. Surface EMG and COP coordinates were collected from 17 subjects at three different stances: feet apart, feet together and tandem. Pearson correlation analysis was applied to check whether the expected greater modulations in TA activity corresponded to a stronger association between fluctuations in EMG amplitude and COP lateral sways. When standing at progressively narrower stances participants showed larger fluctuations in COP lateral sways (pEMG-COP association (pmodulations in TA activity were observed for subjects showing greater association between EMG amplitude and COP sways in feet together and tandem stance (Pearson R>0.56, p<0.02), though not when standing with feet apart (R=-0.22, p=0.40). These results indicate that the contribution of TA activity to lateral sway control increases for narrower stances.

  15. 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.

  16. The micronutrient element zinc modulates sperm activation through the SPE-8 pathway in Caenorhabditis elegans.

    Science.gov (United States)

    Liu, Zhiyu; Chen, Lianwan; Shang, Yunlong; Huang, Ping; Miao, Long

    2013-05-01

    Immotile spermatids produced in the testis must undergo a series of poorly understood morphological, physiological and biochemical processes called sperm activation to become motile, fertilization-competent spermatozoa. In Caenorhabditis elegans, the spe-8 group contains sperm-specific genes active in both males and hermaphrodites, although their activity is required only for hermaphrodite self-sperm activation. The activating signal upstream of the SPE-8 signaling cascade remains unknown. Here, we show that the micronutrient zinc is sufficient to trigger sperm activation in vitro, and that extracellular zinc induces the intracellular redistribution of labile zinc. We demonstrate that other activating signals promote the similar redistribution of labile zinc, indicating that zinc might have first and/or second messenger roles during sperm activation. Moreover, zinc-induced sperm activation is SPE-8 pathway dependent. Labile zinc was enriched in the spermatheca, the normal site for self-sperm activation in hermaphrodites. High levels of zinc were also found in the secretory cells in the male gonad, suggesting that zinc might be secreted from these cells during copulation and become a component of seminal fluid, to modulate sperm activation post-copulation. These data indicate that zinc regulates sperm activation in both male and hermaphrodite C. elegans, a finding with important implications for understanding hermaphroditic evolution.

  17. 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.

  18. A yeast two-hybrid screen reveals a strong interaction between the Legionella chaperonin Hsp60 and the host cell small heat shock protein Hsp10.

    Science.gov (United States)

    Nasrallah, Gheyath K

    2015-06-01

    L. pneumophila is an intracellular bacterium that replicates inside a membrane-bound vacuole called Legionella-containing vacuole (LCV), where it plentifully liberates its HtpB chaperonin. From LCV, HtpB reaches the host cell cytoplasm, where it interacts with SAMDC, a cytoplasmic protein required for synthesis of host polyamines that are important for intracellular growth of L. pneumophila. Additionally, cytoplasmic expression of HtpB in S. cerevisiae induces pseudohyphal growth, and in mammalian cells recruits mitochondria to LCV, and modifies actin microfilaments organization. This led us to hypothesize here that HtpB recruits a protein(s) from eukaryotic cells that is involved in the emergence of the aforementioned phenotypes. To identify this protein, a commercially available HeLa cDNA library was screened using a yeast two-hybrid system. Approximately 5×10(6) yeast clones carrying HeLa cDNA library plasmid were screened. Twenty-one positive clones were identified. DNA sequence analysis revealed that all of these positive clones encoded the mammalian small heat shock protein Hsp10. Based on the fact that chaperonions are required to interact with co-chaperonins to function properly in protein folding, we believe that HtpB recruits the host cell Hsp10 to appropriately interact with SAMDC and to induce the multifunction phenotypes deemed important in L. pneumophila pathogenesis.

  19. 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.

  20. 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

    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...... of lactose present in BC seems to diminish the activity of BC in our test system, since BC with higher amounts of lactose attenuated the stimulatory as well as the suppressive activity of BC....

  1. 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.

  2. 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

  3. 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.

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

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    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.

  5. Body Fat and Physical Activity Modulate the Association Between Sarcopenia and Osteoporosis in Elderly Korean Women

    Science.gov (United States)

    Lee, Inhwan; Cho, Jinkyung; Jin, Youngyun; Ha, Changduk; Kim, Taehee; Kang, Hyunsik

    2016-01-01

    This study examined whether modifiable lifestyle factors, such as body fatness and physical activity, modulate the association between sarcopenia and osteoporosis. In a cross-sectional design, 269 postmenopausal women, aged 65 years and older, underwent dual-energy X-ray absorptiometry (DEXA) scans to measure their body fat percentage, total fat mass, total fat-free mass, appendicular lean mass, bone mineral density (BMD) and bone mineral content. The participants wore a uniaxial accelerometer for seven consecutive days to quantify daily physical activity. The collected data were analyzed using descriptive statistics, Pearson correlation, and a binary logistic regression. Pearson correlation analyses showed that total neck/femur BMD was positively associated with weight-adjusted appendicular skeletal muscle mass (ASM) and objectively-measured physical activities. ASM was positively associated with body fatness. Binary logistic regression analyses showed that the odds ratio (OR) of sarcopenia for osteopenia and/or osteoporosis was substantially attenuated but remained marginally significant when adjusted for age and postmenopausal period (OR = 2.370 and p = 0.050). However, the OR was no longer significant when additionally adjusted for body fatness (OR = 2.218 and p = 0.117) and physical activity (OR = 1.240 and p = 0.448). The findings of the study showed that, in this sample of elderly Korean women, modifiable lifestyle risk factors such as body fatness and physical inactivity played an important role in determining the association between sarcopenia and osteopenia/osteoporosis. Key points Osteoporosis and sarcopenia are major health conditions responsible for an increased risk of bone fractures and reduced functional capacity, respectively, in older adults. We investigated whether lifestyle-related risk factors modulate the association between sarcopenia and osteoporosis in older Korean adults. The current findings of the study suggest that physical activity and

  6. 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.

  7. Slow modulation of ongoing activity in the auditory cortex during an interval-discrimination task

    Directory of Open Access Journals (Sweden)

    Juan M. Abolafia

    2011-10-01

    Full Text Available In this study, we recorded the single unit activity from rat auditory cortex while the animals performed an interval-discrimination task. The animals had to decide whether two auditory stimuli were separated by either 150 or 300 ms, and go to the left or right nose-poke accordingly. Spontaneous firing in between auditory responses was compared in the attentive versus non-attentive brain states. We describe the firing rate modulation detected during intervals while there was no auditory stimulation. Nearly 18% of neurons (n=14 showed a prominent neuronal discharge during the interstimulus interval, in the form of a upward or downward ramp towards the second auditory stimulus. These patterns of spontaneous activity were often modulated in the attentive versus passive trials. Modulation of the spontaneous firing rate during the task was observed not only between auditory stimuli, but also in the interval preceding the stimulus. This slow modulatory components could be locally generated or the result of a top-down influence originated in higher associative association areas. Such a neuronal discharge may be related to the computation of the interval time and contribute to the perception of the auditory stimulus.

  8. Neurogenesis-Promoting Natural Product α-Asarone Modulates Morphological Dynamics of Activated Microglia

    Science.gov (United States)

    Cai, Qing; Li, Yuanyuan; Mao, Jianxin; Pei, Gang

    2016-01-01

    α-Asarone is an active constituent of Acori Tatarinowii, one of the widely used traditional Chinese Medicine to treat cognitive defect, and recently is shown to promote neurogenesis. Here, we demonstrated that low level (3 μM) of α-asarone attenuated LPS-induced BV2 cell bipolar elongated morphological change, with no significant effect on the LPS-induced pro-inflammatory cytokine expressions. In addition, time-lapse analysis also revealed that α-asarone modulated LPS-induced BV2 morphological dynamics. Consistently a significant reduction in the LPS-induced Monocyte Chemoattractant Protein (MCP-1) mRNA and protein levels was also detected along with the morphological change. Mechanistic study showed that the attenuation effect to the LPS-resulted morphological modulation was also detected in the presence of MCP-1 antibodies or a CCR2 antagonist. This result has also been confirmed in primary cultured microglia. The in vivo investigation provided further evidence that α-asarone reduced the proportion of activated microglia, and reduced microglial tip number and maintained the velocity. Our study thus reveals α-asarone effectively modulates microglial morphological dynamics, and implies this effect of α-asarone may functionally relate to its influence on neurogenesis. PMID:28018174

  9. 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.

  10. 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…

  11. 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.

  12. Intensity-dependent modulation of optically active signals in a chiral metamaterial

    Science.gov (United States)

    Rodrigues, Sean P.; Lan, Shoufeng; Kang, Lei; Cui, Yonghao; Panuski, Patrick W.; Wang, Shengxiang; Urbas, Augustine M.; Cai, Wenshan

    2017-01-01

    Chiral media exhibit optical phenomena that provide distinctive responses from opposite circular polarizations. The disparity between these responses can be optimized by structurally engineering absorptive materials into chiral nanopatterns to form metamaterials that provide gigantic chiroptical resonances. To fully leverage the innate duality of chiral metamaterials for future optical technologies, it is essential to make such chiroptical responses tunable via external means. Here we report an optical metamaterial with tailored chiroptical effects in the nonlinear regime, which exhibits a pronounced shift in its circular dichroism spectrum under a modest level of excitation power. Strong nonlinear optical rotation is observed at key spectral locations, with an intensity-induced change of 14° in the polarization rotation from a metamaterial thickness of less than λ/7. The modulation of chiroptical responses by manipulation of input powers incident on chiral metamaterials offers potential for active optics such as all-optical switching and light modulation. PMID:28240288

  13. Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators.

    Directory of Open Access Journals (Sweden)

    Wei Wang

    Full Text Available W1282X is a common nonsense mutation among cystic fibrosis patients that results in the production of a truncated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR channel. Here we show that the channel activity of the W1282X-CFTR polypeptide is exceptionally low in excised membrane patches at normally saturating doses of ATP and PKA (single channel open probability (PO 0.9 when treated with both modulators. VX-770 and curcumin also additively stimulated W1282X-CFTR mediated currents in polarized FRT epithelial monolayers. In this setting, however, the stimulated W1282X-CFTR currents were smaller than those mediated by wild type CFTR (3-5% due presumably to lower expression levels or cell surface targeting of the truncated protein. Combining allosteric modulators of different mechanistic classes is worth considering as a treatment option for W1282X CF patients perhaps when coupled with maneuvers to increase expression of the truncated protein.

  14. Proteolytic modulation of thrombopoietin activity: comparison of thrombin, plasmin, and urokinase.

    Science.gov (United States)

    Reiner, A P; Aramaki, K M

    2000-06-01

    Several observations suggest that limited proteolysis of full-length 70 kD human thrombopoietin (Tpo) may be important for Tpo biology. Recently, it was reported that thrombin cleaves full-length recombinant human Tpo (rhTpo) sequentially at two sites, Arg(195) within the glycan domain followed by Arg(117) within the cytokine domain, and that these cleavages modulate Tpo activity in vitro. We demonstrate that urokinase and plasmin also cleave rhTpo in a time-dependent manner. Urokinase cleavage is confined to the glycan domain, and generates a 35 kD N-terminal fragment that contains the intact cytokine domain, and is associated with increased Tpo activity. In contrast, plasmin cleaves Tpo sequentially at two specific sites (Arg(205) within the glycan domain followed by Lys(52) within the cytokine domain), and is associated with a marked decrease in Tpo activity. These proteolytic events have potential implications for regulation of Tpo activity in vivo.

  15. 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.

  16. 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

  17. Leukotriene B4-loaded microspheres: a new therapeutic strategy to modulate cell activation

    Directory of Open Access Journals (Sweden)

    Sanz Maria J

    2008-07-01

    Full Text Available Abstract Background Leukotriene B4 (LTB4 is a potent inflammatory mediator that also stimulates the immune response. In addition, it promotes polymorphonuclear leukocyte phagocytosis, chemotaxis, chemokinesis and modulates cytokines release. Regarding chemical instability of the leukotriene molecule, in the present study we assessed the immunomodulatory activities conferred by LTB4 released from microspheres (MS. A previous oil-in-water emulsion solvent extraction-evaporation method was chosen to prepare LTB4-loaded MS. Results In the mice cremasteric microcirculation, intraescrotal injection of 0.1 ml of LTB4-loaded MS provoked significant increases in leukocyte rolling flux, adhesion and emigration besides significant decreases in the leukocyte rolling velocity. LTB4-loaded MS also increase peroxisome proliferator-activated receptor-α (PPARα expression by murine peritoneal macrophages and stimulate them to generate nitrite levels. Monocyte chemoattractant protein-1 (MCP-1 and nitric oxide (NO productions were also increased when human umbilical vein and artery endothelial cells (HUVECs and HUAECs, respectively were stimulated with LTB4-loaded MS. Conclusion LTB4-loaded MS preserve the biological activity of the encapsulated mediator indicating their use as a new strategy to modulate cell activation, especially in the innate immune response.

  18. Trait Anxiety Modulates Brain Activity during Performance of Verbal Fluency Tasks.

    Science.gov (United States)

    Gawda, Barbara; Szepietowska, Ewa

    2016-01-01

    Trait anxiety is thought to be associated with pathological anxiety, and a risk factor for psychiatric disorders. The present study examines the brain mechanisms associated with trait anxiety during the performing of verbal fluency tasks. The aim is to show how trait anxiety modulates executive functions as measured by verbal fluency, and to explore the link between verbal fluency and anxiety due to the putative negative biases in high-anxious individuals. Seven tasks of verbal fluency were used: letter "k," "f," verbs, "animals," "vehicles," "joy," and "fear." The results of 35 subjects (whole sample), and 17 subjects (nine men, eight women) selected from the whole sample for the low/high-anxious groups on the basis of Trait Anxiety scores were analyzed. The subjects were healthy, Polish speaking, right-handed and aged from 20 to 35 years old. fMRI (whole-brain analysis with FWE corrections) was used to show the neural signals under active participation in verbal fluency tasks. The results confirm that trait anxiety slightly modulates neural activation during the performance of verbal fluency tasks, especially in the more difficult tasks. Significant differences were found in brain activation during the performance of more complex tasks between individuals with low anxiety and those with high anxiety. Greater activation in the right hemisphere, frontal gyri, and cerebellum was found in people with low anxiety. The results reflect better integration of cognitive and affective capacities in individuals with low anxiety.

  19. Low-frequency physiological activation of the vestibular utricle causes biphasic modulation of skin sympathetic nerve activity in humans.

    Science.gov (United States)

    Grewal, Tarandeep; Dawood, Tye; Hammam, Elie; Kwok, Kenny; Macefield, Vaughan G

    2012-07-01

    We have previously shown that sinusoidal galvanic vestibular stimulation, a means of selectively modulating vestibular afferent activity, can cause partial entrainment of sympathetic outflow to muscle and skin in human subjects. However, it influences the firing of afferents from the entire vestibular apparatus, including the semicircular canals. Here, we tested the hypothesis that selective stimulation of one set of otolithic organs-those located in the utricle, which are sensitive to displacement in the horizontal axis-could entrain sympathetic nerve activity. Skin sympathetic nerve activity (SSNA) was recorded via tungsten microelectrodes inserted into cutaneous fascicles of the common peroneal nerve in 10 awake subjects, seated (head vertical, eyes closed) on a motorised platform. Slow sinusoidal accelerations-decelerations (~4 mG) were applied in the X (antero-posterior) or Y (medio-lateral) direction at 0.08 Hz; composite movements in both directions were also applied. Subjects either reported feeling a vague sense of movement (with no sense of direction) or no movement at all. Nevertheless, cross-correlation analysis revealed a marked entrainment of SSNA for all types of movements: vestibular modulation was 97 ± 3 % for movements in the X axis and 91 ± 5 % for displacements in the Y axis. For each sinusoidal cycle, there were two major peaks of modulation-one associated with acceleration as the platform moved forward or to the side, and one associated with acceleration in the opposite direction. We interpret these observations as reflecting inertial displacement of the stereocilia within the utricle during acceleration, which causes a robust vestibulosympathetic reflex.

  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. 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.

  2. Cyclic modulation of semi-active controllable dampers for tonal vibration isolation

    Science.gov (United States)

    Anusonti-Inthra, P.; Gandhi, F.

    2004-08-01

    The present study examines the potential of using a semi-active controllable damper, whose damping coefficient can be modulated in real time, for tonal vibration isolation applications. A frequency-domain control algorithm is developed for determining the damping coefficient variation (at twice the disturbance frequency) that minimizes the force transmitted to the support at the disturbance frequency. The effectiveness of open-loop, closed-loop, and adaptive controllers in rejecting the transmitted disturbances are evaluated. The results of the study indicate that when limits in damping coefficient variation are considered, the support force could be reduced by about an additional 30%, beyond the levels due to the passive isolation characteristics (no cyclic damping modulation). When the disturbance phase changes during operation, the effectiveness of the open-loop controller is rapidly degraded. While the closed-loop controller (with inputs based on current levels of force transmitted to the support) performed better, there was still some degradation in performance, and transmitted support forces were not reduced to levels prior to the change in disturbance phase. The results show that for the semi-active system to retain its effectiveness in rejecting disturbances, a closed-loop, adaptive controller (with on-line system identification) is required; even when there is only a change in disturbance, and no change in basic system properties. An explanation for this phenomenon, related to the bi-linear nature of the semi-active system, is provided. Cyclic modulations in the damping coefficient were more effective in reducing the transmitted forces at the disturbance frequency than simply reducing the baseline damping coefficient (to improve the passive isolation characteristics).

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. Changing the criteria for old/new recognition judgments can modulate activity in the anterior hippocampus.

    Science.gov (United States)

    Hashimoto, Ryusaku; Abe, Nobuhito; Ueno, Aya; Fujii, Toshikatsu; Takahashi, Shoki; Mori, Etsuro

    2012-02-01

    Numerous functional magnetic resonance imaging (fMRI) studies have reported that the medial temporal lobe (MTL) is activated to a greater extent when subjects encounter novel items as compared with familiar ones. However, it remains unclear whether the novelty signals in the MTL are modulated by the criteria for old/new recognition judgments. In this study, we used fMRI to test our hypothesis that when subjects encounter items similar to previously encountered ones, the novelty signals in the MTL will differ depending on whether the subjects focus on the perceptual features or the semantic aspects of the items. The subjects studied a series of photographs and were later asked to make a recognition judgment of (a) Same items (items identical to those seen during encoding), (b) Similar items (items similar to but not identical to those seen during encoding), and (c) New items (unstudied items) in two types of tasks: Perceptual and Semantic. The subjects judged whether the items were perceptually identical to those seen during encoding in the Perceptual task and whether the items were semantically identical to those seen during encoding in the Semantic task. The left anterior hippocampus was activated when subjects were presented with New items relative to Same items in both tasks. In addition, the hippocampal activity in response to the Similar items was increased only in the Perceptual, but not the Semantic task. Our results indicate that the novelty signals in the hippocampus can be modulated by criteria for old/new recognition judgments.

  8. Study of solar activity modulation of galactic cosmic rays using the Pierre Auger Observatory

    Energy Technology Data Exchange (ETDEWEB)

    Anjos, J.C. dos [Centro Brasileiro de Pesquisas Fisicas (CBPF), Rio de Janeiro, RJ (Brazil)

    2011-07-01

    Full text: We show that the count rates of low energy secondary cosmic ray particles used for self-calibration of the water- Cherenkov detectors of the surface detector array of the Pierre Auger Observatory are highly sensitive, after correcting for atmospheric effects, to modulations of galactic cosmic rays due to solar activity and to transient events. The technique consists in recording low threshold rates - scalers - with all the surface detectors of the array. Transient events such as Gamma Ray Bursts and solar flares are expected to be seen as a significant change of the counting rates from the expected value. Temporal variations related with the activity of the heliosphere can be determined with high accuracy due to the high total count rates. We will present the available data collected since March 2005 together with an analysis focused on the observation of Forbush decreases, transient events characterized by short-term periods of strong depression of the cosmic ray flux observed at earth caused by the transit of a solar ejecta from a Coronal Mass Ejection from the Sun. A strong correlation with neutron monitor data from the close-by Observatory Los Cerrilos is observed, showing that water-Cherenkov detectors operating in scaler mode are highly sensitive to Forbush decreases and other transient events related to solar activity modulation of galactic cosmic rays. (author)

  9. 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.

  10. Module-assisted preparation of {sup 64}Cu with high specific activity

    Energy Technology Data Exchange (ETDEWEB)

    Thieme, S. [Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, P.O. Box 510 119, 01314 Dresden (Germany); Walther, M., E-mail: m.walther@hzdr.de [Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, P.O. Box 510 119, 01314 Dresden (Germany); Pietzsch, H.-J. [Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, P.O. Box 510 119, 01314 Dresden (Germany); Henniger, J. [Institute of Nuclear and Particle Physics, University of Technology Dresden, 01062 Dresden (Germany); Preusche, S.; Maeding, P.; Steinbach, J. [Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, P.O. Box 510 119, 01314 Dresden (Germany)

    2012-04-15

    In this work the production of {sup 64}Cu via the {sup 64}Ni(p,n){sup 64}Cu reaction with optimized conditions for low current irradiation is presented. Different target setups and cleaning steps for lowering metal contaminations in the product were applied. {sup 64}Cu with high specific activities up to 1685 GBq/{mu}mol was produced despite low overall activity ({approx}4.2 GBq per run). The module processing leads to a highly reproducible, reliable product quality (<1 {mu}g Cu and <7 {mu}g Ni). Besides its diagnostic value {sup 64}Cu may be of interest even for therapeutic purposes due to its decay characteristics. - Highlights: Black-Right-Pointing-Pointer Theoretical comparison of {sup 64}Cu and {sup 67}Cu for therapeutical use. Black-Right-Pointing-Pointer Evaluation of different target setups. Black-Right-Pointing-Pointer Different specific activity determination methods in comparison. Black-Right-Pointing-Pointer Detailed description of module operation. Black-Right-Pointing-Pointer Optimized {sup 64}Ni recycling and purification.

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

    Science.gov (United States)

    Li, Yuan; Xie, Yanming; Wang, Lianxin; Zhang, Yingying; Gu, Hao; Chai, Yan

    2016-01-01

    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.

  12. 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.

  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. 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.

  15. 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.

  16. Effects of Modulating M3 Muscarinic Receptor Activity on Azoxymethane-Induced Liver Injury in Mice

    OpenAIRE

    2013-01-01

    Previously, we reported that azoxymethane (AOM)-induced liver injury is robustly exacerbated in M3 muscarinic receptor (M3R)-deficient mice. We used the same mouse model to test the hypothesis that selective pharmacological modulation of M3R activity regulates the liver injury response. Initial experiments confirmed that giving a selective M3R antagonist, darifenacin, to AOM-treated mice mimicked M3R gene ablation. Compared to vehicle controls, mice treated with the M3R antagonist had reduced...

  17. Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK.

    Directory of Open Access Journals (Sweden)

    Steve Pedrini

    2005-01-01

    Full Text Available BACKGROUND: Statins are widely used cholesterol-lowering drugs that act by inhibiting HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Recent evidence suggests that statin use may be associated with a decreased risk for Alzheimer disease, although the mechanisms underlying this apparent risk reduction are poorly understood. One popular hypothesis for statin action is related to the drugs' ability to activate alpha-secretase-type shedding of the alpha-secretase-cleaved soluble Alzheimer amyloid precursor protein ectodomain (sAPP(alpha. Statins also inhibit the isoprenoid pathway, thereby modulating the activities of the Rho family of small GTPases-Rho A, B, and C-as well as the activities of Rac and cdc42. Rho proteins, in turn, exert many of their effects via Rho-associated protein kinases (ROCKs. Several cell-surface molecules are substrates for activated alpha-secretase-type ectodomain shedding, and regulation of shedding typically occurs via activation of protein kinase C or extracellular-signal-regulated protein kinases, or via inactivation of protein phosphatase 1 or 2A. However, the possibility that these enzymes play a role in statin-stimulated shedding has been excluded, leading us to investigate whether the Rho/ROCK1 protein phosphorylation pathway might be involved. METHODS AND FINDINGS: We found that both atorvastatin and simvastatin stimulated sAPP(alpha shedding from a neuroblastoma cell line via a subcellular mechanism apparently located upstream of endocytosis. A farnesyl transferase inhibitor also increased sAPP(alpha shedding, as did a dominant negative form of ROCK1. Most conclusively, a constitutively active ROCK1 molecule inhibited statin-stimulated sAPP(alpha shedding. CONCLUSION: Together, these data suggest that statins exert their effects on shedding of sAPP(alpha from cultured cells, at least in part, by modulation of the isoprenoid pathway and ROCK1.

  18. 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.

  19. 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.

  20. In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity at CYP-450.

    Science.gov (United States)

    Labrie, Philippe; Maddaford, Shawn P; Lacroix, Jacques; Catalano, Concettina; Lee, David K H; Rakhit, Suman; Gaudreault, René C

    2006-12-01

    Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency of the P-glycoprotein (P-gp) transporter. The aromatic spacer group between nitrogen atoms (N1 and N2) in the known inhibitor XR9576 was replaced with a flexible alkyl chain of 2 to 6 carbon atoms in length. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline and their open-chain N-methylhomoveratrylamine counterparts were shown to be potent P-gp inhibitors. The maximal inhibition was obtained when using an ethyl or propyl spacer. Several compounds were more potent than verapamil and intrinsically less cytotoxic than XR9576. In addition, in vitro metabolism studies of 23a with a subset of human CYP-450 isoforms revealed that, unlike XR9576, 23a inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of anticancer drugs such as paclitaxel toward metabolism. In this context, 22a might be a suitable candidate for further drug development.

  1. 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.

  2. 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.

  3. The amygdala modulates neuronal activation in the hippocampus in response to spatial novelty.

    Science.gov (United States)

    Sheth, Archana; Berretta, Sabina; Lange, Nicholas; Eichenbaum, Howard

    2008-01-01

    Emerging evidence indicates that the amygdala and the hippocampus play an important role in the pathophysiology of major psychotic disorders. Consistent with this evidence, and with data indicating amygdala modulation of hippocampal activity, animal model investigations have shown that a disruption of amygdala activity induces neurochemical changes in the hippocampus that are similar to those detected in subjects with schizophrenia. With the present study, we used induction of the immediate early gene Fos, to test the hypothesis that the amygdala may affect neuronal activation of the hippocampus in response to different spatial environments (familiar, modified, and novel). Exploratory and anxiety related behaviors were also assessed. In vehicle-treated rats, exposure to a modified version of the familiar environment was associated with an increase of numerical densities of Fos-immunoreactive nuclei in sectors CA1 and CA2, while exposure to a completely novel environment was associated with an increase in sectors CA1, CA4, and DG, compared with the familiar environment. Pharmacological disruption of amygdala activity resulted in a failure to increase Fos induction in the hippocampus in response to these environments. Exploratory behavior in response to the different environments was not altered by manipulation of amygdala activity. These findings support the idea that the amygdala modulates spatial information processing in the hippocampus and may affect encoding of specific environmental features, while complex behavioral responses to environment may be the result of broader neural circuits. These findings also raise the possibility that amygdala abnormalities may contribute to impairments in cognitive information processing in subjects with major psychoses.

  4. Simvastatin requires activation in accessory cells to modulate T-cell responses in asthma and COPD.

    Science.gov (United States)

    Knobloch, Jürgen; Yakin, Yakup; Körber, Sandra; Grensemann, Barbara; Bendella, Zeynep; Boyaci, Niyazi; Gallert, Willem-Jakob; Yanik, Sarah Derya; Jungck, David; Koch, Andrea

    2016-10-05

    T-cell-dependent airway and systemic inflammation triggers the progression of chronic obstructive pulmonary disease (COPD) and asthma. Retrospective studies suggest that simvastatin has anti-inflammatory effects in both diseases but it is unclear, which cell types are targeted. We hypothesized that simvastatin modulates T-cell activity. Circulating CD4+ and CD8+ T-cells, either pure, co-cultured with monocytes or alveolar macrophages (AM) or in peripheral blood mononuclear cells (PBMCs), were ex vivo activated towards Th1/Tc1 or Th2/Tc2 and incubated with simvastatin. Markers for Th1/Tc1 (IFNγ) and Th2/Tc2 (IL-5, IL-13) were measured by ELISA; with PBMCs this was done comparative between 11 healthy never-smokers, 11 current smokers without airflow limitation, 14 smokers with COPD and 11 never-smokers with atopic asthma. T-cell activation induced IFNγ, IL-5 and IL-13 in the presence and absence of accessory cells. Simvastatin did not modulate cytokine expression in pure T-cell fractions. β-hydroxy-simvastatin acid (activated simvastatin) suppressed IL-5 and IL-13 in pure Th2- and Tc2-cells. Simvastatin suppressed IL-5 and IL-13 in Th2-cells co-cultivated with monocytes or AM, which was partially reversed by the carboxylesterase inhibitor benzil. Simvastatin suppressed IL-5 production of Th2/Tc2-cells in PBMCs without differences between cohorts and IL-13 stronger in never-smokers and asthma compared to COPD. Simvastatin induced IFNγ in Th1/Tc1-cells in PBMCs of all cohorts except asthmatics. Simvastatin requires activation in accessory cells likely by carboxylesterase to suppress IL-5 and IL-13 in Th2/Tc2-cells. The effects on Il-13 are partially reduced in COPD. Asthma pathogenesis prevents simvastatin-induced IFNγ up-regulation. Simvastatin has anti-inflammatory effects that could be of interest for asthma therapy.

  5. Task-modulated activation and functional connectivity of the temporal and frontal areas during speech comprehension.

    Science.gov (United States)

    Yue, Q; Zhang, L; Xu, G; Shu, H; Li, P

    2013-05-01

    There is general consensus in the literature that a distributed network of temporal and frontal brain areas is involved in speech comprehension. However, how active versus passive tasks modulate the activation and the functional connectivity of the critical brain areas is not clearly understood. In this study, we used functional magnetic resonance imaging (fMRI) to identify intelligibility and task-related effects in speech comprehension. Participants performed a semantic judgment task on normal and time-reversed sentences, or passively listened to the sentences without making an overt response. The subtraction analysis demonstrated that passive sentence comprehension mainly engaged brain areas in the left anterior and posterior superior temporal sulcus and middle temporal gyrus (aSTS/MTG and pSTS/MTG), whereas active sentence comprehension recruited bilateral frontal regions in addition to the aSTS/MTG and pSTS/MTG regions. Functional connectivity analysis revealed that during passive sentence comprehension, the left aSTS/MTG was functionally connected with the left Heschl's gyrus (HG) and bilateral superior temporal gyrus (STG) but no area was functionally connected with the left pSTS/MTG; during active sentence comprehension, however, both the left aSTS/MTG and pSTS/MTG were functionally connected with bilateral superior temporal and inferior frontal areas. While these results are consistent with the view that the ventral stream of the temporo-frontal network subserves semantic processing, our findings further indicate that both the activation and the functional connectivity of the temporal and frontal areas are modulated by task demands.

  6. Activity in ventral premotor cortex is modulated by vision of own hand in action

    Directory of Open Access Journals (Sweden)

    Luciano Fadiga

    2013-07-01

    Full Text Available Parietal and premotor cortices of the macaque monkey contain distinct populations of neurons which, in addition to their motor discharge, are also activated by visual stimulation. Among these visuomotor neurons, a population of grasping neurons located in the anterior intraparietal area (AIP shows discharge modulation when the own hand is visible during object grasping. Given the dense connections between AIP and inferior frontal regions, we aimed at investigating whether two hand-related frontal areas, ventral premotor area F5 and primary motor cortex (area F1, contain neurons with similar properties. Two macaques were involved in a grasping task executed in various light/dark conditions in which the to-be-grasped object was kept visible by a dim retro-illumination. Approximately 62% of F5 and 55% of F1 motor neurons showed light/dark modulations. To better isolate the effect of hand-related visual input, we introduced two further conditions characterized by kinematic features similar to the dark condition. The scene was briefly illuminated (i during hand preshaping (pre-touch flash, PT-flash and (ii at hand-object contact (touch flash, T-flash. Approximately 48% of F5 and 44% of F1 motor neurons showed a flash-related modulation. Considering flash-modulated neurons in the two flash conditions, ∼40% from F5 and ∼52% from F1 showed stronger activity in PT- than T-flash (PT-flash-dominant, whereas ∼60% from F5 and ∼48% from F1 showed stronger activity in T- than PT-flash (T-flash-dominant. Furthermore, F5, but not F1, flash-dominant neurons were characterized by a higher peak and mean discharge in the preferred flash condition as compared to light and dark conditions. Still considering F5, the distribution of the time of peak discharge was similar in light and preferred flash conditions. This study shows that the frontal cortex contains neurons, previously classified as motor neurons, which are sensitive to the observation of meaningful

  7. Activation and modulation of recombinantly expressed serotonin receptor type 3A by terpenes and pungent substances.

    Science.gov (United States)

    Ziemba, Paul M; Schreiner, Benjamin S P; Flegel, Caroline; Herbrechter, Robin; Stark, Timo D; Hofmann, Thomas; Hatt, Hanns; Werner, Markus; Gisselmann, Günter

    2015-11-27

    Serotonin receptor type 3 (5-HT3 receptor) is a ligand-gated ion channel that is expressed in the central nervous system (CNS) as well as in the peripheral nervous system (PNS). The receptor plays an important role in regulating peristalsis of the gastrointestinal tract and in functions such as emesis, cognition and anxiety. Therefore, a variety of pharmacologically active substances target the 5-HT3 receptor to treat chemotherapy-induced nausea and vomiting. The 5-HT3 receptors are activated, antagonized, or modulated by a wide range of chemically different substances, such as 2-methyl-serotonin, phenylbiguanide, setrones, or cannabinoids. Whereas the action of all of these substances is well described, less is known about the effect of terpenoids or fragrances on 5-HT3A receptors. In this study, we screened a large number of natural odorous and pungent substances for their pharmacological action on recombinantly expressed human 5-HT3A receptors. The receptors were functionally expressed in Xenopus oocytes and characterized by electrophysiological recordings using the two-electrode voltage-clamp technique. A screening of two odorous mixes containing a total of 200 substances revealed that the monoterpenes, thymol and carvacrol, act as both weak partial agonists and positive modulators on the 5-HT3A receptor. In contrast, the most effective blockers were the terpenes, citronellol and geraniol, as well as the pungent substances gingerol, capsaicin and polygodial. In our study, we identified new modulators of 5-HT3A receptors out of the classes of monoterpenes and vanilloid substances that frequently occur in various plants.

  8. Using the Amino Acid Network to Modulate the Hydrolytic Activity of β-Glycosidases

    Science.gov (United States)

    Souza, Diorge P.; Souza, Valquiria P.; Ikegami, Cecilia M.; Farah, Chuck S.; Marana, Sandro R.

    2016-01-01

    The active site residues in GH1 β-glycosidases are compartmentalized into 3 functional regions, involved in catalysis or binding of glycone and aglycone motifs from substrate. However, it still remains unclear how residues outside the active site modulate the enzymatic activity. To tackle this question, we solved the crystal structure of the GH1 β-glycosidase from Spodoptera frugiperda (Sfβgly) to systematically map its residue contact network and correlate effects of mutations within and outside the active site. External mutations neighbouring the functional residues involved in catalysis and glycone-binding are deleterious, whereas mutations neighbouring the aglycone-binding site are less detrimental or even beneficial. The large dataset of new and previously characterized Sfβgly mutants supports that external perturbations are coherently transmitted to active site residues possibly through contacts and specifically disturb functional regions they interact to, reproducing the effects observed for direct mutations of functional residues. This allowed us to suggest that positions related to the aglycone-binding site are preferential targets for introduction of mutations aiming to further improve the hydrolytic activity of β–glycosidases. PMID:27936116

  9. Modulation of age-related NF-kappaB activation by dietary zingerone via MAPK pathway.

    Science.gov (United States)

    Kim, Mi Kyung; Chung, Sang Woon; Kim, Dae Hyun; Kim, Ji Min; Lee, Eun Kyeong; Kim, Ji Young; Ha, Young Mi; Kim, Yun Hee; No, Jae-Kyung; Chung, Hye Sun; Park, Kun-Young; Rhee, Sook Hee; Choi, Jae Sue; Yu, Byung Pal; Yokozawa, Takako; Kim, Young Jin; Chung, Hae Young

    2010-06-01

    Zingerone, a major component found in ginger root, has been known as anti-mutagenic and anti-carcinogenic activities that are often associated with its anti-oxidative and anti-inflammatory activities. In recent studies, we examined molecular mechanism of zingerone treatment on pro-inflammatory NF-kappaB activation via the redox-related NIK/IKK and MAPK pathways. Action mechanism of zingerone on NF-kappaB signaling was investigated in aged rat kidney and endothelial cells. The results showed that zingerone had not only the antioxidant effect by constitutive suppression of ROS, but also anti-inflammatory effects by suppression of nuclear factor (NF)-kappaB activation in aged rat. In addition, zingerone treatment suppressed gene activation of pro-inflammatory enzymes, COX-2 and iNOS, which were upregulated with aging through NF-kappaB activation and IKK/MAPK signaling pathway. These experiments strongly indicate that zingerone treatment exerts a beneficial efficacy by suppressing both oxidative stress and age-related inflammation through the modulation of several key pro-inflammatory genes and transcription factors. Thus, the significance of our findings is that the zingerone treatment may provide some preventive measure against chronic inflammatory conditions that underlie many age-related inflammatory diseases, such as metabolic syndrome, cardiovascular disease, dementia, arthritis, diabetes, osteoprosis, and cancers.

  10. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke.

    Science.gov (United States)

    Pariente, J; Loubinoux, I; Carel, C; Albucher, J F; Leger, A; Manelfe, C; Rascol, O; Chollet, F

    2001-12-01

    In order to determine the influence of a single dose of fluoxetine on the cerebral motor activation of lacunar stroke patients in the early phase of recovery, we conducted a prospective, double-blind, crossover, placebo-controlled study on 8 patients with pure motor hemiparesia. Each patient underwent two functional magnetic resonance imaging (fMRI) examinations: one under fluoxetine and one under placebo. The first was performed 2 weeks after stroke onset and the second a week later. During the two fMRI examinations, patients performed an active controlled motor task with the affected hand and a passive one conducted by the examiner with the same hand. Motor performance was evaluated by motor tests under placebo and under fluoxetine immediately before the examinations to investigate the effect of fluoxetine on motor function. Under fluoxetine, during the active motor task, hyperactivation in the ipsilesional primary motor cortex was found. Moreover, fluoxetine significantly improved motor skills of the affected side. We found that a single dose of fluoxetine was enough to modulate cerebral sensory-motor activation in patients. This redistribution of activation toward the motor cortex output activation was associated with an enhancement of motor performance.

  11. Antioxidant, Immunomodulating, and Microbial-Modulating Activities of the Sustainable and Ecofriendly Spirulina

    Directory of Open Access Journals (Sweden)

    Alberto Finamore

    2017-01-01

    Full Text Available The highly nutritional and ecofriendly Spirulina (Arthrospira platensis has hypolipidemic, hypoglycemic, and antihypertensive properties. Spirulina contains functional compounds, such as phenolics, phycocyanins, and polysaccharides, with antioxidant, anti-inflammatory, and immunostimulating effects. Studies conducted on Spirulina suggest that it is safe in healthy subjects, but attitude to eating probably affects the acceptability of Spirulina containing foods. Although the antioxidant effect of Spirulina is confirmed by the intervention studies, the concerted modulation of antioxidant and inflammatory responses, suggested by in vitro and animal studies, requires more confirmation in humans. Spirulina supplements seem to affect more effectively the innate immunity, promoting the activity of natural killer cells. The effects on cytokines and on lymphocytes’ proliferation depend on age, gender, and body weight differences. In this context, ageing and obesity are both associated with chronic low grade inflammation, immune impairment, and intestinal dysbiosis. Microbial-modulating activities have been reported in vitro, suggesting that the association of Spirulina and probiotics could represent a new strategy to improve the growth of beneficial intestinal microbiota. Although Spirulina might represent a functional food with potential beneficial effects on human health, the human interventions used only supplements. Therefore, the effect of food containing Spirulina should be evaluated in the future.

  12. Antioxidant, Immunomodulating, and Microbial-Modulating Activities of the Sustainable and Ecofriendly Spirulina.

    Science.gov (United States)

    Finamore, Alberto; Palmery, Maura; Bensehaila, Sarra; Peluso, Ilaria

    2017-01-01

    The highly nutritional and ecofriendly Spirulina (Arthrospira platensis) has hypolipidemic, hypoglycemic, and antihypertensive properties. Spirulina contains functional compounds, such as phenolics, phycocyanins, and polysaccharides, with antioxidant, anti-inflammatory, and immunostimulating effects. Studies conducted on Spirulina suggest that it is safe in healthy subjects, but attitude to eating probably affects the acceptability of Spirulina containing foods. Although the antioxidant effect of Spirulina is confirmed by the intervention studies, the concerted modulation of antioxidant and inflammatory responses, suggested by in vitro and animal studies, requires more confirmation in humans. Spirulina supplements seem to affect more effectively the innate immunity, promoting the activity of natural killer cells. The effects on cytokines and on lymphocytes' proliferation depend on age, gender, and body weight differences. In this context, ageing and obesity are both associated with chronic low grade inflammation, immune impairment, and intestinal dysbiosis. Microbial-modulating activities have been reported in vitro, suggesting that the association of Spirulina and probiotics could represent a new strategy to improve the growth of beneficial intestinal microbiota. Although Spirulina might represent a functional food with potential beneficial effects on human health, the human interventions used only supplements. Therefore, the effect of food containing Spirulina should be evaluated in the future.

  13. IQGAP1 Binds to Yes-associated Protein (YAP) and Modulates Its Transcriptional Activity.

    Science.gov (United States)

    Sayedyahossein, Samar; Li, Zhigang; Hedman, Andrew C; Morgan, Chase J; Sacks, David B

    2016-09-09

    During development, the Hippo signaling pathway regulates key physiological processes, such as control of organ size, regeneration, and stem cell biology. Yes-associated protein (YAP) is a major transcriptional co-activator of the Hippo pathway. The scaffold protein IQGAP1 interacts with more than 100 binding partners to integrate diverse signaling pathways. In this study, we report that IQGAP1 binds to YAP and modulates its activity. IQGAP1 and YAP co-immunoprecipitated from cells. In vitro analysis with pure proteins demonstrated a direct interaction between IQGAP1 and YAP. Analysis with multiple fragments of each protein showed that the interaction occurs via the IQ domain of IQGAP1 and the TEAD-binding domain of YAP. The interaction between IQGAP1 and YAP has functional effects. Knock-out of endogenous IQGAP1 significantly increased the formation of nuclear YAP-TEAD complexes. Transcription assays were performed with IQGAP1-null mouse embryonic fibroblasts and HEK293 cells with IQGAP1 knockdown by CRISPR/Cas9. Quantification demonstrated that YAP-TEAD-mediated transcription in cells lacking IQGAP1 was significantly greater than in control cells. These data reveal that IQGAP1 binds to YAP and modulates its co-transcriptional function, suggesting that IQGAP1 participates in Hippo signaling.

  14. 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

  15. 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.

  16. Spatial profile and differential recruitment of GABAB modulate oscillatory activity in auditory cortex.

    Science.gov (United States)

    Oswald, Anne-Marie M; Doiron, Brent; Rinzel, John; Reyes, Alex D

    2009-08-19

    The interplay between inhibition and excitation is at the core of cortical network activity. In many cortices, including auditory cortex (ACx), interactions between excitatory and inhibitory neurons generate synchronous network gamma oscillations (30-70 Hz). Here, we show that differences in the connection patterns and synaptic properties of excitatory-inhibitory microcircuits permit the spatial extent of network inputs to modulate the magnitude of gamma oscillations. Simultaneous multiple whole-cell recordings from connected fast-spiking interneurons and pyramidal cells in L2/3 of mouse ACx slices revealed that for intersomatic distances <50 microm, most inhibitory connections occurred in reciprocally connected (RC) pairs; at greater distances, inhibitory connections were equally likely in RC and nonreciprocally connected (nRC) pairs. Furthermore, the GABA(B)-mediated inhibition in RC pairs was weaker than in nRC pairs. Simulations with a network model that incorporated these features showed strong, gamma band oscillations only when the network inputs were confined to a small area. These findings suggest a novel mechanism by which oscillatory activity can be modulated by adjusting the spatial distribution of afferent input.

  17. Neurosteroids modulate epileptiform activity and associated high-frequency oscillations in the piriform cortex.

    Science.gov (United States)

    Herrington, R; Lévesque, M; Avoli, M

    2014-01-03

    Allotetrahydrodeoxycorticosterone (THDOC) belongs to a class of pregnane neurosteroidal compounds that enhance brain inhibition by interacting directly with GABAA signaling, mainly through an increase in tonic inhibitory current. Here, we addressed the role of THDOC in the modulation of interictal- and ictal-like activity and associated high-frequency oscillations (HFOs, 80-500 Hz; ripples: 80-200 Hz, fast ripples: 250-500 Hz) recorded in vitro in the rat piriform cortex, a highly excitable brain structure that is implicated in seizure generation and maintenance. We found that THDOC: (i) increased the duration of interictal discharges in the anterior piriform cortex while decreasing ictal discharge duration in both anterior and posterior piriform cortices; (ii) reduced the occurrence of HFOs associated to both interictal and ictal discharges; and (iii) prolonged the duration of 4-aminopyridine-induced, glutamatergic independent synchronous field potentials that are known to mainly result from the activation of GABAA receptors. Our results indicate that THDOC can modulate epileptiform synchronization in the piriform cortex presumably by potentiating GABAA receptor-mediated signaling. This evidence supports the view that neurosteroids regulate neuronal excitability and thus control the occurrence of seizures.

  18. Upper and lower extremity proprioceptive inputs modulate EMG activity of the trapezius.

    Science.gov (United States)

    Tataroglu, Cengiz; Kuçuk, Fatma Kursad; Ozkul, Ayca

    2011-02-01

    Axial muscles like the trapezius have different reflexive and functional properties. The aim of this study was to analyze the long latency reflexes obtained from the trapezius by the electrical stimulation of upper and lower extremity peripheral nerves. Thirty-one healthy volunteers were included in the study. Surface EMG activity of both trapezius muscles was recorded and averaged after electrical stimulation of the median and peroneal mixed nerves. The recordings were performed during supine and erect posture in nine subjects to evaluate of the effect of postural differences on reflex response. Reflex recordings were also performed in six subjects from some other muscles together with the trapezius by the stimulation of the peroneal nerve. Reflex responses including three components were recorded from the trapezius muscle (unilateral or bilateral) by electrical stimulation of the peroneal nerve. The most stable of them was the second component (23/31) which had a latency of 72.6 ± 7.9 ms for the ipsilateral, and 74.2 ± 8.5 ms for the contralateral trapezius (15/31). For median stimulation, the first component recorded at 32.0 ± 6.7 ms was the most stable (25/31). The second component was more frequently recorded on the contralateral side (14/31). Erect posture increased the amplitude of these components. Upper and lower extremity proprioceptive inputs modulate the EMG activity of the trapezius. This modulation probably related with postural adjustments.

  19. Antioxidant, Immunomodulating, and Microbial-Modulating Activities of the Sustainable and Ecofriendly Spirulina

    Science.gov (United States)

    Finamore, Alberto; Bensehaila, Sarra

    2017-01-01

    The highly nutritional and ecofriendly Spirulina (Arthrospira platensis) has hypolipidemic, hypoglycemic, and antihypertensive properties. Spirulina contains functional compounds, such as phenolics, phycocyanins, and polysaccharides, with antioxidant, anti-inflammatory, and immunostimulating effects. Studies conducted on Spirulina suggest that it is safe in healthy subjects, but attitude to eating probably affects the acceptability of Spirulina containing foods. Although the antioxidant effect of Spirulina is confirmed by the intervention studies, the concerted modulation of antioxidant and inflammatory responses, suggested by in vitro and animal studies, requires more confirmation in humans. Spirulina supplements seem to affect more effectively the innate immunity, promoting the activity of natural killer cells. The effects on cytokines and on lymphocytes' proliferation depend on age, gender, and body weight differences. In this context, ageing and obesity are both associated with chronic low grade inflammation, immune impairment, and intestinal dysbiosis. Microbial-modulating activities have been reported in vitro, suggesting that the association of Spirulina and probiotics could represent a new strategy to improve the growth of beneficial intestinal microbiota. Although Spirulina might represent a functional food with potential beneficial effects on human health, the human interventions used only supplements. Therefore, the effect of food containing Spirulina should be evaluated in the future. PMID:28182098

  20. 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.

  1. Real-Time Performance of Mechatronic PZT Module Using Active Vibration Feedback Control.

    Science.gov (United States)

    Aggogeri, Francesco; Borboni, Alberto; Merlo, Angelo; Pellegrini, Nicola; Ricatto, Raffaele

    2016-09-25

    This paper proposes an innovative mechatronic piezo-actuated module to control vibrations in modern machine tools. Vibrations represent one of the main issues that seriously compromise the quality of the workpiece. The active vibration control (AVC) device is composed of a host part integrated with sensors and actuators synchronized by a regulator; it is able to make a self-assessment and adjust to alterations in the environment. In particular, an innovative smart actuator has been designed and developed to satisfy machining requirements during active vibration control. This study presents the mechatronic model based on the kinematic and dynamic analysis of the AVC device. To ensure a real time performance, a H2-LQG controller has been developed and validated by simulations involving a machine tool, PZT actuator and controller models. The Hardware in the Loop (HIL) architecture is adopted to control and attenuate the vibrations. A set of experimental tests has been performed to validate the AVC module on a commercial machine tool. The feasibility of the real time vibration damping is demonstrated and the simulation accuracy is evaluated.

  2. 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

  3. Slow State Transitions of Sustained Neural Oscillations by Activity-Dependent Modulation of Intrinsic Excitability

    Science.gov (United States)

    Fröhlich, Flavio; Bazhenov, Maxim; Timofeev, Igor; Steriade, Mircea; Sejnowski, Terrence J.

    2010-01-01

    Little is known about the dynamics and mechanisms of transitions between tonic firing and bursting in cortical networks. Here, we use a computational model of a neocortical circuit with extracellular potassium dynamics to show that activity-dependent modulation of intrinsic excitability can lead to sustained oscillations with slow transitions between two distinct firing modes: fast run (tonic spiking or fast bursts with few spikes) and slow bursting. These transitions are caused by a bistability with hysteresis in a pyramidal cell model. Balanced excitation and inhibition stabilizes a network of pyramidal cells and inhibitory interneurons in the bistable region and causes sustained periodic alternations between distinct oscillatory states. During spike-wave seizures, neocortical paroxysmal activity exhibits qualitatively similar slow transitions between fast run and bursting. We therefore predict that extracellular potassium dynamics can cause alternating episodes of fast and slow oscillatory states in both normal and epileptic neocortical networks. PMID:16763023

  4. 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.

  5. Gold-Loaded Polymeric Micelles with Temperature-Modulated Catalytic Activity

    Institute of Scientific and Technical Information of China (English)

    HU Na; SHI Dongjian; LI Jihang; LI Junfeng; CHEN Mingqing

    2015-01-01

    Four-armed amphiphilic block copolymers, polystyrene-b-poly(N-isopropylacrylamide) (PS-b-PNIPAM)4, were synthesized by atom transfer radical polymerization (ATRP). (PS-b-PNIPAM)4 self-assembled into micelles with PS block as core and thermoresponsive PNIPAM block as corona. The gold nanoparticles (Au NPs) with average diameter about 5.8 nm were immobilized on the surfaces of the micelles by the reduction of the corresponding ions. The micelle-supported gold nanoparticles (Au-micelles) were applied to catalyze the reduction ofp-nitrophenol. Moreover, the activity of the Au-micelle catalyst could be modulated by the temperature and the Au-micelles could be easily recovered by changing the temperature and recycled four times with high catalytic activity.

  6. 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.

  7. Osteoclast activity modulates B-cell development in the bone marrow

    Institute of Scientific and Technical Information of China (English)

    Anna Mansour; Adrienne Anginot; Stéphane J C Mancini; Claudine Schiff; Georges F Carle; Abdelilah Wakkach; Claudine Blin-Wakkach

    2011-01-01

    B-cell development is dependent on the interactions between B-cell precursors and bone marrow stromal cells, but the role of osteoclasts (OCLs) in this process remains unknown. B lymphocytopenia is a characteristic of osteopetrosis, suggesting a modulation of B lymphopoiesis by OCL activity. To address this question, we first rescued OCL function in osteopetrotic oc/oc mice by dendritic cell transfer, leading to a restoration of both bone phenotype and B-cell development. To further explore the link between OCL activity and B lymphopoiesis, we induced osteopetrosis in normal mice by injections of zoledronic acid (ZA), an inhibitor of bone resorption. B-cell number decreased specifically in the bone marrow of ZA-treated mice. ZA did not directly affect B-cell differentiation, proliferation and apoptosis, but induced a decrease in the expression of CXCL12 and IL-7 by stromal cells, associated with reduced osteoblastic engagement. Equivalent low osteoblastic engagement in oc/oc mice confirmed that it resulted from the reduced OCL activity rather than from a direct effect of ZA on osteoblasts. These dramatic alterations of the bone microenvironment were disadvantageous for B lymphopoiesis, leading to retention of B-cell progenitors outside of their bone marrow niches in the ZA-induced osteopetrotic model. Altogether, our data revealed that OCLs modulate B-cell development in the bone marrow by controlling the bone microenvironment and the fate of osteoblasts. They provide novel basis for the regulation of the retention of B cells in their niche by OCL activity.

  8. Trait anxiety modulates brain activity during performance of verbal fluency tasks

    Directory of Open Access Journals (Sweden)

    Barbara eGawda

    2016-02-01

    Full Text Available Trait anxiety is thought to be associated with pathological anxiety, and a risk factor for psychiatric disorders. The present study examines the brain mechanisms associated with trait anxiety during the performing of verbal fluency tasks. The aim is to show how trait anxiety modulates executive functions as measured by verbal fluency, and to explore the link between verbal fluency and anxiety due to the putative negative biases in high-anxious individuals. Seven tasks of verbal fluency were used: letter ‘k’, ‘f’, verbs, ‘animals’, ‘vehicles’, ‘joy’ and ‘fear’. The results of 35 subjects (whole sample, and 17 subjects (9 men, 8 women selected from the whole sample for the low/high-anxious groups on the basis of Trait Anxiety scores were analyzed. The subjects were healthy, Polish speaking, right-handed and aged from 20 to 35 years old. fMRI (whole-brain analysis with FWE corrections was used to show the neural signals under active participation in verbal fluency tasks. The results confirm that trait anxiety slightly modulates neural activation during the performance of verbal fluency tasks, especially in the more difficult tasks. Significant differences were found in brain activation during the performance of more complex tasks between individuals with low anxiety and those with high anxiety. Greater activation in the right hemisphere, frontal gyri, and cerebellum was found in people with low anxiety. The results reflect better integration of cognitive and affective capacities in individuals with low anxiety.

  9. Osteoclast activity modulates B-cell development in the bone marrow.

    Science.gov (United States)

    Mansour, Anna; Anginot, Adrienne; Mancini, Stéphane J C; Schiff, Claudine; Carle, Georges F; Wakkach, Abdelilah; Blin-Wakkach, Claudine

    2011-07-01

    B-cell development is dependent on the interactions between B-cell precursors and bone marrow stromal cells, but the role of osteoclasts (OCLs) in this process remains unknown. B lymphocytopenia is a characteristic of osteopetrosis, suggesting a modulation of B lymphopoiesis by OCL activity. To address this question, we first rescued OCL function in osteopetrotic oc/oc mice by dendritic cell transfer, leading to a restoration of both bone phenotype and B-cell development. To further explore the link between OCL activity and B lymphopoiesis, we induced osteopetrosis in normal mice by injections of zoledronic acid (ZA), an inhibitor of bone resorption. B-cell number decreased specifically in the bone marrow of ZA-treated mice. ZA did not directly affect B-cell differentiation, proliferation and apoptosis, but induced a decrease in the expression of CXCL12 and IL-7 by stromal cells, associated with reduced osteoblastic engagement. Equivalent low osteoblastic engagement in oc/oc mice confirmed that it resulted from the reduced OCL activity rather than from a direct effect of ZA on osteoblasts. These dramatic alterations of the bone microenvironment were disadvantageous for B lymphopoiesis, leading to retention of B-cell progenitors outside of their bone marrow niches in the ZA-induced osteopetrotic model. Altogether, our data revealed that OCLs modulate B-cell development in the bone marrow by controlling the bone microenvironment and the fate of osteoblasts. They provide novel basis for the regulation of the retention of B cells in their niche by OCL activity.

  10. 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.

  11. Mycobacterium tuberculosis Chaperonin 10 Is Secreted in the Macrophage Phagosome: Is Secretion Due to Dissociation and Adoption of a Partially Helical Structure at the Membrane?

    Science.gov (United States)

    Fossati, Gianluca; Izzo, Gaetano; Rizzi, Emanuele; Gancia, Emanuela; Modena, Daniela; Moras, Maria Luisa; Niccolai, Neri; Giannozzi, Elena; Spiga, Ottavia; Bono, Letizia; Marone, Piero; Leone, Eugenio; Mangili, Francesca; Harding, Stephen; Errington, Neil; Walters, Christopher; Henderson, Brian; Roberts, Michael M.; Coates, Anthony R. M.; Casetta, Bruno; Mascagni, Paolo

    2003-01-01

    To confirm that Mycobacterium tuberculosis chaperonin 10 (Cpn10) is secreted outside the live bacillus, infected macrophages were examined by electron microscopy. This revealed that the mycobacterial protein accumulates both in the wall of the bacterium and in the matrix of the phagosomes in which ingested mycobacteria survive within infected macrophages. To understand the structural implications underlying this secretion, a structural study of M. tuberculosis Cpn10 was performed under conditions that are generally believed to mimic the membrane environment. It was found that in buffer-organic solvent mixtures, the mycobacterial protein forms two main species, namely, a partially helical monomer that prevails in dilute solutions at room temperature and a dimer that folds into a β-sheet-dominated structure and prevails in either concentrated protein solutions at room temperature or in dilute solutions at low temperature. A partially helical monomer was also found and was completely associated with negatively charged detergents in a micelle-bound state. Remarkably, zwitterionic lipids had no effect on the protein structure. By using N- and C-truncated forms of the protein, the C- and N-terminal sequences were identified as possessing an amphiphilic helical character and as selectively associating with acidic detergent micelles. When the study was extended to other chaperonins, it was found that human Cpn10 is also monomeric and partially helical in dilute organic solvent-buffer mixtures. In contrast, Escherichia coli Cpn10 is mostly dimeric and predominately β-sheet in both dilute and concentrated solutions. Interestingly, human Cpn10 also crosses biological membranes, whereas the E. coli homologue is strictly cytosolic. These results suggest that dissociation to partially helical monomers and interaction with acidic lipids may be two important steps in the mechanism of secretion of M. tuberculosis Cpn10 to the external environment. PMID:12837802

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Signal transducer and activator of transcription 5B (STAT5B) modulates adipocyte differentiation via MOF.

    Science.gov (United States)

    Gao, Peng; Zhang, Yuchao; Liu, Yuantao; Chen, Jicui; Zong, Chen; Yu, Cong; Cui, Shang; Gao, Weina; Qin, Dandan; Sun, Wenchuan; Li, Xia; Wang, Xiangdong

    2015-12-01

    The role and mechanism of signal transducer and activator of transcription 5B (STAT5B) in adipogenesis remain unclear. In this study, our data showed that Males absent on the first (MOF) protein expression was increased during 3 T3-L1 preadipocytes differentiation accompanied with STAT5B expression increasing. Over-expression STAT5B enhanced MOF promoter trans-activation in HeLa cells. Mutagenesis assay and ChIP analysis exhibited that STAT5B was able to bind MOF promoter. Knocking-down STAT5B in 3 T3-L1 preadipocytes led to decreased expression of MOF, but resulted in increased expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα) and fatty acid-binding protein 4 (Fabp4), which were important factors or enzymes for adipogenesis. We also found that knocking-down MOF in 3 T3-L1 preadipocytes resulted in increased expression of PPARγ, C/EBPα and Fabp4, which was in the same trend as STAT5B knocking-down. Over-expression MOF resulted in reduced promoter trans-activation activity of C/EBPα. These results suggest that STAT5B and MOF work as negative regulators in adipogenesis, and STAT5B modulates preadipocytes differentiation partially by regulating MOF expression.

  18. sel-11 and cdc-42, two negative modulators of LIN-12/Notch activity in C. elegans.

    Directory of Open Access Journals (Sweden)

    Min Sung Choi

    Full Text Available BACKGROUND: LIN-12/Notch signaling is important for cell-cell interactions during development, and mutations resulting in constitutive LIN-12/Notch signaling can cause cancer. Loss of negative regulators of lin-12/Notch activity has the potential for influencing cell fate decisions during development and the genesis or aggressiveness of cancer. METHODOLOGY/PRINCIPAL FINDINGS: We describe two negative modulators of lin-12 activity in C. elegans. One gene, sel-11, was initially defined as a suppressor of a lin-12 hypomorphic allele; the other gene, cdc-42, is a well-studied Rho GTPase. Here, we show that SEL-11 corresponds to yeast Hrd1p and mammalian Synoviolin. We also show that cdc-42 has the genetic properties consistent with negative regulation of lin-12 activity during vulval precursor cell fate specification. CONCLUSIONS/SIGNIFICANCE: Our results underscore the multiplicity of negative regulatory mechanisms that impact on lin-12/Notch activity and suggest novel mechanisms by which constitutive lin-12/Notch activity might be exacerbated in cancer.

  19. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network.

    Science.gov (United States)

    Palhano-Fontes, Fernanda; Andrade, Katia C; Tofoli, Luis F; Santos, Antonio C; Crippa, Jose Alexandre S; Hallak, Jaime E C; Ribeiro, Sidarta; de Araujo, Draulio B

    2015-01-01

    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.

  20. 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.

  1. Modulation of vagal activity to atria electrical remodeling resulted from rapid atrial pacing

    Institute of Scientific and Technical Information of China (English)

    Shulong Zhang; Yanzong Yang; Yingxue Dong; Lianjun Gao; Donghui Yang; Chunyue Zhao; Hongwei Zhao; Xiaomeng Yin; Jinqiu Liu; Zhihu Lin

    2008-01-01

    Background Atrial electrical remodeling(AER)plays an important role in the pathogenesis and maintenance of atrialfibrillation.However,little is known about modulation of vagal activilty to AER.This study aimed to investigate the relationshipbetween vagal moduation and AER. Methods Twenty four adult mongrel dogs under general anesthesia were randomized into 3groups.Sympathetic activity was blocked by administration of metoprolol in 3 groups.The changes in vagal modulation to atria afterAER were observed in 10 dogs without vagal interruption in group A.The effects of vagal intervention on AER were investigated in 8dogs with administration of atropine in group B.The impact of aggressively vagal activity on AER was studied in 6 dogs with bilateralcervical vag sympathetic trunLks stimulation during AER in group C.Bilateral cervicall vagosympathetic trunks were decentralized.Multipolar catheters wereplaced into high right atria(RA),coronary sinus(CS)and rightventricle(RV).AER was induced by 600 bpmpacing through RA catheter for 30 minutes.Attial effective refractory period(ERP)and vulnerability window (VW)of atrial fibrillationwere measured with and without vagal stimulation before and after AER.Results In group A,ERP decreased significantly at baselineand during vagal stimulation after AER compared with that beforeAER(all P<0.05).In group B,ERP remaind unchanged at baselineand vagal stimulation after AER compared with tbat before AER (all P>0.05).In group C,ERP shortened significantly at baseline andvagal stimulation after AER compared with that before AER(all P<0.05).ERP shortening after AER in Groups A and C increasedsignificantly than that in group B (all P<0.05).Atrial fibrillation could not be induced at baseline(VW close to 0) before and after AERin three groups.VW became widen significantly during vagal stimulation after AER compared with that before AER in Groups A and C(all P<0.05),while VW remained unchanged in group B (VW close to 0).Conclusions

  2. A novel anti-inflammatory activity of lysozyme: modulation of serum complement activation

    Directory of Open Access Journals (Sweden)

    M. O. Ogundele

    1998-01-01

    Full Text Available Lysozyme is an ubiquitous enzyme found in most biological secretions and leukocytes. This study was aimed at investigating its interaction with other inflammatory mediators on mucosa surfaces, particularly the complement system. Lysozyme has been shown in our present study, to inhibit the haemolytic activity of serum complement in a dose-dependent fashion, when tested within the levels present in normal and inflamed breast-milk samples, and other mucosal secretions. This represents a new antiinflammatory action of lysozym e in relation to the serum complement, and the exact mode of the interaction need further studies.

  3. 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.

  4. 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

  5. β-pompilidotoxin modulates spontaneous activity and persistent sodium currents in spinal networks.

    Science.gov (United States)

    Magloire, V; Czarnecki, A; Anwander, H; Streit, J

    2011-01-13

    The origin of rhythm generation in mammalian spinal cord networks is still poorly understood. In a previous study, we showed that spontaneous activity in spinal networks takes its origin in the properties of certain intrinsically spiking interneurons based on the persistent sodium current (INaP). We also showed that depolarization block caused by a fast inactivation of the transient sodium current (INaT) contributes to the generation of oscillatory activity in spinal cord cultures. Recently, a toxin called beta-pompilidotoxin (β-PMTX) that slows the inactivation process of tetrodotoxin (TTX)-sensitive sodium channels has been extracted from the solitary wasp venom. In the present study, we therefore investigated the effect of β-PMTX on rhythm generation and on sodium currents in spinal networks. Using intracellular recordings and multielectrode array (MEA) recordings in dissociated spinal cord cultures from embryonic (E14) rats, we found that β-PMTX reduces the number of population bursts and increases the background asynchronous activity. We then uncoupled the network by blocking all synaptic transmission (APV, CNQX, bicuculline and strychnine) and observed that β-PMTX increases both the intrinsic activity at individual channels and the number of intrinsically activated channels. At the cellular level, we found that β-PMTX has two effects: it switches 58% of the silent interneurons into spontaneously active interneurons and increases the firing rate of intrinsically spiking cells. Finally, we investigated the effect of β-PMTX on sodium currents. We found that this toxin not only affects the inactivation of INaT but also increases the peak amplitude of the persistent sodium current (INaP). Altogether, theses findings suggest that β-PMTX acting on INaP and INaT enhances intrinsic activity leading to a profound modulation of spontaneous rhythmic activity in spinal networks.

  6. Modulation of jaw muscle spindle afferent activity following intramuscular injections with hypertonic saline.

    Science.gov (United States)

    Ro, J Y; Capra, N F

    2001-05-01

    Transient noxious chemical stimulation of small diameter muscle afferents modulates jaw movement-related responses of caudal brainstem neurons. While it is likely that the effect is mediated from the spindle afferents in the mesencephalic nucleus (Vmes) via the caudally projecting Probst's tract, the mechanisms of pain induced modulations of jaw muscle spindle afferents is not known. In the present study, we tested the hypothesis that jaw muscle nociceptors gain access to muscle spindle afferents in the same muscle via central mechanisms and alter their sensitivity. Thirty-five neurons recorded from the Vmes were characterized as muscle spindle afferents based on their responses to passive jaw movements, muscle palpation, and electrical stimulation of the masseter nerve. Each cell was tested by injecting a small volume (250 microl) of either 5% hypertonic and/or isotonic saline into the receptor-bearing muscle. Twenty-nine units were tested with 5% hypertonic saline, of which 79% (23/29) showed significant modulation of mean firing rates (MFRs) during one or more phases of ramp-and-hold movements. Among the muscle spindle primary-like units (n = 12), MFRs of 4 units were facilitated, five reduced, two showed mixed responses and one unchanged. In secondary-like units (n = 17), MFRs of 9 were facilitated, three reduced and five unchanged. Thirteen units were tested with isotonic saline, of which 77% showed no significant changes of MFRs. Further analysis revealed that the hypertonic saline not only affected the overall output of muscle spindle afferents, but also increased the variability of firing and altered the relationship between afferent signal and muscle length. These results demonstrated that activation of muscle nociceptors significantly affects proprioceptive properties of jaw muscle spindles via central neural mechanisms. The changes can have deleterious effects on oral motor function as well as kinesthetic sensibility.

  7. Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells.

    Science.gov (United States)

    Dulak, Jozef; Józkowicz, Alicja; Foresti, Roberta; Kasza, Aneta; Frick, Matthias; Huk, Ihor; Green, Colin J; Pachinger, Otmar; Weidinger, Franz; Motterlini, Roberto

    2002-04-01

    Hypoxia, cytokines, and nitric oxide (NO) stimulate the generation of vascular endothelial growth factor (VEGF) and induce heme oxygenase-1 (HO-1) expression in vascular tissue. HO-1 degrades heme to carbon monoxide (CO), iron, and biliverdin, the latter being reduced to bilirubin by biliverdin reductase. In the present study, we investigated the role of HO-1 in the modulation of VEGF synthesis in rat vascular smooth muscle cells (VSMC). In VSMC stimulated with cytokines, inhibition of NO production significantly, but not completely, reduced VEGF release. In contrast, inhibition of HO activity by tin protoporphyrin IX (SnPPIX) totally prevented cytokine-induced increase in VEGF, despite an augmented synthesis of intracellular NO. Stimulation of HO-1 activity by hemin enhanced VEGF production; this effect was abrogated by blockade of the HO pathway. Similarly, VEGF synthesis induced by hypoxia was down-regulated by SnPPIX, but not by inhibitors of NO synthase. To elucidate further a direct involvement of HO-1 in the observed effects, we generated transfected cells that overexpressed the HO-1 gene. Notably, these cells synthesized significantly more VEGF protein than cells transfected with a control gene. Among the products of HO-1, biliverdin and bilirubin showed no effect, whereas iron ions inhibited VEGF synthesis. Exposure of cells to 1% CO resulted in a marked accumulation of VEGF (20-fold increase) over the basal level. Our data indicate that HO-1 activity influences the generation of VEGF in VSMC in both normoxic and hypoxic conditions. As CO and iron, respectively the inducer and the inhibitor of VEGF synthesis, are concomitantly produced during the degradation of heme, these data indicate that HO by-products may differentially modulate VEGF production.

  8. Inflows towards active regions and the modulation of the solar cycle: A parameter study

    Science.gov (United States)

    Martin-Belda, D.; Cameron, R. H.

    2017-01-01

    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 that are inconsistent with observations. We propose the darkening caused by pores in areas of high magnetic field strength as a possible mechanism preventing this flux-clumping. We find that inflows decrease the amplitude of the axial dipole moment by 30%, relative to a no-inflows scenario. Stronger (weaker) inflows lead to larger (smaller) reductions of the axial dipole moment. The relative amplitude of the generated axial dipole is about 9% larger after very weak cycles than after very strong cycles. This supports the idea that the inflows are a non-linear mechanism that is capable of saturating the global dynamo and contributing to the modulation of the solar cycle within the Babcock-Leighton framework.

  9. Modulation of Hyperpolarization-Activated Cation Currents (Ih) by Ethanol in Rat Hippocampal CA3 Pyramidal Neurons

    OpenAIRE

    Licheri, Valentina

    2015-01-01

    It is well established that ethanol (EtOH), through the interaction with several membrane proteins, as well as intracellular pathways, is capable to modulate many neuronal function. Recent reports show that EtOH increases the firing rate of hippocampal GABAergic interneurons through the positive modulation of the hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels. This effect might be consistent with the increase of GABA release from presynaptic terminals...

  10. Layer selective presynaptic modulation of excitatory inputs to hippocampal CA1 by μ-opioid receptor activation

    OpenAIRE

    McQuiston, A. Rory

    2007-01-01

    Chronic and acute activation of μ-opioid receptors (MOR) in hippocampal CA1 disrupts rhythmic activity, alters activity-dependent synaptic plasticity and impairs spatial memory formation. In CA1, MORs act by hyperpolarizing inhibitory interneurons and suppressing inhibitory synaptic transmission. MOR modulation of inhibitory synaptic function translates into an increase in excitatory activity in all layers of CA1. However, the exact anatomical sites for MOR actions are not completely known. T...

  11. 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.

  12. Temporal expectation and attention jointly modulate auditory oscillatory activity in the beta band.

    Science.gov (United States)

    Todorovic, Ana; Schoffelen, Jan-Mathijs; van Ede, Freek; Maris, Eric; de Lange, Floris P

    2015-01-01

    The neural response to a stimulus is influenced by endogenous factors such as expectation and attention. Current research suggests that expectation and attention exert their effects in opposite directions, where expectation decreases neural activity in sensory areas, while attention increases it. However, expectation and attention are usually studied either in isolation or confounded with each other. A recent study suggests that expectation and attention may act jointly on sensory processing, by increasing the neural response to expected events when they are attended, but decreasing it when they are unattended. Here we test this hypothesis in an auditory temporal cueing paradigm using magnetoencephalography in humans. In our study participants attended to, or away from, tones that could arrive at expected or unexpected moments. We found a decrease in auditory beta band synchrony to expected (versus unexpected) tones if they were unattended, but no difference if they were attended. Modulations in beta power were already evident prior to the expected onset times of the tones. These findings suggest that expectation and attention jointly modulate sensory processing.

  13. Baroreflex modulation of muscle sympathetic nerve activity during posthandgrip muscle ischemia in humans

    Science.gov (United States)

    Cui, J.; Wilson, T. E.; Shibasaki, M.; Hodges, N. A.; Crandall, C. G.

    2001-01-01

    To identify whether muscle metaboreceptor stimulation alters baroreflex control of muscle sympathetic nerve activity (MSNA), MSNA, beat-by-beat arterial blood pressure (Finapres), and electrocardiogram were recorded in 11 healthy subjects in the supine position. Subjects performed 2 min of isometric handgrip exercise at 40% of maximal voluntary contraction followed by 2.5 min of posthandgrip muscle ischemia. During muscle ischemia, blood pressure was lowered and then raised by intravenous bolus infusions of sodium nitroprusside and phenylephrine HCl, respectively. The slope of the relationship between MSNA and diastolic blood pressure was more negative (P ischemia (-201.9 +/- 20.4 units. beat(-1). mmHg(-1)) when compared with control conditions (-142.7 +/- 17.3 units. beat(-1). mmHg(-1)). No significant change in the slope of the relationship between heart rate and systolic blood pressure was observed. However, both curves shifted during postexercise ischemia to accommodate the elevation in blood pressure and MSNA that occurs with this condition. These data suggest that the sensitivity of baroreflex modulation of MSNA is elevated by muscle metaboreceptor stimulation, whereas the sensitivity of baroreflex of modulate heart rate is unchanged during posthandgrip muscle ischemia.

  14. 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.

  15. Serotonin transporter genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults.

    Science.gov (United States)

    Gillihan, Seth J; Rao, Hengyi; Brennan, Lauretta; Wang, Danny J J; Detre, John A; Sankoorikal, Geena Mary V; Brodkin, Edward S; Farah, Martha J

    2011-09-30

    Recent attempts to understand the biological bases of depression vulnerability have revealed that both the short allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) and activity in the amygdala are associated with depression. Other studies have reported amygdala hyperactivity associated with the 5-HTTLPR short allele, linking the genetic and neuroimaging lines of research and suggesting a mechanism whereby the short allele confers depression risk. However, fewer investigations have examined the associations among depression, 5-HTTLPR variability, and amygdala activation in a single study. The current study thus investigated whether 5-HTTLPR genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults. Regional cerebral blood flow was measured with perfusion fMRI during a task-free scan. We hypothesized differential associations between depressive symptoms and amygdala activity among individuals homozygous for the short allele and individuals homozygous for the long allele. Both whole brain analyses and region-of-interest analyses confirmed this prediction, revealing a significant negative association among the long allele group and a trend of positive association among the short allele group. These results complement existing reports of short allele related amygdala hyperactivity and suggest an additional neurobiological mechanism whereby the 5-HTTLPR is associated with psychiatric outcomes.

  16. Spectral modulation of LFP activity in M1 during dexterous finger movements.

    Science.gov (United States)

    Mollazadeh, Mohsen; Aggarwal, Vikram; Singhal, Girish; Law, Andrew; Davidson, Adam; Schieber, Marc; Thakor, Nitish

    2008-01-01

    Recent studies have shown that cortical local field potentials (LFP) contain information about planning or executing hand movement. While earlier research has looked at gross motor movements, we investigate the spectral modulation of LFP activity and its dependence on recording location during dexterous motor actions. In this study, we recorded LFP activity from the primary motor cortex of a primate as it performed a fine finger manipulation task involving different switches. The event-related spectral perturbations (ERSP) in four different frequency bands were considered for the analysis; 4 Hz, 6-15 Hz, 17-40 Hz and 75-170 Hz. LFPs recorded from electrodes in the hand area showed the largest change in ERSP for the highest frequency band (75-170 Hz) (p 0.05), while LFPs recorded from electrodes placed more medially in the arm area showed the largest change in ERSP for the lowest frequency band (4 Hz) (p 0.05). Furthermore, the spectral information from the <4 Hz and 75-150 Hz frequency bands was used to successfully decode the three dexterous grasp movements with an average accuracy of up to 81%. Although previous research has shown that multi-unit neuronal activity can be used to decode fine motor movements, these results demonstrate that LFP activity can also be used to decode dexterous motor tasks. This has implications for future neuroprosthetic devices due to the robustness of LFP signals for chronic recording.

  17. 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.

  18. Activation of unfolded protein response and autophagy during HCV infection modulates innate immune response.

    Science.gov (United States)

    Estrabaud, Emilie; De Muynck, Simon; Asselah, Tarik

    2011-11-01

    Autophagy, a process for catabolizing cytoplasmic components, has been implicated in the modulation of interactions between RNA viruses and their host. However, the mechanism underlying the functional role of autophagy in the viral life cycle still remains unclear. Hepatitis C virus (HCV) is a single-stranded, positive-sense, membrane-enveloped RNA virus that can cause chronic liver disease. Here we report that HCV induces the unfolded protein response (UPR), which in turn activates the autophagic pathway to promote HCV RNA replication in human hepatoma cells. Further analysis revealed that the entire autophagic process through to complete autolysosome maturation was required to promote HCV RNA replication and that it did so by suppressing innate antiviral immunity. Gene silencing or activation of the UPR-autophagy pathway activated or repressed, respectively, IFN-β activation mediated by an HCV-derived pathogen-associated molecular pattern (PAMP). Similar results were achieved with a PAMP derived from Dengue virus (DEV), indicating that HCV and DEV may both exploit the UPR-autophagy pathway to escape the innate immune response. Taken together, these results not only define the physiological significance of HCV-induced autophagy, but also shed light on the knowledge of host cellular responses upon HCV infection as well as on exploration of therapeutic targets for controlling HCV infection.

  19. 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.

  20. Cigarette smoke inhibits ROCK2 activation in T cells and modulates IL-22 production.

    Science.gov (United States)

    Weng, Chien-Huan; Gupta, Sanjay; Geraghty, Patrick; Foronjy, Robert; Pernis, Alessandra B

    2016-03-01

    Gene-environment interactions are known to play a key role in the development of rheumatoid arthritis (RA). Exposure to cigarette smoke (CS) is one of the strongest environmental risk factors associated with RA and has been shown to mediate a range of complex immunomodulatory effects from decreased T and B cell activation to depressed phagocytic function. The effects of CS on the function of TH17 cells, one of the key TH effector subsets implicated in RA pathogenesis, are not fully understood. IRF4 is one of the crucial transcription factors involved in TH-17 differentiation and is absolutely required for the production of IL-17 and IL-21 but, interestingly, inhibits the synthesis of IL-22. The production of IL-17 and IL-21 by IRF4 can be augmented by its phosphorylation by the serine-threonine kinase ROCK2. Given that CS has been reported to increase ROCK activity in endothelial cells, here we investigated the effects of CS on the ROCK2-IRF4 axis in T cells. Surprisingly, we found that CS leads to decreased ROCK2 activation and IRF4 phosphorylation in T cells. This effect was associated with increased IL-22 production. Using a GEF pull-down assay we furthermore identify ARHGEF1 as a key upstream regulator of ROCK2 whose activity in T cells is inhibited by CS. Thus CS can inhibit the ROCK2-IRF4 axis and modulate T cell production of IL-22.

  1. 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.

  2. Modulation of CP2 family transcriptional activity by CRTR-1 and sumoylation.

    Science.gov (United States)

    To, Sarah; Rodda, Stephen J; Rathjen, Peter D; Keough, Rebecca A

    2010-07-22

    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. Prior cognitive activity implicitly modulates subsequent emotional responses to subliminally presented emotional stimuli.

    Science.gov (United States)

    Iida, Saea; Nakao, Takashi; Ohira, Hideki

    2012-06-01

    It has been reported that engagement in several kinds of cognitive activity can successfully inhibit unpleasant emotions. In this study, we tried to replicate the previous finding that cognitive activity can modulate subsequent psychological and physiological emotional processes and to investigate whether prior cognitive activity can attenuate implicit emotional processes triggered by subliminal emotional stimuli. Sixty students were randomly divided into three groups (cognitive task group, noncognitive task group, control group). The cognitive task group was asked to engage in an n-back task, while the control group was asked to stay calm. The noncognitive task group was asked to do a handgrip-squeezing task. All participants then engaged in a version of a subliminal affective priming task where they were unconsciously exposed to affectively negative pictures. The cognitive task group showed lower negative experiences after the subliminal affective priming task and a substantial reduction in their heart rate responses, as compared with the other groups. These results provide evidence that engagement in cognitive activity can attenuate emotional processes in an automatic and unconscious manner.

  4. 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.

  5. 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.

  6. Dimerization of complement factor H-related proteins modulates complement activation in vivo.

    Science.gov (United States)

    Goicoechea de Jorge, Elena; Caesar, Joseph J E; Malik, Talat H; Patel, Mitali; Colledge, Matthew; Johnson, Steven; Hakobyan, Svetlana; Morgan, B Paul; Harris, Claire L; Pickering, Matthew C; Lea, Susan M

    2013-03-19

    The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related (CFHR) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.

  7. Two-dimensional gain cross-grating based on spatial modulation of active Raman gain

    Science.gov (United States)

    Wang, Li; Zhou, Feng-Xue; Guo, Hong-Ju; Niu, Yue-Ping; Gong, Shang-Qing

    2016-11-01

    Based on the spatial modulation of active Raman gain, a two-dimensional gain cross-grating is theoretically proposed. As the probe field propagates along the z direction and passes through the intersectant region of the two orthogonal standing-wave fields in the x-y plane, it can be effectively diffracted into the high-order directions, and the zero-order diffraction intensity is amplified at the same time. In comparison with the two-dimensional electromagnetically induced cross-grating based on electromagnetically induced transparency, the two-dimensional gain cross-grating has much higher diffraction intensities in the first-order and the high-order directions. Hence, it is more suitable to be utilized as all-optical switching and routing in optical networking and communication. Project supported by the National Natural Science Foundation of China (Grant Nos. 11274112 and 11347133).

  8. Technical issues of reduced activation ferritic/martensitic steels for fabrication of ITER test blanket modules

    Energy Technology Data Exchange (ETDEWEB)

    Tanigawa, H. [Japan Atomic Energy Agency, Tokai, Ibaraki 319-1195 (Japan)], E-mail: tanigawa.hiroyasu@jaea.go.jp; Hirose, T.; Shiba, K. [Japan Atomic Energy Agency, Tokai, Ibaraki 319-1195 (Japan); Kasada, R. [Institute of Advanced Energy, Kyoto University, Uji, Kyoto 611-0011 (Japan); Wakai, E. [Japan Atomic Energy Agency, Tokai, Ibaraki 319-1195 (Japan); Serizawa, H.; Kawahito, Y. [Joining and Welding Research Institute, Osaka University, Ibaraki, Osaka 567-0047 (Japan); Jitsukawa, S. [Japan Atomic Energy Agency, Tokai, Ibaraki 319-1195 (Japan); Kimura, A. [Institute of Advanced Energy, Kyoto University, Uji, Kyoto 611-0011 (Japan); Kohno, Y. [Department of Materials Science and Engineering, Muroran Institute of Technology, Muroran, Hokkaido 050-8585 (Japan); Kohyama, A. [Institute of Advanced Energy, Kyoto University, Uji, Kyoto 611-0011 (Japan); Katayama, S. [Joining and Welding Research Institute, Osaka University, Ibaraki, Osaka 567-0047 (Japan); Mori, H.; Nishimoto, K. [Division of Materials and Manufacturing Science, Osaka University, Ibaraki, Osaka 565-0871 (Japan); Klueh, R.L.; Sokolov, M.A.; Stoller, R.E.; Zinkle, S.J. [Materials Science and Technology Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831-6132 (United States)

    2008-12-15

    Reduced activation ferritic/martensitic steels (RAFMs) are recognized as the primary candidate structural materials for fusion blanket systems. The RAFM F82H was developed in Japan with emphasis on high-temperature properties and weldability. Extensive irradiation studies have conducted on F82H, and it has the most extensive available database of irradiated and unirradiated properties of all RAFMs. The objective of this paper is to review the R and D status of F82H and to identify the key technical issues for the fabrication of an ITER test blanket module (TBM) suggested from the recent research achievements in Japan. This work clarified that the primary issues with F82H involve welding techniques and the mechanical properties of weld joints. This is the result of the distinctive nature of the joint caused by the phase transformation that occurs in the weld joint during cooling, and its impact on the design of a TBM will be discussed.

  9. Modulating Composition and Metabolic Activity of the Gut Microbiota in IBD Patients.

    Science.gov (United States)

    Matijašić, Mario; Meštrović, Tomislav; Perić, Mihaela; Čipčić Paljetak, Hana; Panek, Marina; Vranešić Bender, Darija; Ljubas Kelečić, Dina; Krznarić, Željko; Verbanac, Donatella

    2016-04-19

    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.

  10. 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.

  11. Modulation of seizure activity in mice by metabotropic glutamate receptor ligands

    DEFF Research Database (Denmark)

    Dalby, Nils Ole; Thomsen, C

    1996-01-01

    pentylenetetrazol- and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-2-carboxylate (DMCM)-induced clonic convulsions in mice with ED50 values of 400 and 180 nmol/mice, respectively. A modest increase in electrical seizure threshold was observed in mice injected with (S)-4C3HPG. No effect on seizures induced...... by systemic administration of N-methyl-D-aspartate was observed by prior intracerebroventricular infusion of (S)-4C3HPG. The more selective (but less potent) mGluR1a antagonist, (S)-4-carboxyphenylglycine, was a weak anticonvulsant in similar seizure models with the exception of convulsions induced...... against sound-induced convulsions in DBA/2 mice and DMCM-induced seizures in mice but were inactive against seizures induced by administration of pentylenetetrazol or by electrical stimulation. These data suggest that mGluR ligands modulate seizure activity in mice and this effect may be mediated via...

  12. 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

  13. Insecticidal activities of chiral N-trifluoroacetyl sulfilimines as potential ryanodine receptor modulators.

    Science.gov (United States)

    Zhou, Sha; Gu, Yucheng; Liu, Ming; Wu, Changchun; Zhou, Sha; Zhao, Yu; Jia, Zhehui; Wang, Baolei; Xiong, Lixia; Yang, Na; Li, Zhengming

    2014-11-19

    This is the first report of novel chiral N-trifluoroacetyl sulfilimines during research for new environmentally benign and ecologically safe novel insecticides with new modes of action. Four series of phthalamides containing 20 new structures were designed, synthesized, and evaluated against oriental armyworm (Pseudaletia separata Walker) and diamondback moth (Plutella xylostella (L.)) for their insecticidal activities. The target compounds were established by corresponding (1)H NMR, HRMS (or elemental analysis), X-ray diffraction analysis, and optical polarimetry. Introduction of chiral N-trifluoroacetyl sulfiliminyl moieties into the new scaffolds showed that some target compounds possessed impressive activities as commercial flubendiamide. These N-trifluoroacetyl sulfilimines exhibited the sequence of activity against oriental armyworm as (Sc, Ss) ≥ (Sc, Rs) ≫ (Rc, Rs) > (Rc, Ss), in which the chiral carbon influenced the activities stronger than sulfur. For diamondback moth, compounds If, IIa, and IIc exhibited even stronger activity than flubendiamide; especially If displayed a death rate of 100% at 10(-6) mg L(-1), much better than that of flubendiamide (0% at 10(-4) mg L(-1)). Comparative molecular field analysis calculation indicated that stereoisomers with Sc configurations containing more electronegative group as COCF3 are favorable to the insecticidal activity. The present work demonstrated that chiral N-trifluoroacetyl sulfilimines can be considered as potential insect ryanodine receptor modulators. From the standpoint of molecular design, it was concluded that the conventional second methyl group in the aliphatic amido side chain of dicarboxamide might not be a requisite in our research on novel sulfiliminyl insecticides.

  14. Temporal changes in cortical activation during conditioned pain modulation (CPM), a LORETA study.

    Science.gov (United States)

    Moont, Ruth; Crispel, Yonatan; Lev, Rina; Pud, Dorit; Yarnitsky, David

    2011-07-01

    For most healthy subjects, both subjective pain ratings and pain-evoked potentials are attenuated under conditioned pain modulation (CPM; formerly termed diffuse noxious inhibitory controls, or DNIC). Although essentially spinal-bulbar, this inhibition is under cortical control. This is the first study to observe temporal as well as spatial changes in cortical activations under CPM. Specifically, we aimed to investigate the interplay of areas involved in the perception and processing of pain and those involved in controlling descending inhibition. We examined brief consecutive poststimulus time windows of 50 ms using a method of source-localization from pain evoked potentials, sLORETA. This enabled determination of dynamic changes in localized cortical generators evoked by phasic noxious heat stimuli to the left volar forearm in healthy young males, with and without conditioning hot-water pain to the right hand. We found a CPM effect characterized by an initial increased activation in the orbitofrontal cortex (OFC) and amygdala at 250-300 ms poststimulus, which was correlated with the extent of psychophysical pain reduction. This was followed by reduced activations in the primary and secondary somatosensory cortices, supplementary motor area, posterior insula, and anterior cingulate cortex from 400 ms poststimulus. Our findings show that the prefrontal pain-controlling areas of OFC and amygdala increase their activity in parallel with subjective pain reduction under CPM, and that this increased activity occurs prior to reductions in activations of the pain sensory areas. In conclusion, achieving pain inhibition by the CPM process seems to be under control of the OFC and the amygdala.

  15. 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.

  16. Pathogenic Mycobacterium bovis strains differ in their ability to modulate the proinflammatory activation phenotype of macrophages

    Directory of Open Access Journals (Sweden)

    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

  17. 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.

  18. Modulation of voltage-gated sodium channels hyperpolarizes the voltage threshold for activation in spinal motoneurones.

    Science.gov (United States)

    Power, Kevin E; Carlin, Kevin P; Fedirchuk, Brent

    2012-03-01

    Previous work has shown that motoneurone excitability is enhanced by a hyperpolarization of the membrane potential at which an action potential is initiated (V(th)) at the onset, and throughout brainstem-evoked fictive locomotion in the adult decerebrate cat and neonatal rat. Modeling work has suggested the modulation of Na(+) conductance as a putative mechanism underlying this state-dependent change in excitability. This study sought to determine whether modulation of voltage-gated sodium channels could induce V(th) hyperpolarization. Whole-cell patch-clamp recordings were made from antidromically identified lumbar spinal motoneurones in an isolated neonatal rat spinal cord preparation. Recordings were made with and without the bath application of veratridine, a plant alkaloid neurotoxin that acts as a sodium channel modulator. As seen in HEK 293 cells expressing Nav1.2 channels, veratridine-modified channels demonstrated a hyperpolarizing shift in their voltage-dependence of activation and a slowing of inactivation that resulted in an enhanced inward current in response to voltage ramp stimulations. In the native rat motoneurones, veratridine-modified sodium channels induced a hyperpolarization of V(th) in all 29 neonatal rat motoneurones examined (mean hyperpolarization: -6.6 ± 4.3 mV). V(th) hyperpolarization was not due to the effects on Ca(2+) and/or K(+) channels as blockade of these currents did not alter V(th). Veratridine also significantly increased the amplitude of persistent inward currents (PICs; mean increase: 72.5 ± 98.5 pA) evoked in response to slow depolarizing current ramps. However, the enhancement of the PIC amplitude had a slower time course than the hyperpolarization of V(th), and the PIC onset voltage could be either depolarized or hyperpolarized, suggesting that PIC facilitation did not mediate the V(th) hyperpolarization. We therefore suggest that central neuronal circuitry in mammals could affect V(th) in a mechanism similar to that of

  19. Modulation of Na+/K+ ATPase Activity by Hydrogen Peroxide Generated through Heme in L. amazonensis.

    Directory of Open Access Journals (Sweden)

    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.

  20. Structure of the active form of human origin recognition complex and its ATPase motor module

    Energy Technology Data Exchange (ETDEWEB)

    Tocilj, Ante; On, Kin Fan; Yuan, Zuanning; Sun, Jingchuan; Elkayam, Elad; Li, Huilin; Stillman, Bruce; Joshua-Tor, Leemor

    2017-01-23

    Binding of the Origin Recognition Complex (ORC) to origins of replication marks the first step in the initiation of replication of the genome in all eukaryotic cells. Here, we report the structure of the active form of human ORC determined by X-ray crystallography and cryo-electron microscopy. The complex is composed of an ORC1/4/5 motor module lobe in an organization reminiscent of the DNA polymerase clamp loader complexes. A second lobe contains the ORC2/3 subunits. The complex is organized as a double-layered shallow corkscrew, with the AAA+ and AAA+-like domains forming one layer, and the winged-helix domains (WHDs) forming a top layer. CDC6 fits easily between ORC1 and ORC2, completing the ring and the DNA-binding channel, forming an additional ATP hydrolysis site. Analysis of the ATPase activity of the complex provides a basis for understanding ORC activity as well as molecular defects observed in Meier-Gorlin Syndrome mutations.

  1. Kv4.2 mediates histamine modulation of preoptic neuron activity and body temperature.

    Directory of Open Access Journals (Sweden)

    Jasmine Sethi

    Full Text Available Histamine regulates arousal, circadian rhythms, and thermoregulation. Activation of H3 histamine receptors expressed by preoptic GABAergic neurons results in a decrease of their firing rate and hyperthermia. Here we report that an increase in the A-type K⁺ current in preoptic GABAergic neurons in response to activation of H3 histamine receptors results in decreased firing rate and hyperthermia in mice. The Kv4.2 subunit is required for these actions in spite of the fact that Kv4.2⁻/⁻ preoptic GABAergic neurons display A-type currents and firing characteristics similar to those of wild-type neurons. This electrical remodeling is achieved by robust upregulation of the expression of the Kv4.1 subunit and of a delayed rectifier current. Dynamic clamp experiments indicate that enhancement of the A-type current by a similar amount to that induced by histamine is sufficient to mimic its robust effect on firing rates. These data indicate a central role played by the Kv4.2 subunit in histamine regulation of body temperature and its interaction with pERK1/2 downstream of the H3 receptor. We also reveal that this pathway provides a mechanism for selective modulation of body temperature at the beginning of the active phase of the circadian cycle.

  2. Intracellular modulation, extracellular disposal and serum increase of MiR-150 mark lymphocyte activation.

    Directory of Open Access Journals (Sweden)

    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.

  3. The neurobiology of brain and cognitive reserve: mental and physical activity as modulators of brain disorders.

    Science.gov (United States)

    Nithianantharajah, Jess; Hannan, Anthony J

    2009-12-01

    The concept of 'cognitive reserve', and a broader theory of 'brain reserve', were originally proposed to help explain epidemiological data indicating that individuals who engaged in higher levels of mental and physical activity via education, occupation and recreation, were at lower risk of developing Alzheimer's disease and other forms of dementia. Subsequently, behavioral, cellular and molecular studies in animals (predominantly mice and rats) have revealed dramatic effects of environmental enrichment, which involves enhanced levels of sensory, cognitive and motor stimulation via housing in novel, complex environments. Furthermore, increasing levels of voluntary physical exercise, via ad libitum access to running wheels, can have significant effects on brain and behavior, thus informing the relative effects of mental and physical activity. More recently, animal models of brain disorders have been compared under environmentally stimulating and standard housing conditions, and this has provided new insights into environmental modulators and gene-environment interactions involved in pathogenesis. Here, we review animal studies that have investigated the effects of modifying mental and physical activity via experimental manipulations, and discuss their relevance to brain and cognitive reserve (BCR). Recent evidence suggests that the concept of BCR is not only relevant to brain aging, neurodegenerative diseases and dementia, but also to other neurological and psychiatric disorders. Understanding the cellular and molecular mechanisms mediating BCR may not only facilitate future strategies aimed at optimising healthy brain aging, but could also identify molecular targets for novel pharmacological approaches aimed at boosting BCR in 'at risk' and symptomatic individuals with various brain disorders.

  4. 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.

  5. 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.

  6. Hydrogen sulfide inhalation ameliorates allergen induced airway hypereactivity by modulating mast cell activation.

    Science.gov (United States)

    Roviezzo, Fiorentina; Bertolino, Antonio; Sorrentino, Rosalinda; Terlizzi, Michela; Matteis, Maria; Calderone, Vincenzo; Mattera, Valentina; Martelli, Alma; Spaziano, Giuseppe; Pinto, Aldo; D'Agostino, Bruno; Cirino, Giuseppe

    2015-10-01

    Compelling evidence suggests that hydrogen sulfide represents an important gaseous transmitter in the mammalian respiratory system. In the present study, we have evaluated the role of mast cells in hydrogen sulfide-induced effects on airways in a mouse model of asthma. Mice were sensitized to ovalbumin and received aerosol of a hydrogen sulfide donor (NaHS; 100 ppm) starting at day 7 after ovalbumin challenge. Exposure to hydrogen sulfide abrogated ovalbumin-induced bronchial hypereactivity as well as the increase in lung resistance. Concomitantly, hydrogen sulfide prevented mast cell activity as well as FGF-2 and IL-13 upregulation. Conversely, pulmonary inflammation and the increase in plasmatic IgE levels were not affected by hydrogen sulfide. A lack of hydrogen sulfide effects in mast cell deficient mice occurred. Primary fibroblasts harvested from ovalbumin-sensitized mice showed an increased proliferation rate that was inhibited by hydrogen sulfide aerosol. Furthermore, ovalbumin-induced transdifferentiation of pulmonary fibroblasts into myofibroblasts was reversed. Finally, hydrogen sulfide did abrogate in vitro the degranulation of the mast cell-like RBL-2H3 cell line. Similarly to the in vivo experiments the inhibitory effect was present only when the cells were activated by antigen exposure. In conclusion, inhaled hydrogen sulfide improves lung function and inhibits bronchial hyper-reactivity by modulating mast cells and in turn fibroblast activation.

  7. 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...

  8. Melittin modulates keratinocyte function through P2 receptor-dependent ADAM activation.

    Science.gov (United States)

    Sommer, Anselm; Fries, Anja; Cornelsen, Isabell; Speck, Nancy; Koch-Nolte, Friedrich; Gimpl, Gerald; Andrä, Jörg; Bhakdi, Sucharit; Reiss, Karina

    2012-07-06

    Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-α, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent.

  9. Prediction-error in the context of real social relationships modulates reward system activity

    Directory of Open Access Journals (Sweden)

    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.

  10. 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.

  11. Structure of the active form of human origin recognition complex and its ATPase motor module

    Science.gov (United States)

    Tocilj, Ante; On, Kin Fan; Yuan, Zuanning; Sun, Jingchuan; Elkayam, Elad; Li, Huilin; Stillman, Bruce; Joshua-Tor, Leemor

    2017-01-01

    Binding of the Origin Recognition Complex (ORC) to origins of replication marks the first step in the initiation of replication of the genome in all eukaryotic cells. Here, we report the structure of the active form of human ORC determined by X-ray crystallography and cryo-electron microscopy. The complex is composed of an ORC1/4/5 motor module lobe in an organization reminiscent of the DNA polymerase clamp loader complexes. A second lobe contains the ORC2/3 subunits. The complex is organized as a double-layered shallow corkscrew, with the AAA+ and AAA+-like domains forming one layer, and the winged-helix domains (WHDs) forming a top layer. CDC6 fits easily between ORC1 and ORC2, completing the ring and the DNA-binding channel, forming an additional ATP hydrolysis site. Analysis of the ATPase activity of the complex provides a basis for understanding ORC activity as well as molecular defects observed in Meier-Gorlin Syndrome mutations. DOI: http://dx.doi.org/10.7554/eLife.20818.001 PMID:28112645

  12. Distinct activities of Bartonella henselae type IV secretion effector proteins modulate capillary-like sprout formation.

    Science.gov (United States)

    Scheidegger, F; Ellner, Y; Guye, P; Rhomberg, T A; Weber, H; Augustin, H G; Dehio, C

    2009-07-01

    The zoonotic pathogen Bartonella henselae (Bh) can lead to vasoproliferative tumour lesions in the skin and inner organs known as bacillary angiomatosis and bacillary peliosis. The knowledge on the molecular and cellular mechanisms involved in this pathogen-triggered angiogenic process is confined by the lack of a suitable animal model and a physiologically relevant cell culture model of angiogenesis. Here we employed a three-dimensional in vitro angiogenesis assay of collagen gel-embedded endothelial cell (EC) spheroids to study the angiogenic properties of Bh. Spheroids generated from Bh-infected ECs displayed a high capacity to form sprouts, which represent capillary-like projections into the collagen gel. The VirB/VirD4 type IV secretion system and a subset of its translocated Bartonella effector proteins (Beps) were found to profoundly modulate this Bh-induced sprouting activity. BepA, known to protect ECs from apoptosis, strongly promoted sprout formation. In contrast, BepG, triggering cytoskeletal rearrangements, potently inhibited sprouting. Hence, the here established in vitro model of Bartonella- induced angiogenesis revealed distinct and opposing activities of type IV secretion system effector proteins, which together with a VirB/VirD4-independent effect may control the angiogenic activity of Bh during chronic infection of the vasculature.

  13. Disintegrins: integrin selective ligands which activate integrin-coupled signaling and modulate leukocyte functions

    Directory of Open Access Journals (Sweden)

    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.

  14. 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

    2017-01-01

    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.

  15. Modulation of inflammasome activity by Porphyromonas gingivalis in periodontitis and associated systemic diseases

    Directory of Open Access Journals (Sweden)

    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.

  16. 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.

  17. Effects of Modulating M3 Muscarinic Receptor Activity on Azoxymethane-Induced Liver Injury in Mice

    Science.gov (United States)

    Khurana, Sandeep; Jadeja, Ravirajsinh; Twadell, William; Cheng, Kunrong; Rachakonda, Vikrant; Saxena, Neeraj; Raufman, Jean-Pierre

    2013-01-01

    Previously, we reported that azoxymethane (AOM)-induced liver injury is robustly exacerbated in M3 muscarinic receptor (M3R)-deficient mice. We used the same mouse model to test the hypothesis that selective pharmacological modulation of M3R activity regulates the liver injury response. Initial experiments confirmed that giving a selective M3R antagonist, darifenacin, to AOM-treated mice mimicked M3R gene ablation. Compared to vehicle controls, mice treated with the M3R antagonist had reduced survival and increased liver nodularity and fibrosis. We next assessed AOM-induced liver injury in mice treated with a selective M3R agonist, pilocarpine. After pilocarpine treatment, stimulation of post-M3R signaling in the liver was evidenced by ERK and AKT activation. In contrast to the damaging effects of the M3R antagonist, administering pilocarpine to AOM-treated mice significantly attenuated hepatic stellate cell activation, collagen deposition, bile ductule proliferation, and liver fibrosis and nodularity. As anticipated from these findings, livers from pilocarpine-treated mice exhibited reduced expression of key players in fibrosis (α1 collagen, α-smooth muscle actin, TGF-β1, PGDF, TGF-β1R, PGDFR) and decreased mRNA levels for molecules that regulate extracellular matrix formation (TIMP-1, TIMP-2, MMP-2, MMP-13). Cleaved caspase-3, nitrotyrosine and BrdU immunostaining provided evidence that pilocarpine treatment reduced hepatocyte apoptosis and oxidative stress, while increasing hepatocyte proliferation. Collectively, these findings identify several downstream mechanisms whereby M3R activation ameliorates toxic liver injury. These novel observations provide a proof-of-principle that selectively stimulating M3R activation to prevent or diminish liver injury is a therapeutic strategy worthy of further investigation. PMID:23707755

  18. RyR2 modulates a Ca2+-activated K+ current in mouse cardiac myocytes.

    Directory of Open Access Journals (Sweden)

    Yong-Hui Mu

    Full Text Available In cardiomyocytes, Ca2+ entry through voltage-dependent Ca2+ channels (VDCCs binds to and activates RyR2 channels, resulting in subsequent Ca2+ release from the sarcoplasmic reticulum (SR and cardiac contraction. Previous research has documented the molecular coupling of small-conductance Ca2+-activated K+ channels (SK channels to VDCCs in mouse cardiac muscle. Little is known regarding the role of RyRs-sensitive Ca2+ release in the SK channels in cardiac muscle. In this study, using whole-cell patch clamp techniques, we observed that a Ca2+-activated K+ current (IK,Ca recorded from isolated adult C57B/L mouse atrial myocytes was significantly decreased by ryanodine, an inhibitor of ryanodine receptor type 2 (RyR2, or by the co-application of ryanodine and thapsigargin, an inhibitor of the sarcoplasmic reticulum calcium ATPase (SERCA (p<0.05, p<0.01, respectively. The activation of RyR2 by caffeine increased the IK,Ca in the cardiac cells (p<0.05, p<0.01, respectively. We further analyzed the effect of RyR2 knockdown on IK,Ca and Ca2+ in isolated adult mouse cardiomyocytes using a whole-cell patch clamp technique and confocal imaging. RyR2 knockdown in mouse atrial cells transduced with lentivirus-mediated small hairpin interference RNA (shRNA exhibited a significant decrease in IK,Ca (p<0.05 and [Ca2+]i fluorescence intensity (p<0.01. An immunoprecipitated complex of SK2 and RyR2 was identified in native cardiac tissue by co-immunoprecipitation assays. Our findings indicate that RyR2-mediated Ca2+ release is responsible for the activation and modulation of SK channels in cardiac myocytes.

  19. Apigenin inhibits enterovirus 71 replication through suppressing viral IRES activity and modulating cellular JNK pathway.

    Science.gov (United States)

    Lv, Xiaowen; Qiu, Min; Chen, Deyan; Zheng, Nan; Jin, Yu; Wu, Zhiwei

    2014-09-01

    Enterovirus 71 (EV71) is a member of genus Enterovirus in Picornaviridae family, which is one of the major causative agents for hand, foot and mouth disease (HFMD), and sometimes associated with severe central nervous system diseases in children. Currently there are no effective therapeutic medicines or vaccines for the disease. In this report, we found that apigenin and luteolin, two flavones that differ only in the number of hydroxyl groups could inhibit EV71-mediated cytopathogenic effect (CPE) and EV71 replication with low cytotoxicity. Both molecules also showed inhibitory effect on the viral polyprotein expression. They prevented EV71-induced cell apoptosis, intracellular reactive oxygen species (ROS) generation and cytokines up-regulation. Time-of-drug addition study demonstrated that apigenin and luteolin acted after viral entry. We examined the effect of apigenin and luteolin on 2A(pro) and 3C(pro) activity, two viral proteases responsible for viral polyprotein processing, and found that they showed less inhibitory activity on 2A(pro) or 3C(pro). Further studies demonstrated that apigenin, but not luteolin could interfere with viral IRES activity. Also, apigenin inhibited EV71-induced c-Jun N-terminal kinase (JNK) activation which is critical for viral replication, in contrast to luteolin that did not. This study demonstrated that apigenin may inhibit EV71 replication through suppressing viral IRES activity and modulating cellular JNK pathway. It also provided evidence that one hydroxyl group difference in the B ring between apigenin and luteolin resulted in the distinct antiviral mechanisms. This study will provide the basis for better drug development and further identification of potential drug targets.

  20. 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.

  1. Modulation of mutagenic activity in meat samples after deep-frying in vegetable oils.

    Science.gov (United States)

    Perez, C; Lopez de Cerain, A; Bello, J

    2002-01-01

    Previous studies have been carried out on the influence of frying fats on the formation of food mutagens, but most of them have been performed on model systems or under cooking conditions that are more frequent in northern countries. The objective of this work was to study the overall mutagenic activity generated in hamburgers and frankfurters deep-fried under cooking conditions that are normal practice in Spain and other Mediterranean countries, in order to determine if there was any modulation of the mutagenic activity with respect to other cooking conditions previously studied. Hamburgers were prepared from beef purchased in a butcher's shop. Frankfurters as well as the oils [olive, marc olive ('orujo'), sunflower and soya bean oil] and butter were purchased in a local supermarket. The samples were fried in a teflon-coated frying pan at 170-180 degrees C for 10, 20 or 30 min. The mutagens were extracted and the mutagenic activity evaluated using the Salmonella mammalian microsome assay with strain TA98. Two independent assays were carried out for each experimental condition. All the hamburgers showed a mutagenic activity that was more than four times higher than that of the controls. Frankfurters showed a lower mutagenic activity than hamburgers (fried under the same conditions) because they have a lower protein content and a higher fat content. Hamburgers fried in olive oil for 10 min showed a significant increase in the number of revertants with respect to the other oils, probably due to the fact that the temperature reached was approximately 10 degrees C higher. Longer frying times significantly increased the number of revertants in samples fried in oils, except in olive oil, probably due to its lower content of polyunsaturated fatty acids.

  2. Modulating temporal control of NF-kappaB activation: implications for therapeutic and assay selection.

    Science.gov (United States)

    Klinke, David J; Ustyugova, Irina V; Brundage, Kathleen M; Barnett, John B

    2008-06-01

    The activation of transcription factor NF-kappaB (nuclear factor-kappaB) plays a central role in the induction of many inflammatory response genes. This process is characterized by either oscillations or stable induction of NF-kappaB nuclear binding. Changes in dynamics of binding result in the expression of distinct subsets of genes leading to different physiological outcomes. We examined NF-kappaB DNA binding activity in lipopolysaccharide (LPS)-stimulated IC-21 cells by electromobility shift assay and nonradioactive transcription factor assay and interpreted the results using a kinetic model of NF-kappaB activation. Both assays detected damped oscillatory behavior of NF-kappaB with differences in sensitivity and reproducibility. 3,4-Dichloropropionaniline (DCPA) was used to modulate the oscillatory behavior of NF-kappaB after LPS stimulation. DCPA is known to inhibit the production of two NF-kappaB-inducible cytokines, IL-6 and tumor necrosis factor alpha, by reducing but not completely abrogating NF-kappaB-induced transcription. DCPA treatment resulted in a potentiation of early LPS-induced NF-kappaB activation. The nonradioactive transcription factor assay, which has a higher signal/noise ratio than the electromobility shift assay, combined with in silico modeling, produced results that revealed changes in NF-kappaB dynamics which, to the best of our knowledge, have never been previously reported. These results highlight the importance of cell type and stimulus specificity in transcription factor activity assessment. In addition, assay selection has important implications for network inference and drug discovery.

  3. 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.

  4. 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

  5. Two discrete components of the 20 Hz steady-state response are distinguished through the modulation of activation level

    DEFF Research Database (Denmark)

    Griskova, Inga; Mørup, Morten; Parnas, Josef

    2009-01-01

    Objective: To investigate the modulation of amplitude and phase precision of the auditory steady-state response (SSR) to 20 Hz stimulation in two conditions varying in the level of activation. Methods: Click stimuli (20 Hz) were applied while subjects were sitting upright silently reading a book......-negative multi-way factorization (NMWF). Results: The NMWF decomposition of amplitude and phase precision measures resulted in the observation of two distinct components: a component at the frequency of stimulation – 20 Hz SSR and a component emerging at 40 Hz – 20 Hz SSR-related 40 Hz activity. Modulation...

  6. Modulation of The Balance Between Cannabinoid CB1 and CB2 Receptor Activation During Cerebral Ischemic/Reperfusion Injury

    OpenAIRE

    ZHANG, Ming; Martin, Billy R.; Adler, Martin W.; Razdan, Raj K.; Ganea, Doina; Tuma, Ronald F.

    2008-01-01

    Cannabinoid receptor activation has been shown to modulate both neurotransmission (CB1) and neuroinflammatory (CB2) responses. There are conflicting reports in the literature describing the influence of cannabinoid receptor activation on ischemic/reperfusion injury. The goal of this study was to evaluate how changing the balance between CB1 and CB2 activation following cerebral ischemia influences outcome. CB1 and CB2 expression were tested at different times after transient middle cerebral a...

  7. In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity on CYP-450 (Part 2).

    Science.gov (United States)

    Labrie, Philippe; Maddaford, Shawn P; Lacroix, Jacques; Catalano, Concettina; Lee, David K H; Rakhit, Suman; Gaudreault, René C

    2007-06-01

    Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency on the P-glycoprotein (P-gp) transporter. Previous studies showed that the replacement of the aromatic spacer group between nitrogen atoms (N(1) and N(2)) in the P-gp inhibitor XR9576 with ethyl or propyl chain is optimal for P-gp inhibition potency. To confirm that observation, the ethyl or the propyl linker arm was replaced with a pyrrolidine or an alicyclic group such as cyclohexyl. In addition, an arylpiperazinyl group and two methoxyl groups onto the anthranilic part were introduced to assess their effect on the anti P-gp activity. Five molecules were prepared and evaluated on CEM/VLB500. All new anthranilamides were more potent than verapamil, most of them exhibited a lower cytotoxicity than XR9576. Compound 5 was the most potent and its inhibition activity was similar to XR9576. Interestingly, in vitro biotransformation studies of compounds 4 and 5 using human CYP-450 isoforms revealed, that conversely to XR9576, compounds 4 and 5 inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of numerous drugs, notably paclitaxel. In that context, 5 might be suitable for further drug development.

  8. 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.

  9. Activities of the task group 8 on thin film PV module reliability (Conference Presentation)

    Science.gov (United States)

    Dhere, Neelkanth G.

    2016-09-01

    Photovoltaic (PV) modules and systems are being used increasingly to provide renewable energy to schools, residences, small businesses and utilities. At this time, the home owners and small businesses have considerable difficulty in detecting module and/or system degradation and especially enforcing warranty. It needs to be noted that IEC 61215-1 (test req.), -2 (test proc.) and -1-1 (c-Si) are forecasted to be circulated end of Feb 2016 and only editorial changes would be possible. 61215 series does include thin film technologies and would be replacing 61646. Moreover, IEC 61215-1, section 7.2 power output and electric circuitry does contain significant changes to acceptance criteria regarding rated label values, particularly rated power. Even though it is believed that consensus could be achieved within IEC TC82 WG2, some of the smaller players that do not participate actively in IEC TC82 - may not be surprised and must be informed. The other tech specific parts 61215-1-2 (CdTe), -1-3 (a-Si, µc-Si) and -1-4 (CIS, CIGS) are out for comments. The IEC closing date was January 29, 2016. The additions alternative damp heat (DH) test proposed Solar Frontier is being reviewed. In the past, only 600 V systems were permitted in the grid-connected residential and commercial systems in the US. The US commercial systems can now use higher voltage (1,000-1500V) in order to reduce BOS component costs. It is believed that there would not be any problems. The Task Group 8 is collecting data on higher voltage systems.

  10. The endocannabinoids anandamide and virodhamine modulate the activity of the candidate cannabinoid receptor GPR55.

    Science.gov (United States)

    Sharir, Haleli; Console-Bram, Linda; Mundy, Christina; Popoff, Steven N; Kapur, Ankur; Abood, Mary E

    2012-12-01

    The role of cannabinoid receptors in inflammation has been the topic of many research endeavors. Despite this effort, to date the involvement of the endocannabinoid system (ECS) in inflammation remains obscure. The ambiguity of cannabinoid involvement may be explained by the existence of cannabinoid receptors, other than CB(1) and CB(2), or a consequence of interaction of endocannabinoids with other signaling systems. GPR55 has been proposed to be a cannabinoid receptor; however the interaction of the endocannabinoid system with GPR55 remains elusive. Consequently this study set about to examine the effects of the endocannabinoids, anandamide (AEA) and virodhamine, on GPR55 mediated signaling. Specifically, we assessed changes in β-arrestin2 (βarr2) distribution and GPR55 receptor internalization following activation by lysophosphatidylinositol (LPI), the synthetic cannabinoid ligand SR141716A, and new selective synthetic GPR55 agonists. Data obtained from the experiments presented herein demonstrate that AEA and virodhamine modulate agonist-mediated recruitment of βarr2. AEA and virodhamine act as partial agonists; enhancing the agonist effect at low concentrations and inhibiting it at high concentrations. Furthermore, both virodhamine and AEA significantly attenuated agonist-induced internalization of GPR55. These effects are attributed to the expression of GPR55, and not CB(1) and CB(2) receptors, as we have established negligible expression of CB(1) and CB(2) in these GPR55-transfected U2OS cells. The identification of select endocannabinoids as GPR55 modulators will aide in elucidating the function of GPR55 in the ECS.

  11. 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.

  12. Somatostatinergic modulation of firing pattern and calcium-activated potassium currents in medium spiny neostriatal neurons.

    Science.gov (United States)

    Galarraga, E; Vilchis, C; Tkatch, T; Salgado, H; Tecuapetla, F; Perez-Rosello, T; Perez-Garci, E; Hernandez-Echeagaray, E; Surmeier, D J; Bargas, J

    2007-05-11

    Somatostatin is synthesized and released by aspiny GABAergic interneurons of the neostriatum, some of them identified as low threshold spike generating neurons (LTS-interneurons). These neurons make synaptic contacts with spiny neostriatal projection neurons. However, very few somatostatin actions on projection neurons have been described. The present work reports that somatostatin modulates the Ca(2+) activated K(+) currents (K(Ca) currents) expressed by projection cells. These actions contribute in designing the firing pattern of the spiny projection neuron; which is the output of the neostriatum. Small conductance (SK) and large conductance (BK) K(Ca) currents represent between 30% and 50% of the sustained outward current in spiny cells. Somatostatin reduces SK-type K(+) currents and at the same time enhances BK-type K(+) currents. This dual effect enhances the fast component of the after hyperpolarizing potential while reducing the slow component. Somatostatin then modifies the firing pattern of spiny neurons which changed from a tonic regular pattern to an interrupted "stuttering"-like pattern. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) tissue expression analysis of dorsal striatal somatostatinergic receptors (SSTR) mRNA revealed that all five SSTR mRNAs are present. However, single cell RT-PCR profiling suggests that the most probable receptor in charge of this modulation is the SSTR2 receptor. Interestingly, aspiny interneurons may exhibit a "stuttering"-like firing pattern. Therefore, somatostatin actions appear to be the entrainment of projection neurons to the rhythms generated by some interneurons. Somatostatin is then capable of modifying the processing and output of the neostriatum.

  13. Fc gamma receptor CD64 modulates the inhibitory activity of infliximab.

    Directory of Open Access Journals (Sweden)

    Kacper A Wojtal

    Full Text Available BACKGROUND: Tumor necrosis factor (TNF is an important cytokine in the pathogenesis of inflammatory bowel disease (IBD. Anti-TNF antibodies have been successfully implemented in IBD therapy, however their efficacies differ among IBD patients. Here we investigate the influence of CD64 Fc receptor on the inhibitory activity of anti-TNFs in cells of intestinal wall. METHODS: Intestinal cell lines, monocytes/macrophages and peripheral blood mononuclear cells (PBMCs were used as models. The efficacies of adalimumab, infliximab and certolizumab-pegol were assessed by RT-PCR for target genes. Protein levels and localizations were examined by Western blotting and immunofluorescence. Antibody fragments were obtained by proteolytic digestion, immunoprecipitation and protein chip analysis. Knock-down of specific gene expression was performed using siRNAs. RESULTS: Infliximab had limited efficacy towards soluble TNF in cell types expressing Fc gamma receptor CD64. Both adalimumab and infliximab had lower efficacies in PBMCs of IBD patients, which express elevated levels of CD64. Infliximab-TNF complexes were more potent in activating CD64 in THP-1 cells than adalimumab, which was accompanied by distinct phospho-tyrosine signals. Blocking Fc parts and isolation of Fab fragments of infliximab improved its efficacy. IFN-γ-induced expression of CD64 correlated with a loss of efficacy of infliximab, whereas reduction of CD64 expression by either siRNA or PMA treatment improved inhibitory activity of this drug. Colonic mRNA expression levels of CD64 and other Fc gamma receptors were significantly increased in the inflamed tissues of infliximab non-responders. CONCLUSIONS: CD64 modulates the efficacy of infliximab both in vitro and ex vivo, whereas the presence of this receptor has no impact on the inhibitory activity of certolizumab-pegol, which lacks Fc fragment. These data could be helpful in both predicting and evaluating the outcome of anti-TNF therapy in

  14. IκB Kinases Modulate the Activity of the Androgen Receptor in Prostate Carcinoma Cell Lines

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    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.

  15. The plasminogen activation system modulates differently adipogenesis and myogenesis of embryonic stem cells.

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    Ola Hadadeh

    Full Text Available Regulation of the extracellular matrix (ECM plays an important functional role either in physiological or pathological conditions. The plasminogen activation (PA system, comprising the uPA and tPA proteases and their inhibitor PAI-1, is one of the main suppliers of extracellular proteolytic activity contributing to tissue remodeling. Although its function in development is well documented, its precise role in mouse embryonic stem cell (ESC differentiation in vitro is unknown. We found that the PA system components are expressed at very low levels in undifferentiated ESCs and that upon differentiation uPA activity is detected mainly transiently, whereas tPA activity and PAI-1 protein are maximum in well differentiated cells. Adipocyte formation by ESCs is inhibited by amiloride treatment, a specific uPA inhibitor. Likewise, ESCs expressing ectopic PAI-1 under the control of an inducible expression system display reduced adipogenic capacities after induction of the gene. Furthermore, the adipogenic differentiation capacities of PAI-1(-/- induced pluripotent stem cells (iPSCs are augmented as compared to wt iPSCs. Our results demonstrate that the control of ESC adipogenesis by the PA system correspond to different successive steps from undifferentiated to well differentiated ESCs. Similarly, skeletal myogenesis is decreased by uPA inhibition or PAI-1 overexpression during the terminal step of differentiation. However, interfering with uPA during days 0 to 3 of the differentiation process augments ESC myotube formation. Neither neurogenesis, cardiomyogenesis, endothelial cell nor smooth muscle formation are affected by amiloride or PAI-1 induction. Our results show that the PA system is capable to specifically modulate adipogenesis and skeletal myogenesis of ESCs by successive different molecular mechanisms.

  16. Coordinative modulation of human zinc transporter 2 gene expression through active and suppressive regulators.

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    Lu, Yu-Ju; Liu, Ya-Chuan; Lin, Meng-Chieh; Chen, Yi-Ting; Lin, Lih-Yuan

    2015-04-01

    Zinc transporter 2 (ZnT2) is one of the cellular factors responsible for Zn homeostasis. Upon Zn overload, ZnT2 reduces cellular Zn by transporting it into excretory vesicles. We investigated the molecular mechanism that regulates human ZnT2 (hZnT2) gene expression. Zn induces hZnT2 expression in dose- and time-dependent manners. Overexpression of metal-responsive transcription factor 1 (MTF-1) increases hZnT2 transcription, whereas depletion of MTF-1 reduces hZnT2 expression. There are five putative metal response elements (MREs) within 1kb upstream of the hZnT2 gene. A serial deletion of the hZnT2 promoter region (from 5' to 3') shows that the two MREs proximal to the gene are essential for Zn-induced promoter activity. Further mutation analysis concludes that the penultimate MRE (MREb) supports the metal-induced promoter activity. The hZnT2 promoter has also a zinc finger E-box binding homeobox (ZEB) binding element. Mutation or deletion of this ZEB binding element elevates the basal and Zn-induced hZnT2 promoter activities. Knockdown of ZEB1 mRNA enhances the hZnT2 transcript level in HEK-293 cells. In MCF-7 (ZEB-deficient) cells, expression of ZEB proteins attenuates the Zn-induced hZnT2 expression. However, expressions of MTF-1 target genes such as human ZnT1 and metallothionein IIA were not affected. Our study shows the expression of the hZnT2 gene is coordinately regulated via active and suppressive modulators.

  17. Rhythmic Components in Extracranial Brain Signals Reveal Multifaceted Task Modulation of Overlapping Neuronal Activity.

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    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.

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

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    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.

  19. Bone Microenvironment Modulates Expression and Activity of Cathepsin B in Prostate Cancer

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    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.

  20. Macromolecular depletion modulates the binding of red blood cells to activated endothelial cells.

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    Yang, Yang; Koo, Stephanie; Lin, Cheryl Shuyi; Neu, Björn

    2010-09-01

    Adhesion of red blood cells (RBCs) to endothelial cells (ECs) is usually insignificant but an enhanced adhesion has been observed in various diseases associated with vascular complications. This abnormal adhesion under pathological conditions such as sickle cell disease has been correlated with increased levels of various plasma proteins but the detailed underlying mechanism(s) remains unclear. Usually it is assumed that the proadhesive effects of plasma proteins originate from ligand interactions cross-linking receptors on adjacent cells, but explicit results detailing binding sites or receptors for some proteins (e.g., fibrinogen) on either RBC or EC surfaces that would support this model are missing. In this study, the authors tested whether there is an alternative mechanism. Their results demonstrate that dextran 2 MDa promotes the adhesion of normal RBCs to thrombin-activated ECs and that this effect becomes more pronounced with increasing thrombin concentration or with prolonged thrombin incubation time. It is concluded that depletion interaction originating from nonadsorbing macromolecules (i.e., dextran) can modulate the adhesion of red blood cells to thrombin-activated EC. This study thereby suggests macromolecular depletion as an alternative mechanism for the adhesion-promoting effects of nonadsorbing plasma proteins. These findings should not only aid in getting a better understanding of diseases associated with vascular complications but should also have many potential applications in biomedical or biotechnological areas that require the control of cell-cell or cell surface interactions.

  1. Temporal pattern of acoustic imaging noise asymmetrically modulates activation in the auditory cortex.

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    Ranaweera, Ruwan D; Kwon, Minseok; Hu, Shuowen; Tamer, Gregory G; Luh, Wen-Ming; Talavage, Thomas M

    2016-01-01

    This study investigated the hemisphere-specific effects of the temporal pattern of imaging related acoustic noise on auditory cortex activation. Hemodynamic responses (HDRs) to five temporal patterns of imaging noise corresponding to noise generated by unique combinations of imaging volume and effective repetition time (TR), were obtained using a stroboscopic event-related paradigm with extra-long (≥27.5 s) TR to minimize inter-acquisition effects. In addition to confirmation that fMRI responses in auditory cortex do not behave in a linear manner, temporal patterns of imaging noise were found to modulate both the shape and spatial extent of hemodynamic responses, with classically non-auditory areas exhibiting responses to longer duration noise conditions. Hemispheric analysis revealed the right primary auditory cortex to be more sensitive than the left to the presence of imaging related acoustic noise. Right primary auditory cortex responses were significantly larger during all the conditions. This asymmetry of response to imaging related acoustic noise could lead to different baseline activation levels during acquisition schemes using short TR, inducing an observed asymmetry in the responses to an intended acoustic stimulus through limitations of dynamic range, rather than due to differences in neuronal processing of the stimulus. These results emphasize the importance of accounting for the temporal pattern of the acoustic noise when comparing findings across different fMRI studies, especially those involving acoustic stimulation.

  2. 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.

  3. VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity.

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    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.

  4. VAMP-associated protein B (VAPB promotes breast tumor growth by modulation of Akt activity.

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    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.

  5. 5-HT7 receptor modulators: Amino groups attached to biphenyl scaffold determine functional activity.

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    Kim, Youngjae; Park, Hyeri; Lee, Jeongeun; Tae, Jinsung; Kim, Hak Joong; Min, Sun-Joon; Rhim, Hyewhon; Choo, Hyunah

    2016-11-10

    5-HT7 receptor (5-HT7R) agonists and antagonists have been reported to be used for treatment of neuropathic pain and depression, respectively. In this study, as a novel scaffold for 5-HT7R modulators, we designed and prepared a series of biphenyl-3-yl-methanamine derivatives with various amino groups. Evaluation of functional activities as well as binding affinities of the title compounds identified partial agonists (EC50 = 0.55-3.2 μM) and full antagonists (IC50 = 5.57-23.1 μM) depending on the amino substituents. Molecular docking study suggested that the ligand-based switch in functional activity from agonist to antagonist results from the size of the amino groups and thereby different binding modes to 5-HT7R. In particular, interaction of the ligand with Arg367 of 5-HT7R is shown to differentiate agonists and antagonists. In the pharmacophore model study, two distinct pharmacophore models can tell whether a ligand is an agonist or an antagonist. Taken together, this study provides valuable information for designing novel compounds with selective agonistic or antagonistic properties against 5-HT7R.

  6. Sorting Nexin 27 Regulates Aβ Production through Modulating γ-Secretase Activity

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    Xin Wang

    2014-11-01

    Full Text Available Patients with Down syndrome (DS invariably develop Alzheimer’s disease (AD pathology in their 40s. We have recently found that overexpression of a chromosome 21-encoded microRNA-155 results in decreased levels of the membrane trafficking component, SNX27, diminishing glutamate receptor recycling and thereby impairing synaptic functions in DS. Here, we report a function of SNX27 in regulating β-amyloid (Aβ generation by modulating γ-secretase activity. Downregulation of SNX27 using RNAi increased Aβ production, whereas overexpression of full-length SNX27, but not SNX27ΔPDZ, reversed the RNAi-mediated Aβ elevation. Moreover, genetic deletion of Snx27 promoted Aβ production and neuronal loss, whereas overexpression of SNX27 using an adeno-associated viral (AAV vector reduced hippocampal Aβ levels in a transgenic AD mouse model. SNX27 associates with the γ-secretase complex subunit presenilin 1; this interaction dissociates the γ-secretase complex, thus decreasing its proteolytic activity. Our study establishes a molecular mechanism for Aβ-dependent pathogenesis in both DS and AD.

  7. Augmented vagal heart rate modulation in active hypoestrogenic pre-menopausal women with functional hypothalamic amenorrhoea.

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    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.

  8. Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans.

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    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.

  9. Modulation of mitogen-activated protein kinases (MAPK) activity in response to different immune stimuli in haemocytes of the common periwinkle Littorina littorea.

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    Iakovleva, Nadya V; Gorbushin, Alexander M; Storey, Kenneth B

    2006-09-01

    The modulation of mitogen-activated protein kinase (MAPK) activity in haemocytes of the common periwinkle (Littorina littorea) in response to immune challenges by lipopolysaccharide from Echerichia coli (LPS), mannan from baker's yeast Saccharomyces cerevisiae and secretory-excretory products (SEP) of trematodes Himasthla elongata (Echinostomatidae) or after the treatment with phorbol ester (PMA) has been studied by Western blotting using affinity purified rabbit polyclonal antibodies. Exposure of the cells in suspension to PMA, LPS and mannan triggered an activation of p38 and ERK2. The JNK-mediated cascade was modulated differently by the elicitors examined. PMA treatment caused a transient activation of the JNK54 isoform, LPS exposure resulted in a decrease in activity of JNK46, and mannan had no effect on JNK phosphorylation status. Incubation of periwinkle haemocytes in culture medium containing trematode SEP did not affect the activity of any MAPK.

  10. Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation.

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    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.

  11. 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.

  12. Deep brain stimulation mechanisms: the control of network activity via neurochemistry modulation.

    Science.gov (United States)

    McIntyre, Cameron C; Anderson, Ross W

    2016-10-01

    Deep brain stimulation (DBS) has revolutionized the clinical care of late-stage Parkinson's disease and shows promise for improving the treatment of intractable neuropsychiatric disorders. However, after over 25 years of clinical experience, numerous questions still remain on the neurophysiological basis for the therapeutic mechanisms of action. At their fundamental core, the general purpose of electrical stimulation therapies in the nervous system are to use the applied electric field to manipulate the opening and closing of voltage-gated sodium channels on neurons, generate stimulation induced action potentials, and subsequently, control the release of neurotransmitters in targeted pathways. Historically, DBS mechanisms research has focused on characterizing the effects of stimulation on neurons and the resulting impact on neuronal network activity. However, when electrodes are placed within the central nervous system, glia are also being directly (and indirectly) influenced by the stimulation. Mounting evidence shows that non-neuronal tissue can play an important role in modulating the neurochemistry changes induced by DBS. The goal of this review is to evaluate how DBS effects on both neuronal and non-neuronal tissue can potentially work together to suppress oscillatory activity (and/or information transfer) between brain regions. These resulting effects of ~ 100 Hz electrical stimulation help explain how DBS can disrupt pathological network activity in the brain and generate therapeutic effects in patients. Deep brain stimulation is an effective clinical technology, but detailed therapeutic mechanisms remain undefined. This review provides an overview of the leading hypotheses, which focus on stimulation-induced disruption of network oscillations and integrates possible roles for non-neuronal tissue in explaining the clinical response to therapeutic stimulation. This article is part of a special issue on Parkinson disease.

  13. Melittin Modulates Keratinocyte Function through P2 Receptor-dependent ADAM Activation*

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    Sommer, Anselm; Fries, Anja; Cornelsen, Isabell; Speck, Nancy; Koch-Nolte, Friedrich; Gimpl, Gerald; Andrä, Jörg; Bhakdi, Sucharit; Reiss, Karina

    2012-01-01

    Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-α, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent. PMID:22613720

  14. 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.

  15. Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK cells

    Directory of Open Access Journals (Sweden)

    Maria A Johansson

    2016-07-01

    Full Text Available 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 regulato-ry 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 muco-sal 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 supernatant (CFS, staphylococcal en-terotoxin A or CD3/CD28-beads alone or in combination with Lactobacillus rhamnosus (L. rhamnosus GG-CFS or Lactobacillus reuteri (L. 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. Co-stimulation with lactobacilli-CFS dampened lymphocyte activation in all cell types analysed. Pre-incubation with lactobacilli-CFS was enough to reduce subsequent activation and the ab-sence of APC or APC-derived IL-10 did not prevent lactobacilli-mediated dampening. Final-ly, 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 modulation of induced T and NK cell activation.

  16. 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.

  17. MSFC Skylab airlock module, volume 2. [systems design and performance, systems support activity, and reliability and safety programs

    Science.gov (United States)

    1974-01-01

    System design and performance of the Skylab Airlock Module and Payload Shroud are presented for the communication and caution and warning systems. Crew station and storage, crew trainers, experiments, ground support equipment, and system support activities are also reviewed. Other areas documented include the reliability and safety programs, test philosophy, engineering project management, and mission operations support.

  18. Modulation of Active Site Electronic Structure by the Protein Matrix to Control [NiFe] Hydrogenase Reactivity

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Dayle MA; Raugei, Simone; Squier, Thomas C.

    2014-09-30

    Control of the reactivity of the nickel center of the [NiFe] hydrogenase and other metalloproteins commonly involves outer coordination sphere ligands that act to modify the geometry and physical properties of the active site metal centers. We carried out a combined set of classical molecular dynamics and quantum/classical mechanics calculations to provide quantitative estimates of how dynamic fluctuations of the active site within the protein matrix modulate the electronic structure at the catalytic center. Specifically we focused on the dynamics of the inner and outer coordination spheres of the cysteinate-bound Ni–Fe cluster in the catalytically active Ni-C state. There are correlated movements of the cysteinate ligands and the surrounding hydrogen-bonding network, which modulate the electron affinity at the active site and the proton affinity of a terminal cysteinate. On the basis of these findings, we hypothesize a coupling between protein dynamics and electron and proton transfer reactions critical to dihydrogen production.

  19. 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

  20. Hippocampal somatostatin receptors and modulation of adenylyl cyclase activity in histamine-treated rats.

    Science.gov (United States)

    Puebla, L; Rodríguez-Martín, E; Arilla, E

    1996-01-01

    In the present study, the effects of an intracerebroventricular (i.c.v.) dose of histamine (0.1, 1.0 or 10.0 micrograms) on the hippocampal somatostatin (SS) receptor/effector system in Wistar rats were investigated. In view of the rapid onset of histamine action, the effects of histamine on the somatostatinergic system were studied 2 h after its administration. Hippocampal SS-like immunoreactivity (SSLI) levels were not modified by any of the histamine doses studied. SS-mediated inhibition of basal and forskolin (FK)-stimulated adenylyl cyclase (AC) activity was markedly increased in hippocampal membranes from rats treated with 10 micrograms of histamine (23% +/- 1% vs. 17% +/- 1% and 37% +/- 2% vs. 23% +/- 1%, respectively). In contrast, neither the basal nor the FK-stimulated enzyme activities were affected by histamine administration. The functional activity of the hippocampal guanine-nucleotide binding inhibitory protein (Gi protein), as assessed by the capacity of the stable GTP analogue 5'-guanylylimidodiphosphate (Gpp[NH]p) to inhibit FK-stimulated AC activity, was not modified by histamine administration. These data suggest that the increased response of the enzyme to SS was not related to an increased functional activity of Gi proteins. In fact, the increased AC response to SS in hippocampal membranes from histamine (10 micrograms)-treated rats was associated with quantitative changes in the SS receptors. Equilibrium binding data obtained with [125I]Tyr11-SS indicate an increase in the number with specific SS receptors (541 +/- 24 vs. 365 +/- 16 fmol/mg protein, P histamine (10 micrograms)-treated rats as compared to control animals. With the aim of determining if these changes were related to histamine binding to its specific receptor sites, the histaminergic H1 and H2 receptor antagonists mepyramine and cimetidine, respectively, were administered 1 h before histamine injection. The pretreatment with mepyramine or cimetidine induced an increase in the

  1. Action Potential Modulation in CA1 Pyramidal Neuron Axons Facilitates OLM Interneuron Activation in Recurrent Inhibitory Microcircuits of Rat Hippocampus

    OpenAIRE

    Sooyun Kim

    2014-01-01

    Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive ...

  2. 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.

  3. 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…

  4. The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation.

    Science.gov (United States)

    Moskot, Marta; Montefusco, Sandro; Jakóbkiewicz-Banecka, Joanna; Mozolewski, Paweł; Węgrzyn, Alicja; Di Bernardo, Diego; Węgrzyn, Grzegorz; Medina, Diego L; Ballabio, Andrea; Gabig-Cimińska, Magdalena

    2014-06-13

    Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) has been previously proposed as a potential drug for use in substrate reduction therapy for mucopolysaccharidoses, a group of inherited metabolic diseases caused by mutations leading to inefficient degradation of glycosaminoglycans (GAGs) in lysosomes. It was demonstrated that this isoflavone can cross the blood-brain barrier, making it an especially desirable potential drug for the treatment of neurological symptoms present in most lysosomal storage diseases. So far, no comprehensive genomic analyses have been performed to elucidate the molecular mechanisms underlying the effect elicited by genistein. Therefore, the aim of this work was to identify the genistein-modulated gene network regulating GAG biosynthesis and degradation, taking into consideration the entire lysosomal metabolism. Our analyses identified over 60 genes with known roles in lysosomal biogenesis and/or function whose expression was enhanced by genistein. Moreover, 19 genes whose products are involved in both GAG synthesis and degradation pathways were found to be remarkably differentially regulated by genistein treatment. We found a regulatory network linking genistein-mediated control of transcription factor EB (TFEB) gene expression, TFEB nuclear translocation, and activation of TFEB-dependent lysosome biogenesis to lysosomal metabolism. Our data indicate that the molecular mechanism of genistein action involves not only impairment of GAG synthesis but more importantly lysosomal enhancement via TFEB. These findings contribute to explaining the beneficial effects of genistein in lysosomal storage diseases as well as envisage new therapeutic approaches to treat these devastating diseases.

  5. Modulation of LAT1 (SLC7A5) transporter activity and stability by membrane cholesterol

    Science.gov (United States)

    Dickens, David; Chiduza, George N.; Wright, Gareth S. A.; Pirmohamed, Munir; Antonyuk, Svetlana V.; Hasnain, S. Samar

    2017-01-01

    LAT1 (SLC7A5) is a transporter for both the uptake of large neutral amino acids and a number of pharmaceutical drugs. It is expressed in numerous cell types including T-cells, cancer cells and brain endothelial cells. However, mechanistic knowledge of how it functions and its interactions with lipids are unknown or limited due to inability of obtaining stable purified protein in sufficient quantities. Our data show that depleting cellular cholesterol reduced the Vmax but not the Km of the LAT1 mediated uptake of a model substrate into cells (L-DOPA). A soluble cholesterol analogue was required for the stable purification of the LAT1 with its chaperon CD98 (4F2hc,SLC3A2) and that this stabilised complex retained the ability to interact with a substrate. We propose cholesterol interacts with the conserved regions in the LAT1 transporter that have been shown to bind to cholesterol/CHS in Drosophila melanogaster dopamine transporter. In conclusion, LAT1 is modulated by cholesterol impacting on its stability and transporter activity. This novel finding has implications for other SLC7 family members and additional eukaryotic transporters that contain the LeuT fold. PMID:28272458

  6. Modulating supramolecular binding of carbon dioxide in a redox-active porous metal-organic framework

    Science.gov (United States)

    Lu, Zhenzhong; Godfrey, Harry G. W.; da Silva, Ivan; Cheng, Yongqiang; Savage, Mathew; Tuna, Floriana; McInnes, Eric J. L.; Teat, Simon J.; Gagnon, Kevin J.; Frogley, Mark D.; Manuel, Pascal; Rudić, Svemir; Ramirez-Cuesta, Anibal J.; Easun, Timothy L.; Yang, Sihai; Schröder, Martin

    2017-01-01

    Hydrogen bonds dominate many chemical and biological processes, and chemical modification enables control and modulation of host–guest systems. Here we report a targeted modification of hydrogen bonding and its effect on guest binding in redox-active materials. MFM-300(VIII) {[VIII2(OH)2(L)], LH4=biphenyl-3,3′,5,5′-tetracarboxylic acid} can be oxidized to isostructural MFM-300(VIV), [VIV2O2(L)], in which deprotonation of the bridging hydroxyl groups occurs. MFM-300(VIII) shows the second highest CO2 uptake capacity in metal-organic framework materials at 298 K and 1 bar (6.0 mmol g−1) and involves hydrogen bonding between the OH group of the host and the O-donor of CO2, which binds in an end-on manner, =1.863(1) Å. In contrast, CO2-loaded MFM-300(VIV) shows CO2 bound side-on to the oxy group and sandwiched between two phenyl groups involving a unique ···c.g.phenyl interaction [3.069(2), 3.146(3) Å]. The macroscopic packing of CO2 in the pores is directly influenced by these primary binding sites. PMID:28194014

  7. Modulation of physiological mirror activity with transcranial direct current stimulation over dorsal premotor cortex.

    Science.gov (United States)

    Beaulé, Vincent; Tremblay, Sara; Lafleur, Louis-Philippe; Ferland, Marie C; Lepage, Jean-François; Théoret, Hugo

    2016-11-01

    Humans have a natural tendency towards symmetrical movements, which rely on a distributed cortical network that allows for complex unimanual movements. Studies on healthy humans using rTMS have shown that disruption of this network, and particularly the dorsal premotor cortex (dPMC), can result in increased physiological mirror movements. The aim of the present set of experiments was to further investigate the role of dPMC in restricting motor output to the contralateral hand and determine whether physiological mirror movements could be decreased in healthy individuals. Physiological mirror movements were assessed before and after transcranial direct current stimulation (tDCS) over right and left dPMC in three conditions: bilateral, unilateral left and unilateral right stimulation. Mirror EMG activity was assessed immediately before, 0, 10 and 20 min after tDCS. Results show that physiological mirroring increased significantly in the hand ipsilateral to cathodal stimulation during bilateral stimulation of the dPMC, 10 and 20 min after stimulation compared to baseline. There was no significant modulation of physiological mirroring in the hand ipsilateral to anodal stimulation in the bilateral condition or following unilateral anodal or unilateral cathodal stimulation. The present data further implicate the dPMC in the control of unimanual hand movements and show that physiological mirroring can be increased but not decreased with dPMC tDCS.

  8. Modulation of brown adipocyte activity by milk by-products: Stimulation of brown adipogenesis by buttermilk.

    Science.gov (United States)

    Asano, Hiroki; Kida, Ryosuke; Muto, Kengo; Nara, Takayuki Y; Kato, Ken; Hashimoto, Osamu; Kawada, Teruo; Matsui, Tohru; Funaba, Masayuki

    2016-12-01

    Brown adipocytes dissipate chemical energy in the form of heat through the expression of mitochondrial uncoupling protein 1 (Ucp1); Ucp1 expression is further upregulated by the stimulation of β-adrenergic receptors in brown adipocytes. An increase in energy expenditure by activated brown adipocytes potentially contributes to the prevention of or therapeutics for obesity. The present study examined the effects of milk by-products, buttermilk and butter oil, on brown adipogenesis and the function of brown adipocytes. The treatment with buttermilk modulated brown adipogenesis, depending on the product tested; during brown adipogenesis, buttermilk 1 inhibited the differentiation of HB2 brown preadipocytes. In contrast, buttermilk 3 and 5 increased the expression of Ucp1 in the absence of isoproterenol (Iso), a β-adrenergic receptor agonist, suggesting the stimulation of brown adipogenesis. In addition, the Iso-induced expression of Ucp1 was enhanced by buttermilk 2 and 3. The treatment with buttermilk did not affect the basal or induced expression of Ucp1 by Iso in HB2 brown adipocytes, except for buttermilk 5, which increased the basal expression of Ucp1. Conversely, butter oil did not significantly affect the expression of Ucp1, irrespective of the cell phase of HB2 cells, ie, treatment during brown adipogenesis or of brown adipocytes. The results of the present study indicate that buttermilk is a regulator of brown adipogenesis and suggest its usefulness as a potential food material for antiobesity.

  9. Salicylic acid promotes seed germination under high salinity by modulating antioxidant activity in Arabidopsis.

    Science.gov (United States)

    Lee, Sangmin; Kim, Sang-Gyu; Park, Chung-Mo

    2010-10-01

    • Findings regarding the role of salicylic acid (SA) in seed germination are somewhat variable, depending on the plant genotypes and experimental conditions used, and thus the molecular mechanisms underlying SA regulation of germination are still unclear. Here, we report that physiological concentrations of SA promote germination under high salinity by modulating antioxidant activity in Arabidopsis. • Germination of SA induction deficient 2 (sid2) seeds was hypersensitive to high salinity. While the inhibitory effect of high salinity was exaggerated in the presence of higher concentrations of SA (> 100 μM), it was significantly reduced in the presence of lower concentrations of SA (salinity, the endogenous contents of H(2) O(2) were elevated in wild-type and sid2 seeds but reduced to original concentrations after treatment with 1 μM SA. • Germination of NahG transgenic plants was influenced to a lesser degree by high salinity (NahG is a bacterial gene encoding salicylate hydroxylase that converts salicylic acid to catechol). We found that catechol, an SA degradation product accumulated in the transgenic plants, acts as an antioxidant that compromises the inhibitory effects of high salinity. • Our observations indicate that, although SA is not essential for germination under normal growth conditions, it plays a promotive role in seed germination under high salinity by reducing oxidative damage.

  10. Multifunctional carbon nanotube/bioceramics modulate the directional growth and activity of osteoblastic cells.

    Science.gov (United States)

    Mata, D; Oliveira, F J; Ferro, M; Gomes, P S; Fernandes, M H; Lopes, M A; Silval, R F

    2014-05-01

    Biomaterials can still be reinvented to become simple and universal bone regeneration solutions. Following this roadmap, a bone graft of carbon nanotube (CNT)/glass/hydroxyapatite (HA) with controlled CNT agglomeration state was designed with multifunctionalities able to stimulate the bone cell phenotype. The preparation route, the mechanical and electrical behavior and the in vitro profiles of degradation and osteocompatibility were described. A non-destructive dynamic route was found to have a higher influence than the Diels-Alder functionalization one on controlling the CNT agglomerate state in the ceramic-matrix composite. Biologically safe CNT agglomerates, with diameter sizes below 3 microm homogenously distributed, were obtained in non-functionalized and functionalized composites. Yet, the lowest CNT damage and the highest mechanical and electrical properties were found for the non-functionalized materials. Even though that these composites present higher degradation rate at pH:3 than the ceramic matrix, the CNT agglomerates are released with safe diameter sizes. Also, non-functionalized composites allowed cellular adhesion and modulated the orientation of the cell growth, with a proliferation/differentiation relationship favoring osteoblastic functional activity. Findings offer further contributions for bone tissue engineering by showing that multifunctional bone grafts with high electroconductivity, and integrating CNT agglomerates with maximized interfacing area, allow the in situ control of bone cell functions.

  11. Pharmacological and Genetic Modulation of REV-ERB Activity and Expression Affects Orexigenic Gene Expression.

    Directory of Open Access Journals (Sweden)

    Ariadna Amador

    Full Text Available The nuclear receptors REV-ERBα and REV-ERBβ are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERBβ-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression.

  12. Modulating supramolecular binding of carbon dioxide in a redox-active porous metal-organic framework

    Science.gov (United States)

    Lu, Zhenzhong; Godfrey, Harry G. W.; da Silva, Ivan; Cheng, Yongqiang; Savage, Mathew; Tuna, Floriana; McInnes, Eric J. L.; Teat, Simon J.; Gagnon, Kevin J.; Frogley, Mark D.; Manuel, Pascal; Rudić, Svemir; Ramirez-Cuesta, Anibal J.; Easun, Timothy L.; Yang, Sihai; Schröder, Martin

    2017-02-01

    Hydrogen bonds dominate many chemical and biological processes, and chemical modification enables control and modulation of host-guest systems. Here we report a targeted modification of hydrogen bonding and its effect on guest binding in redox-active materials. MFM-300(VIII) {[VIII2(OH)2(L)], LH4=biphenyl-3,3',5,5'-tetracarboxylic acid} can be oxidized to isostructural MFM-300(VIV), [VIV2O2(L)], in which deprotonation of the bridging hydroxyl groups occurs. MFM-300(VIII) shows the second highest CO2 uptake capacity in metal-organic framework materials at 298 K and 1 bar (6.0 mmol g-1) and involves hydrogen bonding between the OH group of the host and the O-donor of CO2, which binds in an end-on manner, =1.863(1) Å. In contrast, CO2-loaded MFM-300(VIV) shows CO2 bound side-on to the oxy group and sandwiched between two phenyl groups involving a unique ...c.g.phenyl interaction [3.069(2), 3.146(3) Å]. The macroscopic packing of CO2 in the pores is directly influenced by these primary binding sites.

  13. 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.

  14. Morin modulates the oxidative stress-induced NF-kappaB pathway through its anti-oxidant activity.

    Science.gov (United States)

    Kim, Ji Min; Lee, Eun Kyeong; Park, Gwangli; Kim, Mi Kyung; Yokozawa, Takako; Yu, Byung Pal; Chung, Hae Young

    2010-04-01

    Morin is a flavone that has anti-inflammatory effects through a mechanism that is not well understood. Based on the extreme sensitive nature of the transcription factor, NF-kB to redox change, it is postulated that morin's anti-NF-kappaB activation likely depends on its ability to scavenge excessive reactive species [RS]. The present study assessed the extent of morin's ability to modulate RS-induced NF-kappaB activation through its scavenging activity. Results indicate that morin neutralized RS in vitro and inhibited t-BHP-induced RS generation. It also examined morin for suppressed redox-sensitive transcription factor NF-kappaB activation via reduced DNA binding activity, I kappaB alpha phosphorylation and p65/p50 nuclear translocation. The more important finding was that suppression of the NF-kappaB cascade by morin was modulated through the ERK and p38 MAPKs signal transduction pathways in endothelial cells. As a consequence, morin's anti-oxidant effect extended expression level of NF-kappaB dependent pro-inflammatory genes, thereby reducing COX-2, iNOS and 5-LOX. The data indicate that morin has strong anti-oxidative power against RS-induced NF-kappaB modulation through the ERK and p38 MAPKs signalling pathways by its RS scavenging activity. The significance of the current study is the new revelation that morin may have potential as an effective anti-inflammatory therapeutic agent.

  15. Decreased modulation by the risk level on the brain activation during decision making in adolescents with internet gaming disorder

    Directory of Open Access Journals (Sweden)

    Xin eQi

    2015-11-01

    Full Text Available Greater impulse and risk-taking and reduced decision-making ability were reported as the main behavioral impairments in individuals with Internet gaming disorder (IGD, which has become a serious mental health issue worldwide. However, it is not clear to date how the risk level modulates brain activity during the decision-making process in IGD individuals. In this study, 23 adolescents with IGD and 24 healthy controls (HCs without IGD were recruited, and the Balloon Analog Risk Task (BART was used in a functional magnetic resonance imaging (fMRI experiment to evaluate the modulation of the risk level (the probability of balloon explosion on brain activity during risky decisionmaking in IGD adolescents. Reduced modulation of the risk level on the activation of the right dorsolateral prefrontal cortex (DLPFC during the active BART was found in IGD group compared to the HCs. In the IGD group, there was a significant negative correlation between the risk-related DLPFC activation during the active BART and the Barratt impulsivity scale (BIS-11 scores, which were significantly higher in IGD group compared with the HCs. Our study demonstrated that, as a critical decision-making-related brain region, the right DLPFC is less sensitive to risk in IGD adolescents compared with the HCs, which may contribute to the higher impulsivity level in IGD adolescents.

  16. Decreased modulation by the risk level on the brain activation during decision making in adolescents with internet gaming disorder.

    Science.gov (United States)

    Qi, Xin; Du, Xin; Yang, Yongxin; Du, Guijin; Gao, Peihong; Zhang, Yang; Qin, Wen; Li, Xiaodong; Zhang, Quan

    2015-01-01

    Greater impulse and risk-taking and reduced decision-making ability were reported as the main behavioral impairments in individuals with internet gaming disorder (IGD), which has become a serious mental health issue worldwide. However, it is not clear to date how the risk level modulates brain activity during the decision-making process in IGD individuals. In this study, 23 adolescents with IGD and 24 healthy controls (HCs) without IGD were recruited, and the balloon analog risk task (BART) was used in a functional magnetic resonance imaging experiment to evaluate the modulation of the risk level (the probability of balloon explosion) on brain activity during risky decision making in IGD adolescents. Reduced modulation of the risk level on the activation of the right dorsolateral prefrontal cortex (DLPFC) during the active BART was found in IGD group compared to the HCs. In the IGD group, there was a significant negative correlation between the risk-related DLPFC activation during the active BART and the Barratt impulsivity scale (BIS-11) scores, which were significantly higher in IGD group compared with the HCs. Our study demonstrated that, as a critical decision-making-related brain region, the right DLPFC is less sensitive to risk in IGD adolescents compared with the HCs, which may contribute to the higher impulsivity level in IGD adolescents.

  17. Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons

    Science.gov (United States)

    Linehan, Victoria; Trask, Robert B.; Briggs, Chantalle; Rowe, Todd M.; Hirasawa, Michiru

    2017-01-01

    Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups, where orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying DA action on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using whole cell patch clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration dependent, bidirectional manner. Low (1 μM) and high concentrations (100 μM) of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors, whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours. PMID:26036709

  18. Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1.

    Science.gov (United States)

    Khare, Vineeta; Lyakhovich, Alex; Dammann, Kyle; Lang, Michaela; Borgmann, Melanie; Tichy, Boris; Pospisilova, Sarka; Luciani, Gloria; Campregher, Christoph; Evstatiev, Rayko; Pflueger, Maren; Hundsberger, Harald; Gasche, Christoph

    2013-01-15

    Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action.

  19. 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.

  20. Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons.

    Science.gov (United States)

    Linehan, Victoria; Trask, Robert B; Briggs, Chantalle; Rowe, Todd M; Hirasawa, Michiru

    2015-08-01

    Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups: orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying the action of DA on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using the whole-cell patch-clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration-dependent bidirectional manner. Low (1 μM) and high (100 μM) concentrations of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G-protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours.

  1. 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.

  2. 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)

  3. 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.

  4. Activation of PPARγ by a Natural Flavonoid Modulator, Apigenin Ameliorates Obesity-Related Inflammation Via Regulation of Macrophage Polarization.

    Science.gov (United States)

    Feng, Xiujing; Weng, Dan; Zhou, Feifei; Owen, Young D; Qin, Haohan; Zhao, Jingfa; WenYu; Huang, Yahong; Chen, Jiajia; Fu, Haijian; Yang, Nanfei; Chen, Dianhua; Li, Jianxin; Tan, Renxiang; Shen, Pingping

    2016-07-01

    PPARγ has emerged as a master regulator of macrophage polarization and is the molecular target of the thiazolidinedione drugs. Here we show that apigenin binds and activates PPARγ by acting as a modulator. Activation of PPARγ by apigenin blocks p65 translocation into nuclei through inhibition of p65/PPARγ complex translocation into nuclei, thereby decreasing NF-κB activation and favoringM2 macrophage polarization. In HFD and ob/ob mice, apigenin significantly reverses M1 macrophage into M2 and reduces the infiltration of inflammatory cells in liver and adipose tissues, as well as decreases the levels of pro-inflammatory cytokines, thereby alleviating inflammation. Strikingly, apigenin reduces liver and muscular steatosis, decreases the levels of ALT, AST, TC and TG, improving glucose resistance obviously. Unlike rosiglitazone, apigenin does not cause significant weight gain, osteoporosis et al. Our findings identify apigenin as a modulator of PPARγ and a potential lead compound for treatment of metabolic disorders.

  5. Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGluR5) attenuate microglial activation.

    Science.gov (United States)

    Xue, Fengtian; Stoica, Bogdan A; Hanscom, Marie; Kabadi, Shruti V; Faden, Alan I

    2014-01-01

    Traumatic brain injury causes progressive neurodegeneration associated with chronic microglial activation. Recent studies show that neurodegeneration and neuroinflammation after traumatic brain injury can be inhibited as late as one month in animals by the activation of the metabotropic glutamate receptor 5 in microglia using (RS)-2-chloro-5- hydroxy-phenylglycine. However, the therapeutic potential of this agonist is limited due to its relatively weak potency and brain permeability. To address such concerns, we evaluated the anti-inflammatory activities of several positive allosteric modulators using various in vitro assays, and found that 3,3'-difluorobenzaldazine, 3-cyano-N-(1,3-diphenyl-1H-pyrazol- 5-yl)benzamide and 4-nitro-N-(1-(2-fluorophenyl)-3-phenyl-1H-pyrazol-5-yl)benzamide showed significantly improved potency which makes them potential lead compounds for further development of positive allosteric modulators for the treatment of traumatic brain injury.

  6. 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.

  7. 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.

  8. 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

  9. Chaperonin-containing t-complex protein-1 subunit β as a possible biomarker for the phase of glomerular hyperfiltration of diabetic nephropathy.

    Science.gov (United States)

    Wu, Chung-Ze; Chang, Li-Chien; Lin, Yuh-Feng; Hung, Yi-Jen; Pei, Dee; Chen, Jin-Shuen

    2015-01-01

    In cell model, we discovered the association between chaperonin-containing t-complex polypeptide 1 subunit β (TCP-1β) and early diabetic nephropathy (DN). In this study, we further explored the relationships between TCP-1β and type 2 diabetic mellitus (DM). To mimic the clinical hyperfiltration state, a type 2 DM mice model was established by feeding a high-fat diet in combination with treatment of streptozotocin and nicotinamide. Blood and urine were collected to determine creatinine clearance (C cr), and kidney tissues were harvested for evaluation of TCP-1β expression by immunohistochemistry and Western blot. Meanwhile, clinical subjects of healthy controls and type 2 DM were recruited to strengthen the evidence with urine TCP-1β. Results showed that C cr and the expression of TCP-1β in kidney were significantly higher one week after hyperglycemia development, suggesting that the hyperfiltration state was successfully established in the mice model. TCP-1β was expressed predominantly on renal tubules. By using the estimated glomerular filtration rate to index progression in clinical investigation, urine TCP-1β level was associated with the hyperfiltration phase in type 2 DM patients. Conclusively, we confirmed that TCP-1β is a possible biomarker for early nephropathy of type 2 DM, but further mechanistic study to elucidate its cause and pathway is needed.

  10. Effects of the chaperonin GroE on the refolding of tryptophanase from Escherichia coli. Refolding is enhanced in the presence of ADP.

    Science.gov (United States)

    Mizobata, T; Akiyama, Y; Ito, K; Yumoto, N; Kawata, Y

    1992-09-01

    The refolding of the tetrameric enzyme tryptophanase was facilitated by the chaperonin GroE. Maximum refolding yield of tryptophanase molecules (about 80%) was attained in the presence of a 15-fold excess of GroE 21-mer over tryptophanase monomer. The GroEL subunit was required for this improvement in refolding yield, whereas the GroES subunit was not. Light scattering experiments of the refolding reaction revealed that GroE bound to tryptophanase folding intermediates and suppressed their aggregation. The presence of ATP was required for the efficient dissociation of tryptophanase from GroEL. However, our experiments indicated that tryptophanase dissociated readily from GroEL in the presence of not only ATP, but also in the presence of non-hydrolyzable ATP analogues such as ATP gamma S (adenosine 5'-O-(3-thiotriphosphate)) and AMP-PNP (adenyl-5'-yl imidodiphosphate) as well. Surprisingly, the release of tryptophanase from GroEL was facilitated in the presence of ADP as well. We concluded that the binding of nucleotides such as ATP and ADP changed the conformation of GroEL and facilitated the dissociation of tryptophanase molecules. The conformation formed in the presence of ADP was distinct from the conformation formed in the presence of ATP, as shown by the selective dissociation of various folding proteins from the two conformations.

  11. Chaperonin-Containing t-Complex Protein-1 Subunit β as a Possible Biomarker for the Phase of Glomerular Hyperfiltration of Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Chung-Ze Wu

    2015-01-01

    Full Text Available In cell model, we discovered the association between chaperonin-containing t-complex polypeptide 1 subunit β (TCP-1β and early diabetic nephropathy (DN. In this study, we further explored the relationships between TCP-1β and type 2 diabetic mellitus (DM. To mimic the clinical hyperfiltration state, a type 2 DM mice model was established by feeding a high-fat diet in combination with treatment of streptozotocin and nicotinamide. Blood and urine were collected to determine creatinine clearance (Ccr, and kidney tissues were harvested for evaluation of TCP-1β expression by immunohistochemistry and Western blot. Meanwhile, clinical subjects of healthy controls and type 2 DM were recruited to strengthen the evidence with urine TCP-1β. Results showed that Ccr and the expression of TCP-1β in kidney were significantly higher one week after hyperglycemia development, suggesting that the hyperfiltration state was successfully established in the mice model. TCP-1β was expressed predominantly on renal tubules. By using the estimated glomerular filtration rate to index progression in clinical investigation, urine TCP-1β level was associated with the hyperfiltration phase in type 2 DM patients. Conclusively, we confirmed that TCP-1β is a possible biomarker for early nephropathy of type 2 DM, but further mechanistic study to elucidate its cause and pathway is needed.

  12. Control of Mycosphaerella graminicola on wheat seedlings by medical drugs known to modulate the activity of ATP-binding cassette transporters

    NARCIS (Netherlands)

    Roohparvar, R.; Huser, A.; Zwiers, L.H.; Waard, de M.A.

    2007-01-01

    Medical drugs known to modulate the activity of human ATP-binding cassette (ABC) transporter proteins (modulators) were tested for the ability to potentiate the activity of the azole fungicide cyproconazole against in vitro growth of Mycosphaerella graminicola and to control disease development due

  13. 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.

  14. Action potential modulation in CA1 pyramidal neuron axons facilitates OLM interneuron activation in recurrent inhibitory microcircuits of rat hippocampus.

    Directory of Open Access Journals (Sweden)

    Sooyun Kim

    Full Text Available Oriens-lacunosum moleculare (O-LM interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outside-out patch recordings from CA1 pyramidal neuron axons revealed a high density of α-dendrotoxin (α-DTX-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron-O-LM interneuron excitatory postsynaptic currents (EPSCs showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron-interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.

  15. Action potential modulation in CA1 pyramidal neuron axons facilitates OLM interneuron activation in recurrent inhibitory microcircuits of rat hippocampus.

    Science.gov (United States)

    Kim, Sooyun

    2014-01-01

    Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outside-out patch recordings from CA1 pyramidal neuron axons revealed a high density of α-dendrotoxin (α-DTX)-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron-O-LM interneuron excitatory postsynaptic currents (EPSCs) showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron-interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.

  16. Few layers graphene as thermally activated optical modulator in the visible-near IR spectral range.

    Science.gov (United States)

    Benítez, J L; Hernández-Cordero, Juan; Muhl, S; Mendoza, D

    2016-01-01

    We report the temperature modulation of the optical transmittance of a few layers of graphene (FLG). The FLG was heated either by the Joule effect of the current flowing between coplanar electrodes or by the absorption of a continuous-wave 532 nm laser. The optical signals used to evaluate the modulation of the FLG were at 633, 975, and 1550 nm; the last wavelengths are commonly used in optical communications. We also evaluated the effect of the substrate on the modulation effect by comparing the performance of a freely suspended FLG sample with one mounted on a glass substrate. Our results show that the modulation of the optical transmittance of FLG can be from millihertz to kilohertz.

  17. Impact of Diabetes Type 1 in Children on Autonomic Modulation at Rest and in Response to the Active Orthostatic Test

    Science.gov (United States)

    Giacon, Thais Roque; Vanderlei, Franciele Marques; Christofaro, Diego Giulliano Destro; Vanderlei, Luiz Carlos Marques

    2016-01-01

    Introduction Cardiovascular autonomic neuropathy is one of the most common complications of diabetes mellitus type 1 (DM1), of which one of the first subclinical manifestations is changes in heart rate variability (HRV). Thus, analysis of HRV associated with the autonomic active orthostatic test is important in this population. Objectives To analyze the autonomic modulation responses induced by the implementation of the active orthostatic test, in children with DM1, and study the autonomic modulation by means of HRV indices. Method Data of 35 children were analyzed, of both sexes, aged between 7 and 15 years, who were divided into two groups: Diabetic (n = 16) and Control (n = 19). The following variables were collected initially: weight, height, body fat percentage, heart rate, blood pressure and casual blood glucose. Subsequently, for analysis of autonomic modulation, the beat-to-beat heart rate was captured by a heart rate monitor in the supine position for 30 minutes and after 10 minutes standing during performance of the active orthostatic test. HRV indices were calculated in the time and frequency domains. For data analysis, covariance analysis was used to compare groups and ANOVA for repeated measures to compare the effects of the active orthostatic test. These data were adjusted for age, sex, ethnicity, body fat percentage and casual blood glucose, with a 5% significance level. Results The results suggested that diabetic children at rest present a decrease in SDNN (50.4 vs. 75.2), rMSSD (38.7 vs 57.6) and LF [ms2] (693.6 vs 1874.6). During the active orthostatic test the children in both groups demonstrated a reduction in SDNN, RMSSD and LF [ms2] compared to the resting position, and this response was less pronounced in the diabetic group. Conclusion We conclude that regardless of age, sex, ethnicity, body fat percentage and casual blood glucose, performing the active orthostatic test promoted increased sympathetic modulation and reduced parasympathetic

  18. Structure-activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators.

    Science.gov (United States)

    Nguyen, Thuy; German, Nadezhda; Decker, Ann M; Li, Jun-Xu; Wiley, Jenny L; Thomas, Brian F; Kenakin, Terry P; Zhang, Yanan

    2015-05-01

    A series of substituted 1H-indole-2-carboxamides structurally related to compounds Org27569 (1), Org29647 (2) and Org27759 (3) were synthesized and evaluated for CB1 allosteric modulating activity in calcium mobilization assays. Structure-activity relationship studies showed that the modulation potency of this series at the CB1 receptor was enhanced by the presence of a diethylamino group at the 4-position of the phenyl ring, a chloro or fluoro group at the C5 position and short alkyl groups at the C3 position on the indole ring. The most potent compound (45) had an IC₅₀ value of 79 nM which is ∼2.5 and 10 fold more potent than the parent compounds 3 and 1, respectively. These compounds appeared to be negative allosteric modulators at the CB1 receptor and dose-dependently reduced the Emax of agonist CP55,940. These analogs may provide the basis for further optimization and use of CB1 allosteric modulators.

  19. The effects of cryopreservation on angiogenesis modulation activity of human amniotic membrane.

    Science.gov (United States)

    Yazdanpanah, Ghasem; Paeini-Vayghan, Ghodsieh; Asadi, Samira; Niknejad, Hassan

    2015-12-01

    Amniotic membrane (AM), as the innermost layer of placenta, has side dependent effects on the angiogenesis. Cryopreservation is a necessary process to avoid the challenging problems of fresh tissues; a procedure which makes the AM ready-to-use. Since the cryopreservation can influence the AM characteristics for experimental and clinical purposes, in this study the effects of cryopreservation were evaluated on angiogenesis modulation activity of the AM compared to fresh tissues in an animal model. The AM was implanted mesenchymal side up or epithelial side up in a rat dorsal skinfold chamber. The length and number of branches of formed capillaries were measured via intravital microscopy after 7 days. The amount of IL-8 (interleukin-8) and TIMP-2 (Tissue Inhibitor of Matrix Metalloproteinase-2) as two factors in amniotic cells which have great impacts on angiogenesis were evaluated using ELISA assay. The epithelial surface of cryopreserved AM had inhibitory effects on vessel formation. The cryopreserved amniotic mesenchymal side increased the vessel length and sprout. The result of cryopreserved AM on angiogenesis was similar to that of fresh tissues. The levels of IL-8 and TIMP-2 in cryopreserved samples were significantly less than fresh AMs which shows that angio-modulatory properties are not limited to the effects of amnion epithelial and mesenchymal stem cells and the other components such as extracellular matrix may contribute in angio-modulatory effects. These promising results show that inducing and inhibitory effects of the AM, which make it an appropriate candidate for different clinical situations, were maintained after cryopreservation.

  20. Individual attachment style modulates human amygdala and striatum activation during social appraisal.

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    Pascal Vrticka

    Full Text Available Adult attachment style refers to individual personality traits that strongly influence emotional bonds and reactions to social partners. Behavioral research has shown that adult attachment style reflects profound differences in sensitivity to social signals of support or conflict, but the neural substrates underlying such differences remain unsettled. Using functional magnetic resonance imaging (fMRI, we examined how the three classic prototypes of attachment style (secure, avoidant, anxious modulate brain responses to facial expressions conveying either positive or negative feedback about task performance (either supportive or hostile in a social game context. Activation of striatum and ventral tegmental area was enhanced to positive feedback signaled by a smiling face, but this was reduced in participants with avoidant attachment, indicating relative impassiveness to social reward. Conversely, a left amygdala response was evoked by angry faces associated with negative feedback, and correlated positively with anxious attachment, suggesting an increased sensitivity to social punishment. Secure attachment showed mirror effects in striatum and amygdala, but no other specific correlate. These results reveal a critical role for brain systems implicated in reward and threat processing in the biological underpinnings of adult attachment style, and provide new support to psychological models that have postulated two separate affective dimensions to explain these individual differences, centered on the ventral striatum and amygdala circuits, respectively. These findings also demonstrate that brain responses to face expressions are not driven by facial features alone but determined by the personal significance of expressions in current social context. By linking fundamental psychosocial dimensions of adult attachment with brain function, our results do not only corroborate their biological bases but also help understand their impact on behavior.

  1. Deactivation of the inferior colliculus by cooling demonstrates intercollicular modulation of neuronal activity

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    Llwyd David Orton

    2012-12-01

    Full Text Available The auditory pathways coursing through the brainstem are organised bilaterally in mirror image about the midline and at several levels the two sides are interconnected. One of the most prominent points of interconnection is the commissure of the inferior colliculus (CoIC. Anatomical studies have revealed that these fibres make reciprocal connections which follow the tonotopic organisation of the inferior colliculus (IC, and that the commissure contains both excitatory and, albeit fewer, inhibitory fibres. The role of these connections in sound processing is largely unknown. Here we describe a method to address this question in the anaesthetised guinea pig. We used a cryoloop placed on one IC to produce reversible deactivation while recording electrophysiological responses to sounds in both ICs. We recorded single units, multi-unit clusters and local field potentials (LFPs before, during and after cooling. The degree and spread of cooling was measured with a thermocouple placed in the IC and other auditory structures. Cooling sufficient to eliminate firing was restricted to the IC contacted by the cryoloop. The temperature of other auditory brainstem structures, including the contralateral IC and the cochlea were minimally affected. Cooling below 20 °C reduced or eliminated the firing of action potentials in frequency laminae at depths corresponding to characteristic frequencies up to ~8 kHz. Modulation of neural activity also occurred in the un-cooled IC with changes in single unit firing and LFPs. Components of LFPs signalling lemniscal afferent input to the IC showed little change in amplitude or latency with cooling, whereas the later components, which likely reflect inter- and intra-collicular processing, showed marked changes in form and amplitude. We conclude that the cryoloop is an effective method of selectively deactivating one IC in guinea pig, and demonstrate that auditory processing in the IC is strongly influenced by the other.

  2. Brain-computer interfacing using modulations of alpha activity induced by covert shifts of attention

    Directory of Open Access Journals (Sweden)

    Schmidt Nico M

    2011-05-01

    Full Text Available Abstract Background Visual brain-computer interfaces (BCIs often yield high performance only when targets are fixated with the eyes. Furthermore, many paradigms use intense visual stimulation, which can be irritating especially in long BCI sessions. However, BCIs can more directly directly tap the neural processes underlying visual attention. Covert shifts of visual attention induce changes in oscillatory alpha activity in posterior cortex, even in the absence of visual stimulation. The aim was to investigate whether different pairs of directions of attention shifts can be reliably differentiated based on the electroencephalogram. To this end, healthy participants (N = 8 had to strictly fixate a central dot and covertly shift visual attention to one out of six cued directions. Results Covert attention shifts induced a prolonged alpha synchronization over posterior electrode sites (PO and O electrodes. Spectral changes had specific topographies so that different pairs of directions could be differentiated. There was substantial variation across participants with respect to the direction pairs that could be reliably classified. Mean accuracy for the best-classifiable pair amounted to 74.6%. Furthermore, an alpha power index obtained during a relaxation measurement showed to be predictive of peak BCI performance (r = .66. Conclusions Results confirm posterior alpha power modulations as a viable input modality for gaze-independent EEG-based BCIs. The pair of directions yielding optimal performance varies across participants. Consequently, participants with low control for standard directions such as left-right might resort to other pairs of directions including top and bottom. Additionally, a simple alpha index was shown to predict prospective BCI performance.

  3. Modulation of attention network activation under antidepressant agents in healthy subjects.

    Science.gov (United States)

    Graf, Heiko; Abler, Birgit; Hartmann, Antonie; Metzger, Coraline D; Walter, Martin

    2013-07-01

    While antidepressants are supposed to exert similar effects on mood and drive via various mechanisms of action, diverging effects are observed regarding side-effects and accordingly on neural correlates of motivation, emotion, reward and salient stimuli processing as a function of the drugs impact on neurotransmission. In the context of erotic stimulation, a unidirectional modulation of attentional functioning despite opposite effects on sexual arousal has been suggested for the selective serotonin reuptake-inhibitor (SSRI) paroxetine and the selective dopamine and noradrenaline reuptake-inhibitor (SDNRI) bupropion. To further elucidate the effects of antidepressant-related alterations of neural attention networks, we investigated 18 healthy males under subchronic administration (7 d) of paroxetine (20 mg), bupropion (150 mg) and placebo within a randomized placebo-controlled cross-over double-blind functional magnetic resonance imaging (fMRI) design during an established preceding attention task. Neuropsychological effects beyond the fMRI-paradigm were assessed by measuring alertness and divided attention. Comparing preceding attention periods of salient vs. neutral pictures, we revealed congruent effects of both drugs vs. placebo within the anterior midcingulate cortex, dorsolateral prefrontal cortex, anterior prefrontal cortex, superior temporal gyrus, anterior insula and the thalamus. Relatively decreased activation in this network was paralleled by slower reaction times in the divided attention task in both verum conditions compared to placebo. Our results suggest similar effects of antidepressant treatments on behavioural and neural attentional functioning by diverging neurochemical pathways. Concurrent alterations of brain regions within a fronto-parietal and cingulo-opercular attention network for top-down control could point to basic neural mechanisms of antidepressant action irrespective of receptor profiles.

  4. Pituitary adenylate cyclase activating polypeptide modulates catecholamine storage and exocytosis in PC12 cells.

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    Yan Dong

    Full Text Available A number of efforts have been made to understand how pituitary adenylate cyclase activating polypeptide (PACAP functions as a neurotrophic and neuroprotective factor in Parkinson's disease (PD. Recently its effects on neurotransmission and underlying mechanisms have generated interest. In the present study, we investigate the effects of PACAP on catecholamine storage and secretion in PC12 cells with amperometry and transmission electron microscopy (TEM. PACAP increases quantal release induced by high K+ without significantly regulating the frequency of vesicle fusion events. TEM data indicate that the increased volume of the vesicle is mainly the result of enlargement of the fluidic space around the dense core. Moreover, the number of docked vesicles isn't modulated by PACAP. When cells are acutely treated with L-DOPA, the vesicular volume and quantal release both increase dramatically. It is likely that the characteristics of amperometric spikes from L-DOPA treated cells are associated with increased volume of individual vesicles rather than a direct effect on the mechanics of exocytosis. Treatment with PACAP versus L-DOPA results in different profiles of the dynamics of exocytosis. Release via the fusion pore prior to full exocytosis was observed with the same frequency following treatment with PACAP and L-DOPA. However, release events have a shorter duration and higher average current after PACAP treatment compared to L-DOPA. Furthermore, PACAP reduced the proportion of spikes having rapid decay time and shortened the decay time of both fast and slow spikes. In contrast, the distributions of the amperometric spike decay for both fast and slow spikes were shifted to longer time following L-DOPA treatment. Compared to L-DOPA, PACAP may produce multiple favorable effects on dopaminergic neurons, including protecting dopaminergic neurons against neurodegeneration and potentially regulating dopamine storage and release, making it a promising

  5. Altered activity profile of a tertiary silanol analog of multi-targeting nuclear receptor modulator T0901317.

    Science.gov (United States)

    Toyama, Hirozumi; Sato, Shoko; Shirakawa, Hitoshi; Komai, Michio; Hashimoto, Yuichi; Fujii, Shinya

    2016-04-01

    We report the design, synthesis, and physicochemical/biological evaluation of novel silanol derivative 6 (sila-T) as a silanol analog of multi-target nuclear receptor modulator T0901317 (5). Compound 6 showed intermediate hydrophobicity between the corresponding alcohol 13 and perfluoroalcohol 5. While 5 exhibited potent activities toward liver X receptor α and β, farnesoid X receptor, pregnane X receptor (PXR) and retinoic acid receptor-related orphan receptor (ROR)γ, silanol 6 exhibited activity only toward PXR and RORs. Incorporation of silanol instead of perfluoroalcohol is a promising option for developing novel target-selective, biologically active compounds.

  6. DEVELOPMENT OF A CO2 SEQUESTRATION MODULE BY INTEGRATING MINERAL ACTIVATION AND AQUEOUS CARBONATION

    Energy Technology Data Exchange (ETDEWEB)

    M. Mercedes Maroto-Valer; John M. Andresen; George Alexander

    2004-11-15

    Mineral carbonation is a promising concept for permanent CO{sub 2} sequestration due to the vast natural abundance of the raw minerals, the permanent storage of CO{sub 2} in solid form as carbonates, and the overall reaction being exothermic. However, the primary drawback to mineral carbonation is the reaction kinetics. To accelerate the reaction, aqueous carbonation processes are preferred, where the minerals are firstly dissolved in solution. In aqueous carbonation, the key step is the dissolution rate of the mineral, where the mineral dissolution reaction is likely to be surface controlled. In order to accelerate the dissolution process, the serpentine can be ground to very fine particle size (<37 {micro}m), but this is a very energy intensive process. Alternatively, magnesium could be chemically extracted in aqueous solution. Phase I showed that chemical surface activation helps to dissolve the magnesium from the serpentine minerals (particle size {approx}100 {micro}m), and furthermore, the carbonation reaction can be conducted under mild conditions (20 C and 650 psig) compared to previous studies that required >185 C, >1850 psig and <37 {micro}m particle size. Phase I also showed that over 70% of the magnesium can be extracted at ambient temperature leaving amorphous SiO{sub 2} with surface areas {approx} 330m{sup 2}/g. The overall objective of Phase 2 of this research program is to optimize the active carbonation process developed in Phase I in order to design an integrated CO{sub 2} sequestration module. During the current reporting period, Task 1 ''Mineral activation'' was initiated and focused on a parametric study to optimize the operation conditions for the mineral activation, where serpentine and sulfuric acid were reacted, as following the results from Phase 1. Several experimental factors were outlined as having a potential influence on the mineral activation. This study has focused to date on the effects of varying the acid

  7. Cognitive emotion regulation in children: Reappraisal of emotional faces modulates neural source activity in a frontoparietal network

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    Ida Wessing

    2015-06-01

    Full Text Available Emotion regulation has an important role in child development and psychopathology. Reappraisal as cognitive regulation technique can be used effectively by children. Moreover, an ERP component known to reflect emotional processing called late positive potential (LPP can be modulated by children using reappraisal and this modulation is also related to children's emotional adjustment. The present study seeks to elucidate the neural generators of such LPP effects. To this end, children aged 8–14 years reappraised emotional faces, while neural activity in an LPP time window was estimated using magnetoencephalography-based source localization. Additionally, neural activity was correlated with two indexes of emotional adjustment and age. Reappraisal reduced activity in the left dorsolateral prefrontal cortex during down-regulation and enhanced activity in the right parietal cortex during up-regulation. Activity in the visual cortex decreased with increasing age, more adaptive emotion regulation and less anxiety. Results demonstrate that reappraisal changed activity within a frontoparietal network in children. Decreasing activity in the visual cortex with increasing age is suggested to reflect neural maturation. A similar decrease with adaptive emotion regulation and less anxiety implies that better emotional adjustment may be associated with an advance in neural maturation.

  8. The influence of allosteric modulators and transmembrane mutations on desensitisation and activation of α7 nicotinic acetylcholine receptors.

    OpenAIRE

    Chatzidaki, A.; D Oyley, J. M.; Gill-Thind, J. K.; Sheppard, T. D.; Millar, N S

    2015-01-01

    Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding at an extracellular orthosteric site. Previous studies have described several positive allosteric modulators (PAMs) that are selective for homomeric α7 nAChRs. These include type I PAMs, which exert little or no effect on the rate of receptor desensitisation, and type II PAMs, which cause a dramatic loss of agonist-induced desensitisation. Here we report evidence that transmembrane mutations in α7 nAChRs have divers...

  9. The influence of allosteric modulators and transmembrane mutations on desensitisation and activation of α7 nicotinic acetylcholine receptors

    OpenAIRE

    Chatzidaki, Anna; D'Oyley, Jarryl M; Gill-Thind, JasKiran K.; Sheppard, Tom D; Millar, Neil S.

    2015-01-01

    Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding at an extracellular orthosteric site. Previous studies have described several positive allosteric modulators (PAMs) that are selective for homomeric α7 nAChRs. These include type I PAMs, which exert little or no effect on the rate of receptor desensitisation, and type II PAMs, which cause a dramatic loss of agonist-induced desensitisation. Here we report evidence that transmembrane mutations in α7 nAChRs have divers...

  10. Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action

    Energy Technology Data Exchange (ETDEWEB)

    Gee, K.W.; Bolger, M.B.; Brinton, R.E.; Coirini, H.; McEwen, B.S.

    1988-08-01

    Further in vitro studies of steroids active at the gamma-aminobutyric acidA (GABAA) receptor regulated Cl- channel labeled by (35S)-t-butylbicyclophosphorothionate ((35S)TBPS) reveal additional structural requirements necessary for activity. Evaluation of selected steroids for activity against TBPS-induced convulsions show similar requirements for activity. Interestingly, steroids (e.g., 5 alpha-pregnan-3 alpha, 20 alpha-diol) were identified that have high potency but limited efficacy as modulators of (35S)TBPS binding. These characteristics are reminiscent of the clinically useful benzodiazepines (BZs) such as clonazepam. However, interactions between the prototypical anesthetic-barbiturate, sodium pentobarbital, and steroids active at the Cl- channel suggest that they do not share a common site of action as allosteric modulators of (35S)TBPS and BZ receptor binding. The most potent steroid evaluated, 5 alpha-pregnan-3 alpha-ol-20-one, modulates (35S)TBPS binding at low concentrations (IC50 approximately 17 nM) in a regionally dependent manner. All (35S)TBPS binding sites appear to be functionally coupled to a steroid modulatory site. Because several of the active steroids are metabolites of progesterone, their ability to inhibit the binding of (3H)promegestrone to the cytosolic progestin receptor in rat uterus was evaluated. Those steroids showing potent activity at the GABAA receptor-Cl- ionophore were inactive at the intracellular progestin receptor. Such specificity coupled with their high potency provide additional support for the hypothesis that some of these steroids may be involved in the homeostatic regulation of brain excitability via the GABAA-BZ receptor complex.

  11. Modulation of endotoxicity of Shigella generalized modules for membrane antigens (GMMA) by genetic lipid A modifications: relative activation of TLR4 and TLR2 pathways in different mutants.

    Science.gov (United States)

    Rossi, Omar; Pesce, Isabella; Giannelli, Carlo; Aprea, Susanna; Caboni, Mariaelena; Citiulo, Francesco; Valentini, Sara; Ferlenghi, Ilaria; MacLennan, Calman Alexander; D'Oro, Ugo; Saul, Allan; Gerke, Christiane

    2014-09-05

    Outer membrane particles from Gram-negative bacteria are attractive vaccine candidates as they present surface antigens in their natural context. We previously developed a high yield production process for genetically derived particles, called generalized modules for membrane antigens (GMMA), from Shigella. As GMMA are derived from the outer membrane, they contain immunostimulatory components, especially lipopolysaccharide (LPS). We examined ways of reducing their reactogenicity by modifying lipid A, the endotoxic part of LPS, through deletion of late acyltransferase genes, msbB or htrB, in GMMA-producing Shigella sonnei and Shigella flexneri strains. GMMA with resulting penta-acylated lipid A from the msbB mutants showed a 600-fold reduced ability, and GMMA from the S. sonnei ΔhtrB mutant showed a 60,000-fold reduced ability compared with GMMA with wild-type lipid A to stimulate human Toll-like receptor 4 (TLR4) in a reporter cell line. In human peripheral blood mononuclear cells, GMMA with penta-acylated lipid A showed a marked reduction in induction of inflammatory cytokines (S. sonnei ΔhtrB, 800-fold; ΔmsbB mutants, 300-fold). We found that the residual activity of these GMMA is largely due to non-lipid A-related TLR2 activation. In contrast, in the S. flexneri ΔhtrB mutant, a compensatory lipid A palmitoleoylation resulted in GMMA with hexa-acylated lipid A with ∼10-fold higher activity to stimulate peripheral blood mononuclear cells than GMMA with penta-acylated lipid A, mostly due to retained TLR4 activity. Thus, for use as vaccines, GMMA will likely require lipid A penta-acylation. The results identify the relative contributions of TLR4 and TLR2 activation by GMMA, which need to be taken into consideration for GMMA vaccine development.

  12. Auditory cortical areas activated by slow frequency-modulated sounds in mice.

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    Yuusuke Honma

    Full Text Available Species-specific vocalizations in mice have frequency-modulated (FM components slower than the lower limit of FM direction selectivity in the core region of the mouse auditory cortex. To identify cortical areas selective to slow frequency modulation, we investigated tonal responses in the mouse auditory cortex using transcranial flavoprotein fluorescence imaging. For differentiating responses to frequency modulation from those to stimuli at constant frequencies, we focused on transient fluorescence changes after direction reversal of temporally repeated and superimposed FM sweeps. We found that the ultrasonic field (UF in the belt cortical region selectively responded to the direction reversal. The dorsoposterior field (DP also responded weakly to the reversal. Regarding the responses in UF, no apparent tonotopic map was found, and the right UF responses were significantly larger in amplitude than the left UF responses. The half-max latency in responses to FM sweeps was shorter in UF compared with that in the primary auditory cortex (A1 or anterior auditory field (AAF. Tracer injection experiments in the functionally identified UF and DP confirmed that these two areas receive afferent inputs from the dorsal part of the medial geniculate nucleus (MG. Calcium imaging of UF neurons stained with fura-2 were performed using a two-photon microscope, and the presence of UF neurons that were selective to both direction and direction reversal of slow frequency modulation was demonstrated. These results strongly suggest a role for UF, and possibly DP, as cortical areas specialized for processing slow frequency modulation in mice.

  13. Motor Planning under Unpredictable Reward: Modulations of Movement Vigor and Primate Striatum Activity

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    Ioan eOpris

    2011-05-01

    Full Text Available Although reward probability is an important factor that shapes animal behavior, it is not well understood however, how the primate brain translates reward expectation into the vigor of movement (reaction time and speed. To address this question, we trained two monkeys in a reaction time task that required wrist movements in response to vibrotactile and visual stimuli, with a variable reward schedule. Correct performance was rewarded in 75 % of the trials. Monkeys were certain that they would be rewarded only in the trials immediately following withheld rewards. In these trials, the animals responded sooner and moved faster. Single-unit recordings from the dorsal striatum revealed that modulations in striatal neurons reflected such modulations of movement vigor. First, in the trials with certain rewards, striatal neurons modulated their firing rates earlier. Second, magnitudes of changes in neuronal firing rates depended on whether or not monkeys were certain about the reward. Third, these modulations depended on the sensory modality of the cue (visual vs. vibratory and/or movement direction (flexions vs. extensions. We conclude that dorsal striatum may be a part of the mechanism responsible for the modulation of movement vigor in response to changes of reward predictability.

  14. Nectar intake rate is modulated by changes in sucking pump activity according to colony starvation in carpenter ants.

    Science.gov (United States)

    Falibene, Agustina; Josens, Roxana

    2008-05-01

    Dynamics of fluid feeding has been deeply studied in insects. However, the ability to vary the nectar-intake rate depending only on the carbohydrate deprivation has been clearly demonstrated only in Camponotus mus ants. When insect morphometry and fluid properties remain constant, changes in intake rate could only be attributed to variations in sucking pump activity. Previous records of the electrical activity generated during feeding in C. mus have revealed two different signal patterns: the regular (RP, frequencies: 2-5 Hz) and the irregular (IP, frequencies: 7-12 Hz). This work studies the mechanism underlying food intake-rate modulation in ants by analysing whether these patterns are involved. Behaviour and electrical activity generated by ants at different starvation levels were analysed during feeding on sucrose solutions. Ants were able to modulate the intake rate for a variety of sucrose concentrations (10, 40 and 60%w/w). The IP only occurred for 60% of solutions and its presence did not affect the intake rate. However, during the RP generated under the starved state, we found frequencies up to 7.5 Hz. RP frequencies positively correlated with the intake-rate for all sucrose concentrations. Hence, intake-rate modulation according to sugar deprivation is mainly achieved by the ant's ability to vary the pumping frequency.

  15. Design and Analysis of Sliding Mode Controller and Simplified Space Vector Modulation for Three Phase Shunt Active Power Filter

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    S. Elangovan

    2014-07-01

    Full Text Available The main aim of this study is to control a multivariable coupled system by choosing sliding mode switching function. A Sliding mode control approach is developed to control a three phase three wire voltage source inverter operating as a shunt active power filter. Hence, no need to divide the system model developed in the synchronous ‘dq’ reference frame into two separate loops. Furthermore, the proposed control strategy allows a better stability and robustness over a wide range of operation. When sine PWM is used for generation of pulses for the switches, a variable switching nature is exhibited. The pulses for the active filter are fed by a Space Vector Modulation in order to have a constant switching of converter switches. But, the conventional space vector modulation, if implemented practically, needs a complicated algorithm which uses the trigonometric functions such as arctan, Sine and Cosine functions which in turn needs look up tables to store the pre-calculated trigonometric values. In this study, a very simplified algorithm is proposed for generating Space vector modulated pulse for all six switches without the use of look up tables and only by sensing the voltages and currents of the voltage source inverter acting as shunt active filter. The simulation using PSIM and MATLAB software verifies the results very well.

  16. A low-voltage high-speed terahertz spatial light modulator using active metamaterial

    Science.gov (United States)

    Rout, Saroj; Sonkusale, Sameer R.

    2016-11-01

    An all solid-state metamaterial based terahertz (THz) spatial light modulator (SLM) is presented which uses high mobility 2DEG to manipulate the metamaterial resonant frequency (0.45 THz) leading to terahertz wave modulation. The 2DEG is created by embedding pseudomorphic high-electron mobility transistors in the capacitive gap of each electrical-LC resonator, allowing the charge density to be controlled with very low voltage (1 V) and modulating speeds up to 10 MHz while consuming sub-milliwatt power. We have demonstrated our SLM as a 2 × 2 pixel array operating around 0.45 THz by raster scanning a 6 × 6 image of an occluded metal object behind a thick polystyrene screen using a single-pixel THz imaging setup.

  17. Modulation of Network Oscillatory Activity and GABAergic Synaptic Transmission by CB1 Cannabinoid Receptors in the Rat Medial Entorhinal Cortex

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    Nicola H. Morgan

    2008-01-01

    Full Text Available Cannabinoids modulate inhibitory GABAergic neurotransmission in many brain regions. Within the temporal lobe, cannabinoid receptors are highly expressed, and are located presynaptically at inhibitory terminals. Here, we have explored the role of type-1 cannabinoid receptors (CB1Rs at the level of inhibitory synaptic currents and field-recorded network oscillations. We report that arachidonylcyclopropylamide (ACPA; 10 M, an agonist at CB1R, inhibits GABAergic synaptic transmission onto both superficial and deep medial entorhinal (mEC neurones, but this has little effect on network oscillations in beta/gamma frequency bands. By contrast, the CB1R antagonist/inverse agonist LY320135 (500 nM, increased GABAergic synaptic activity and beta/gamma oscillatory activity in superficial mEC, was suppressed, whilst that in deep mEC was enhanced. These data indicate that cannabinoid-mediated effects on inhibitory synaptic activity may be constitutively active in vitro, and that modulation of CB1R activation using inverse agonists unmasks complex effects of CBR function on network activity.

  18. The RecX protein interacts with the RecA protein and modulates its activity in Herbaspirillum seropedicae

    Energy Technology Data Exchange (ETDEWEB)

    Galvão, C.W. [Departamento de Biologia Estrutural, Molecular e Genética, Universidade Estadual de Ponta Grossa, Ponta Grossa, PR (Brazil); Souza, E.M. [Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, PR (Brazil); Etto, R.M. [Departamento de Biologia Estrutural, Molecular e Genética, Universidade Estadual de Ponta Grossa, Ponta Grossa, PR (Brazil); Pedrosa, F.O.; Chubatsu, L.S.; Yates, M.G. [Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, PR (Brazil); Schumacher, J.; Buck, M. [Department of Life Sciences, Imperial College London, London (United Kingdom); Steffens, M.B.R. [Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, PR (Brazil)

    2012-10-15

    DNA repair is crucial to the survival of all organisms. The bacterial RecA protein is a central component in the SOS response and in recombinational and SOS DNA repairs. The RecX protein has been characterized as a negative modulator of RecA activity in many bacteria. The recA and recX genes of Herbaspirillum seropedicae constitute a single operon, and evidence suggests that RecX participates in SOS repair. In the present study, we show that the H. seropedicae RecX protein (RecX{sub Hs}) can interact with the H. seropedicae RecA protein (RecA{sub Hs}) and that RecA{sub Hs} possesses ATP binding, ATP hydrolyzing and DNA strand exchange activities. RecX{sub Hs} inhibited 90% of the RecA{sub Hs} DNA strand exchange activity even when present in a 50-fold lower molar concentration than RecA{sub Hs}. RecA{sub Hs} ATP binding was not affected by the addition of RecX, but the ATPase activity was reduced. When RecX{sub Hs} was present before the formation of RecA filaments (RecA-ssDNA), inhibition of ATPase activity was substantially reduced and excess ssDNA also partially suppressed this inhibition. The results suggest that the RecX{sub Hs} protein negatively modulates the RecA{sub Hs} activities by protein-protein interactions and also by DNA-protein interactions.

  19. Status of design and experimental activity on module of lithium divertor for KTM tokamak

    Energy Technology Data Exchange (ETDEWEB)

    Lyublinski, Igor E., E-mail: lyublinski@yandex.ru [JSC “Red Star”, Moscow (Russian Federation); Vertkov, Alexey V.; Zharkov, Mikhail Yu.; Semenov, Vladimir V. [JSC “Red Star”, Moscow (Russian Federation); Mirnov, Sergey V.; Lazarev, Vladimir B. [GSC RF TRINITI, Troitsk, Moscow Region (Russian Federation); Tazhibayeva, Irina L.; Shapovalov, Gennadiy V.; Kulsartov, Timur V.; D’yachenko, Alexandr V. [IAE of National Nuclear Center, Kurchatov (Kazakhstan); Mazzitelli, Giuseppe [Associazione EURATOM-ENEA sulla Fusione, C.R. ENEA Frascati, Rome (Italy); Agostini, Pietro [ENEA Brasimone, Camugnano, BO (Italy)

    2013-10-15

    Highlights: • Lithium divertor module based on capillary-porous system is created for KTM tokamak. • The hydraulic tests of lithium divertor module were conducted. • The results were compared with the calculation data. • The analysis of results’ discrepancies was conducted. • The lithium divertor module is ready for tests on KTM tokamak. -- Abstract: The projects of ITER and DEMO reactors showed that there are serious difficulties with solving the issues of plasma facing elements (PFE) based on the solid materials. Problems of PFE can be overcome by the use of liquid lithium. Application of lithium will allow to create a self-renewal and MHD stable liquid metal surface of the in-vessel devices possessing practically unlimited service life. Realization of these advantages is based on use of so-called lithium capillary-porous system (CPS) – new material, in which liquid lithium fills a solid matrix from porous material. The progress in development of lithium technology and also lithium experiments in the tokamaks TFTR, T-11M, T-10, FTU, NSTX, LTX, HT-7 and stellarator TJ II is a good basis for development of the project of steady-state operating lithium divertor module for Kazakhstan tokamak. At present the lithium divertor module for KTM tokamak is development and manufacturing. The paper describes main design features of the module of lithium divertor (MLD). The first step of the hydraulic tests of MLD with fully assembled external thermo-stabilization system, which was connected to in-vessel lithium unit, were performed using ethanol as a model heat transfer media. Test results of MLD have shown that operating parameters of designed and manufactured system for thermo-stabilization are sufficient for proper operation; basic hydraulic characteristics of the system are close to expected values.

  20. Development of a CO2 Sequestration Module by Integrating Mineral Activation and Aqueous Carbonation

    Energy Technology Data Exchange (ETDEWEB)

    George Alexander; Parvana Aksoy; John Andresen; Mercedes Maroto-Valer; Harold Schobert

    2006-08-14

    process to design an integrated CO{sub 2} sequestration module. A parametric study was conducted to optimize conditions for mineral activation, in which serpentine and sulfuric acid were reacted. The study focused on the effects of varying the acid concentration, particle size, and reaction time. The reaction yield was as high as 48% with a 5 M acid concentration, with lower values directly corresponding to lower acid concentrations. Significant improvements in the removal of moisture, as well as in the dissolution, can be realized with comminution of particles to a D{sub 50} less than 125 ?m. A minimum threshold of 3 M concentration of sulfuric acid was found to exist in terms of removal of moisture from serpentine. The effect of reaction time was insignificant. The treated serpentine had low BET surface areas. Results demonstrated that acid concentration provided primary control on the dissolution via the removal of water, which is closely correlated with the extraction of magnesium from serpentine. Single-variable experimentation demonstrated dissolution enhancements with increased reaction time and temperature. An increase in magnesium dissolution of 46% and 70%, relative to a baseline test, occurred for increased reaction time and temperature, respectively. In addition to the challenges presented by the dissolution of serpentine, another challenge is the subsequent carbonation of the magnesium ions. A stable hydration sphere for the magnesium ion reduces the carbonation kinetics by obstructing the formation of the carbonation products. Accordingly, this research has evaluated the solubility of carbon dioxide in aqueous solution, the interaction between the dissociation products of carbon dioxide, and the carbonation potential of the magnesium ion.

  1. Zizyphus lotus L. (Desf. modulates antioxidant activity and human T-cell proliferation

    Directory of Open Access Journals (Sweden)

    Belarbi Meriem

    2010-09-01

    Full Text Available Abstract Background Zizyphus lotus L. (Desf. also known as Jujube, is a deciduous shrub which belongs to Rhamnaceae family. This plant is used in Algerian traditional medicine for its anti-diabetic, sedative, analgesic, anti-inflammatory and hypoglycaemic activities. In the present study, we determined the concentrations of different vitamins (vitamin A, C and E and fatty acids in root, stem, leaves, fruit pulp and seed of Zizyphus lotus L. (Desf. and assessed the effects of their aqueous extracts on antioxidant status and human T-cell proliferation. Methods Aqueous filtrates from different parts, i.e, root, leaf, stem, fruit pulp and seed, of Zizyphus lotus L. (Desf. were prepared. Vitamin C levels were determined by precipitating with 10% trichloroacetic acid and vitamin A and E were assessed by HPLC. Lipid composition of these extracts was determined by gas-liquid chromatography. Anti-oxidant capacity was evaluated by using anti-radical resistance kit [Kit Radicaux Libres (KRL@; Kirial International SA, Couternon, France]. T-cell blastogenesis was assessed by the incorporation of 3H-thymidine. IL-2 gene expression was evaluated by RT-qPCR. Results Our results show that fruit pulp contained higher vitamin A and C contents than other parts of the plant. Furthermore, the fruit pulp was the richest source of linoleic acid (18:2n-6, a precursor of n-6 fatty acids. Fruit seeds possessed higher vitamin C levels than leaves, roots and stem. The leaves were the richest source of vitamin E and linolenic acid (18:3n-3, a precursor of n-3 fatty acids. The antioxidant capacity of the different extracts, measured by KRL@ test, was as follows: pulp Zizyphus lotus L. (Desf. exerted immunosuppressive effects. Conclusion Seed extracts exerted the most potent immunosuppressive effects on T cell proliferation and IL-2 mRNA expression. The results of the present study are discussed in the light of their use to modulate the immune-mediated diseases.

  2. Structural Basis by Which Alternative Splicing Modulates the Organizer Activity of FGF8 in the Brain

    Energy Technology Data Exchange (ETDEWEB)

    Olsen,S.; Li, J.; Eliseenkova, A.; Ibrahimi, O.; Lao, Z.; Zhang, F.; Linhardt, R.; Joyner, A.; Mohammadi, M.

    2006-01-01

    Two of the four human FGF8 splice isoforms, FGF8a and FGF8b, are expressed in the mid-hindbrain region during development. Although the only difference between these isoforms is the presence of an additional 11 amino acids at the N terminus of FGF8b, these isoforms possess remarkably different abilities to pattern the midbrain and anterior hindbrain. To reveal the structural basis by which alternative splicing modulates the organizing activity of FGF8, we solved the crystal structure of FGF8b in complex with the 'c' splice isoform of FGF receptor 2 (FGFR2c). Using surface plasmon resonance (SPR), we also characterized the receptor-binding specificity of FGF8a and FGF8b, the 'b' isoform of FGF17 (FGF17b), and FGF18. The FGF8b-FGFR2c structure shows that alternative splicing permits a single additional contact between phenylalanine 32 (F32) of FGF8b and a hydrophobic groove within Ig domain 3 of the receptor that is also present in FGFR1c, FGFR3c, and FGFR4. Consistent with the structure, mutation of F32 to alanine reduces the affinity of FGF8b toward all these receptors to levels characteristic of FGF8a. More importantly, analysis of the mid-hindbrain patterning ability of the FGF8b{sup F32A} mutant in chick embryos and murine midbrain explants shows that this mutation functionally converts FGF8b to FGF8a. Moreover, our data suggest that the intermediate receptor-binding affinities of FGF17b and FGF18, relative to FGF8a and FGF8b, also account for the distinct patterning abilities of these two ligands. We also show that the mode of FGF8 receptor-binding specificity is distinct from that of other FGFs and provide the first biochemical evidence for a physiological FGF8b-FGFR1c interaction during mid-hindbrain development. Consistent with the indispensable role of FGF8 in embryonic development, we show that the FGF8 mode of receptor binding appeared as early as in nematodes and has been preserved throughout evolution.

  3. Modulation of motor area activity by the outcome for a player during observation of a baseball game.

    Directory of Open Access Journals (Sweden)

    Sotaro Shimada

    Full Text Available BACKGROUND: Observing competitive games such as sports is a pervasive entertainment among humans. The inclination to watch others play may be based on our social-cognitive ability to understand the internal states of others. The mirror neuron system, which is activated when a subject observes the actions of others, as well as when they perform the same action themselves, seems to play a crucial role in this process. Our previous study showed that activity of the mirror neuron system was modulated by the outcome of the subject's favored player during observation of a simple competitive game (rock-paper-scissors. However, whether the mirror neuron system responds similarly in a more complex and naturalistic sports game has not yet been fully investigated. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we measured the activity of motor areas when the subjects, who were amateur baseball field players (non-pitchers, watched short movie clips of scenes in professional baseball games. The subjects were instructed to support either a batter or a pitcher when observing the movie clip. The results showed that activity in the motor area exhibited a strong interaction between the subject's supported side (batter or pitcher and the outcome (a hit or an out. When the subject supported the batter, motor area activity was significantly higher when the batter made an out than when he made a hit. However, such modulation was not apparent when the subject supported the pitcher. CONCLUSIONS/SIGNIFICANCE: This result indicates that mirror neuron system activity is modulated by the outcome for a particular player in a competitive game even when observing a complex and naturalistic sports game. We suggest that our inclination to watch competitive games is facilitated by this characteristic of the mirror neuron system.

  4. Objective measurement of weekly physical activity and sensory modulation problems in children with attention deficit hyperactivity disorder.

    Science.gov (United States)

    Lin, Chung-Ying; Yang, Ai-Lun; Su, Chia-Ting

    2013-10-01

    This study aimed to objectively compare the daily physical activity (PA), as indicated by moderate-to-vigorous physical activity (MVPA) during a week and metabolic equivalents (METs) per minute, between children with attention deficit hyperactivity disorder (ADHD) and typically developing children. Moreover, sensory modulation problems were examined using behavioral and physiological measures. Twenty boys with ADHD (mean age 8.64 ± 2.57 years), and 20 matched typically developing boys (mean age 9.10 ± 1.79 years) participated in our study. Each child wore a PA monitor for 14 h a day, seven days a week. All participants' parents were asked to fill out daily activity logs for their children. The problems of sensory modulation were detected using sensory profile (SP) questionnaires and Sensory Challenge Protocol that measured electrodermal response (EDR) to repeated sensory stimulation. Compared with the controls, the children with ADHD had a generally higher level of PA (1.48 ± 0.10 vs. 1.60 ± 0.12 METs/min; p=001), and tended to spend more time in MVPA on weekdays (35.71%) and the weekend (57.14%). However, when analyzing hourly recorded PA, the group differences were obvious only for certain hours. Our data suggested that children with ADHD were more hyperactive in structure-free than structured settings. The ADHD group showed their sensory modulation problems on the SP but not on the EDR. We found some correlations between sensory modulation problems and hyperactivity in children with ADHD.

  5. Evidence for a modulation of neutral trehalase activity by Ca2+ and cAMP signaling pathways in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Souza A.C.

    2002-01-01

    Full Text Available Saccharomyces cerevisiae neutral trehalase (encoded by NTH1 is regulated by cAMP-dependent protein kinase (PKA and by an endogenous modulator protein. A yeast strain with knockouts of CMK1 and CMK2 genes (cmk1cmk2 and its isogenic control (CMK1CMK2 were used to investigate the role of CaM kinase II in the in vitro activation of neutral trehalase during growth on glucose. In the exponential growth phase, cmk1cmk2 cells exhibited basal trehalase activity and an activation ratio by PKA very similar to that found in CMK1CMK2 cells. At diauxie, even though both cells presented comparable basal trehalase activities, cmk1cmk2 cells showed reduced activation by PKA and lower total trehalase activity when compared to CMK1CMK2 cells. To determine if CaM kinase II regulates NTH1 expression or is involved in post-translational modulation of neutral trehalase activity, NTH1 promoter activity was evaluated using an NTH1-lacZ reporter gene. Similar ß-galactosidase activities were found for CMK1CMK2 and cmk1cmk2 cells, ruling out the role of CaM kinase II in NTH1 expression. Thus, CaM kinase II should act in concert with PKA on the activation of the cryptic form of neutral trehalase. A model for trehalase regulation by CaM kinase II is proposed whereby the target protein for Ca2+/CaM-dependent kinase II phosphorylation is not the neutral trehalase itself. The possible identity of this target protein with the recently identified trehalase-associated protein YLR270Wp is discussed.

  6. Using active resonator impedance matching for shot-noise limited, cavity enhanced amplitude modulated laser absorption spectroscopy.

    Science.gov (United States)

    Chow, Jong H; Littler, Ian C M; Rabeling, David S; McClelland, David E; Gray, Malcolm B

    2008-05-26

    We introduce a closed-loop feedback technique to actively control the coupling condition of an optical cavity, by employing amplitude modulation of the interrogating laser. We show that active impedance matching of the cavity facilitates optimal shot-noise sensing performance in a cavity enhanced system, while its control error signal can be used for intra-cavity absorption or loss signal extraction. We present the first demonstration of this technique with a fiber ring cavity, and achieved shot-noise limited loss sensitivity. We also briefly discuss further use of impedance matching control as a tool for other applications.

  7. The Pierre Auger Observatory scaler mode for the study of solar activity modulation of galactic cosmic rays

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2011-01-15

    Since data-taking began in January 2004, the Pierre Auger Observatory has been recording the count rates of low energy secondary cosmic ray particles for the self-calibration of the ground detectors of its surface detector array. After correcting for atmospheric effects, modulations of galactic cosmic rays due to solar activity and transient events are observed. Temporal variations related with the activity of the heliosphere can be determined with high accuracy due to the high total count rates. In this study, the available data are presented together with an analysis focused on the observation of Forbush decreases, where a strong correlation with neutron monitor data is found.

  8. The Pierre Auger Observatory scaler mode for the study of solar activity modulation of galactic cosmic rays

    Energy Technology Data Exchange (ETDEWEB)

    Abreu, P.; /Lisbon, LIFEP /Lisbon, IST; Aglietta, M.; /Turin Observ. /Turin U. /INFN, Turin; Ahn, E.J.; /Fermilab; Allard, D.; /APC, Paris; Allekotte, I.; /Centro Atomico Bariloche /Balseiro Inst., San Carlos de Bariloche; Allen, J.; /New York U.; Alvarez Castillo, J.; /Mexico U.; Alvarez-Muniz, J.; /Santiago de Compostela U.; Ambrosio, M.; /Naples U. /INFN, Naples; Aminaei, A.; /Nijmegen U., IMAPP; Anchordoqui, L.; /Wisconsin U., Milwaukee /Lisbon, LIFEP /Lisbon, IST

    2011-01-01

    Since data-taking began in January 2004, the Pierre Auger Observatory has been recording the count rates of low energy secondary cosmic ray particles for the self-calibration of the ground detectors of its surface detector array. After correcting for atmospheric effects, modulations of galactic cosmic rays due to solar activity and transient events are observed. Temporal variations related with the activity of the heliosphere can be determined with high accuracy due to the high total count rates. In this study, the available data are presented together with an analysis focused on the observation of Forbush decreases, where a strong correlation with neutron monitor data is found.

  9. Chromospheric activity and rotational modulation of the RS Canum Venaticorum binary V711 Tauri during 1998-2004

    Science.gov (United States)

    Cao, Dongtao; Gu, Shenghong

    2015-05-01

    We present long-term high-resolution spectroscopic observations of the very active RS Canum Venaticorum-type star V711 Tau, obtained during several observing runs from 1998 to 2004, and study its chromospheric activity. Using the spectral subtraction technique, several optical chromospheric activity indicators [including the He I D3, Na I D1, D2, Hα and Ca II infrared triplet (IRT) lines] formed at different atmospheric heights are analysed. Strong chromospheric emission supports earlier results that indicate that V711 Tau is a very active system. Two large optical flares were detected during our observations. The results suggest that the main part of chromospheric emission is attributed to the primary star of the system. The secondary also presents weak emission but is less active. The ratios of EW8542/EW8498 indicate that Ca II IRT emission arises predominantly from plage-like regions. We have found rotational modulation of chromospheric activity in the Hα and Ca II IRT lines, which suggests the presence of the chromospheric active longitudes over the surface of V711 Tau. Two active longitudes separated by about 180° were observed to dominate the activity, and the so-called flip-flop phenomenon was seen during our observations. Moreover, the chromospheric activity level shows a long-term variation that gradually increases from a deep minimum near the year 2002. A close spatial connection of photospheric spots and chromospheric active regions in both short and long timescales was found for V711 Tau.

  10. Control of high power IGBT modules in the active region for fast pulsed power converters

    CERN Document Server

    Cravero, J M; Garcia Retegui, R; Maestri, S; Uicich, G

    2014-01-01

    At CERN, fast pulsed power converters are used to supply trapezoidal current in different magnet loads. These converters perform output current regulation by using a high power IGBT module in its ohmic region. This paper presents a new strategy for pulsed current control applications using a specifically designed IGBT driver.

  11. Modulation of spectral properties and pump activity of proteorhodopsins by retinal analogues

    NARCIS (Netherlands)

    Ganapathy, S.; Becheau, O.; Venselaar, H.; Frolich, S.; Steen, J.B. van der; Chen, Q.; Radwan, S.; Lugtenburg, J.; Hellingwerf, K.J.; Groot, H.J. de; Grip, W.J. de

    2015-01-01

    Proteorhodopsins are heptahelical membrane proteins which function as light-driven proton pumps. They use all-trans-retinal A1 as a ligand and chromophore and absorb visible light (520-540 nm). In the present paper, we describe modulation of the absorbance band of the proteorhodopsin from Monterey B

  12. Modulation of spectral properties and pump activity of proteorhodopsins by retinal analogues.

    NARCIS (Netherlands)

    S. Ganapathy; O. Bécheau; H. Venselaar; S. Frölich; J.B. van der Steen; Q. Chen; S. Radwan; J. Lugtenburg; K.J. Hellingwerf; H.J. de Groot; W.J. de Grip

    2015-01-01

    Proteorhodopsins are heptahelical membrane proteins which function as light-driven proton pumps. They use all-trans-retinal A1 as a ligand and chromophore and absorb visible light (520-540 nm). In the present paper, we describe modulation of the absorbance band of the proteorhodopsin from Monterey B

  13. Perspectives on the origin of microfilaments, microtubules, the relevant chaperonin system and cytoskeletal motors--a commentary on the spirochaete origin of flagella

    Institute of Scientific and Technical Information of China (English)

    JING YAN LI; CHUAN FEN WU

    2003-01-01

    The origin of cytoskeleton and the origin of relevant intracellular transportation system are big problems for understanding the emergence of eukaryotic cells. The present article summarized relevant information of evidences and molecular traces on the origin of actin, tubulin, the chaperonin system for folding them,myosins, kinesins, axonemal dyneins and cytoplasmic dyneins. On this basis the authors proposed a series of works, which should be done in the future, and indicated the ways for reaching the targets. Thesetargets are mainly: 1) the reconstruction of evolutionary path from MreB protein of archaeal ancestor of eukaryotic cells to typical actin; 2) the finding of the MreB or MreB-related proteins in crenarchaea and using them to examine J. A. Lake's hypothesis on the origin of eukaryote from "eocytes" crenarchaea);3) the examinations of the existence and distribution of cytoskeleton made of MreB-related protein within coccoid archaea, especially in amoeboid archaeon Thermoplasm acidophilum; 4) using Thermoplasma as a model of archaeal ancestor of eukaryotic cells; 5) the searching for the homolog of ancestral dynein in present-day living archaea. During the writing of this article, Margulis' famous spirochaete hypothesis on the origin of flagella and cilia was unexpectedly involved and analyzed from aspects of tubulins, dyneins and spirochaetes. Actually, spirochaete cannot be reasonably assumed as the ectosymbiotic ancestor of eukaryotic flagella and cilia, since their swing depends upon large amount of bacterial flagella beneath the flexible outer wall, but not depends upon their intracellular tubules and the assumed dyneins. In this case,if they had "evolved" into cilia and lost their bacterial flagella, they would immediately become immobile!In fact, tubulin and dynein-like proteins have not been found in any spirochaete.

  14. Modulation of Mitochondrial Complex I Activity Averts Cognitive Decline in Multiple Animal Models of Familial Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Liang Zhang

    2015-04-01

    Full Text Available Development of therapeutic strategies to prevent Alzheimer's disease (AD is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest that metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.

  15. Coumestrol, Bisphenol-A, DDT, and TCDD Modulation of Interleukin-2 Expression in Activated CD+4 Jurkat T Cells

    Directory of Open Access Journals (Sweden)

    Robert W. McMurray

    2004-02-01

    Full Text Available 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 by ELISA and Western Blot. At the transcriptional level, protein expression was examined by RT-PCR. Coumestrol, DDT and TCDD (but not BPA significantly suppressed IL-2 production in activated CD4+ Jurkat T cells, at the transcriptional and translational levels. The transcriptional suppression of IL-2 was associated with decreased protein levels of NF-κβ, an important IL-2 positive transcription factor, without affecting the expression of Iκ−Βα protein expression, an important inhibitor of NF-κβ nuclear translocation. Although the direct mechanisms of xenoestrogens modulation of the immune system remain to be elucidated, coumestrol-, DDT- and TCDD-induced suppression of IL-2 may have ramifications for our understanding of the impact of xenoestrogens on health and disease.

  16. Using Standardized Clients in the Classroom: An Evaluation of a Training Module to Teach Active Listening Skills to Social Work Students

    Science.gov (United States)

    Rogers, Anissa; Welch, Benjamin

    2009-01-01

    This article describes the implementation of a module that utilizes drama students to teach social work students how to use active listening skills in an interview environment. The module was implemented during a semester-long micro skills practice course taught to 13 undergraduate social work seniors in a western liberal arts university. Four…

  17. Modulation of cortical activity during comprehension of familiar and unfamiliar text topics in speed reading and speed listening.

    Science.gov (United States)

    Buchweitz, Augusto; Mason, Robert A; Meschyan, Gayane; Keller, Timothy A; Just, Marcel Adam

    2014-12-01

    Brain activation associated with normal and speeded comprehension of expository texts on familiar and unfamiliar topics was investigated in reading and listening. The goal was to determine how brain activation and the comprehension processes it reflects are modulated by comprehension speed and topic familiarity. Passages on more familiar topics differentially activated a set of areas in the anterior temporal lobe and medial frontal gyrus, areas often associated with text-level integration processes, which we interpret to reflect integration of previous knowledge with the passage content. Passages presented at the faster presentation resulted in more activation of a network of frontal areas associated with strategic and working-memory processes (as well as visual or auditory sensory-related regions), which we interpret to reflect maintenance of local coherence among briefly available passage segments. The implications of this research is that the brain system for text comprehension adapts to varying perceptual and knowledge conditions.

  18. Phytochemical Analysis and Modulation of Antibiotic Activity by Luehea paniculata Mart. & Zucc. (Malvaceae) in Multiresistant Clinical Isolates of Candida Spp.

    Science.gov (United States)

    Calixto Júnior, João T.; Morais, Selene M.; Martins, Clécio G.; Vieira, Larissa G.; Morais-Braga, Maria Flaviana B.; Carneiro, Joara N. P.; Machado, Antonio J. P.; Menezes, Irwin R. A.; Tintino, Saulo R.; Coutinho, Henrique D. M.

    2015-01-01

    The high incidence of fungal infections has led to the continuous search for new drugs. Extracts of Luehea paniculata, a tree of multiple medicinal uses, were evaluated for anti-Candida activity, as well as its modulator potential of the Fluconazole antibiotic. Chemical prospecting of ethanol extracts of leaf and bark was carried out, the quantification of total phenols and flavonoids, characterized by the HPLC-DAD technique. The rosmarinic acid and the vitexin flavonoid were observed as major constituents in ELELP and ESWELP, respectively. Antioxidant activity was also evaluated by the method of scavenging the free radical DPPH, and quercetin was used as standard, obtaining IC50 values: 0.341 (mg/mL) for ELELP and 0.235 (mg/mL) for ESWELP. The microdilution assay was performed for antifungal activity against strains of Candida albicans, C. krusei, and C. tropicalis and showed minimum inhibitory concentrations values ≥1024 μg/mL. In the modulator action of extracts on Fluconazole against multiresistant clinical isolates of Candida (subinhibitory concentration minimum of 128 μg/mL), a significant synergism was observed, indicating that the extracts potentiated the antifungal effect against C. tropicalis, where antioxidant flavonoids could be responsible. This is the first report about modifying activity of the antibiotic action of a species of the genus Luehea. PMID:25821822

  19. STAT3 Activity and Function in Cancer: Modulation by STAT5 and miR-146b

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Sarah R.; Xiang, Michael; Frank, David A., E-mail: david_frank@dfci.harvard.edu [Department of Medical Oncology, Dana-Farber Cancer Institute, and Departments of Medicine, Brigham and Women' s Hospital and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215 (United States)

    2014-04-23

    The transcription factor STAT3 regulates genes that control critical cellular processes such as proliferation, survival, pluripotency, and motility. Thus, under physiological conditions, the transcriptional function of STAT3 is tightly regulated as one part of a complex signaling matrix. When these processes are subverted through mutation or epigenetic events, STAT3 becomes highly active and drives elevated expression of genes underlying these phenotypes, leading to malignant cellular behavior. However, even in the presence of activated STAT3, other cellular modulators can have a major impact on the biological properties of a cancer cell, which is reflected in the clinical behavior of a tumor. Recent evidence has suggested that two such key modulators are the activation status of other STAT family members, particularly STAT5, and the expression of STAT3-regulated genes that are part of negative feedback circuits, including microRNAs such as miR-146b. With attention to these newly emerging areas, we will gain greater insight into the consequence of STAT3 activation in the biology of human cancers. In addition, understanding these subtleties of STAT3 signaling in cancer pathogenesis will allow the development of more rational molecular approaches to cancer therapy.

  20. Phytochemical analysis and modulation of antibiotic activity by Luehea paniculata Mart. & Zucc. (Malvaceae) in multiresistant clinical isolates of Candida spp.

    Science.gov (United States)

    Calixto Júnior, João T; Morais, Selene M; Martins, Clécio G; Vieira, Larissa G; Morais-Braga, Maria Flaviana B; Carneiro, Joara N P; Machado, Antonio J P; Menezes, Irwin R A; Tintino, Saulo R; Coutinho, Henrique D M

    2015-01-01

    The high incidence of fungal infections has led to the continuous search for new drugs. Extracts of Luehea paniculata, a tree of multiple medicinal uses, were evaluated for anti-Candida activity, as well as its modulator potential of the Fluconazole antibiotic. Chemical prospecting of ethanol extracts of leaf and bark was carried out, the quantification of total phenols and flavonoids, characterized by the HPLC-DAD technique. The rosmarinic acid and the vitexin flavonoid were observed as major constituents in ELELP and ESWELP, respectively. Antioxidant activity was also evaluated by the method of scavenging the free radical DPPH, and quercetin was used as standard, obtaining IC50 values: 0.341 (mg/mL) for ELELP and 0.235 (mg/mL) for ESWELP. The microdilution assay was performed for antifungal activity against strains of Candida albicans, C. krusei, and C. tropicalis and showed minimum inhibitory concentrations values ≥1024 μg/mL. In the modulator action of extracts on Fluconazole against multiresistant clinical isolates of Candida (subinhibitory concentration minimum of 128 μg/mL), a significant synergism was observed, indicating that the extracts potentiated the antifungal effect against C. tropicalis, where antioxidant flavonoids could be responsible. This is the first report about modifying activity of the antibiotic action of a species of the genus Luehea.

  1. Cellular immune activation in children with acute dengue virus infections is modulated by apoptosis.

    Science.gov (United States)

    Myint, Khin S; Endy, Timothy P; Mongkolsirichaikul, Duangrat; Manomuth, Choompun; Kalayanarooj, Siripen; Vaughn, David W; Nisalak, Ananda; Green, Sharone; Rothman, Alan L; Ennis, Francis A; Libraty, Daniel H

    2006-09-01

    Apoptosis is an important modulator of cellular immune responses during systemic viral infections. Peripheral-blood mononuclear cell (PBMC) apoptosis and plasma soluble levels of CD95, a mediator of apoptosis, were determined in sequential samples from children participating in a prospective study of dengue virus (DV) infections. During the period of defervescence, levels of PBMC apoptosis were higher in children developing dengue hemorrhagic fever (DHF), the most severe form of illness, than in those with dengue fever (DF) and other, nondengue, febrile illnesses. CD8(+) T lymphocytes made up approximately half of the peak circulating apoptotic PBMCs in DHF and DF. Maximum plasma levels of soluble CD95 were also higher in children with DHF than in those with DF. The level of PBMC apoptosis correlated with dengue disease severity. Apoptosis appears to be involved in modulation of the innate and adaptive immune responses to DV infection and is likely involved in the evolution of immune responses in other viral hemorrhagic fevers.

  2. Disrupting SMA activity modulates explicit and implicit emotional responses: an rTMS study.

    Science.gov (United States)

    Rodigari, Alessia; Oliveri, Massimiliano

    2014-09-05

    Supplementary Motor Area (SMA) has been considered as an interface between the emotional/motivational system and motor effector system. Here, we investigated whether it is possible to modulate emotional responses using non-invasive brain stimulation of the SMA. 1Hz repetitive transcranial magnetic stimulation (rTMS) trains were applied over the SMA of healthy subjects performing a task requiring to judge the valence and arousal of emotional stimuli. rTMS trains over the SMA increased the perceived valence of emotionally negative visual stimuli, while decreasing the perceived valence of emotionally positive ones. The modulatory effect on emotional valence was specific for stimuli with emotional content, since it was not observed for neutral visual stimuli. The effect was also specific for the site of stimulation, since rTMS of the visual cortex failed to modulate either perceived valence or arousal. These findings provide the first example of neuromodulation of emotional responses based on non-invasive brain stimulation.

  3. Active modulation of visible light with graphene-loaded ultrathin metal plasmonic antennas.

    Science.gov (United States)

    Yu, Renwen; Pruneri, Valerio; García de Abajo, F Javier

    2016-08-26

    Electro-optical modulation of visible and near-infrared light is important for a wide variety of applications, ranging from communications to sensing and smart windows. However, currently available approaches result in rather bulky devices, suffer from low integrability, and can hardly operate at the low power consumption levels and fast switching rates required by microelectronic drivers. Here we show that planar nanostructures patterned in ultrathin metal-graphene hybrid films sustain highly tunable plasmons in the visible and near-infrared spectral regions. Strong variations in the reflection and absorption of incident light take place when the plasmons are tuned on- and off-resonance with respect to externally incident light. As a result, a remarkable modulation depth (i.e., the maximum relative variation with/without graphene doping) exceeding 90% in transmission and even more dramatic in reflection (>600%) is predicted for graphene-loaded silver films of 1-5 nm thickness and currently attainable lateral dimensions. These new structures hold great potential for fast low-power electro-optical modulation.

  4. Active modulation of visible light with graphene-loaded ultrathin metal plasmonic antennas

    Science.gov (United States)

    Yu, Renwen; Pruneri, Valerio; García de Abajo, F. Javier

    2016-08-01

    Electro-optical modulation of visible and near-infrared light is important for a wide variety of applications, ranging from communications to sensing and smart windows. However, currently available approaches result in rather bulky devices, suffer from low integrability, and can hardly operate at the low power consumption levels and fast switching rates required by microelectronic drivers. Here we show that planar nanostructures patterned in ultrathin metal-graphene hybrid films sustain highly tunable plasmons in the visible and near-infrared spectral regions. Strong variations in the reflection and absorption of incident light take place when the plasmons are tuned on- and off-resonance with respect to externally incident light. As a result, a remarkable modulation depth (i.e., the maximum relative variation with/without graphene doping) exceeding 90% in transmission and even more dramatic in reflection (>600%) is predicted for graphene-loaded silver films of 1-5 nm thickness and currently attainable lateral dimensions. These new structures hold great potential for fast low-power electro-optical modulation.

  5. The activity in the contralateral primary motor cortex, dorsal premotor and supplementary motor area is modulated by performance gains

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    Ronen eSosnik

    2014-04-01

    Full Text Available There is growing experimental evidence that the engagement of different brain areas in a given motor task may change with practice, although the specific brain activity patterns underlying different stages of learning, as defined by kinematic or dynamic performance indices, are not well understood. Here we studied the change in activation in motor areas during practice on sequences of handwriting-like trajectories, connecting four target points on a digitizing table 'as rapidly and as accurately as possible' while lying inside an fMRI scanner. Analysis of the subjects' pooled kinematic and imaging data, acquired at the beginning, middle and end of the training period, revealed no correlation between the amount of activation in the contralateral M1, PM (dorsal and ventral, SMA, preSMA and PPC and the amount of practice per-se. Single trial analysis has revealed that the correlation between the amount of activation in the contralateral M1 and trial mean velocity was partially modulated by performance gains related effects, such as increased hand motion smoothness. Furthermore, it was found that the amount of activation in the contralateral preSMA increased when subjects shifted from generating straight point-to-point trajectories to their spatiotemporal concatenation into a smooth, curved trajectory. Altogether, our results indicate that the amount of activation in the contralateral M1, PMd and preSMA during the learning of movement sequences is correlated with performance gains and that high level motion features (e.g., motion smoothness may modulate, or even mask correlations between activity changes and low-level motion attributes (e.g., trial mean velocity.

  6. Highly active modulators of indole signaling alter pathogenic behaviors in Gram-negative and Gram-positive bacteria.

    Science.gov (United States)

    Minvielle, Marine J; Eguren, Kristen; Melander, Christian

    2013-12-16

    Indole is a universal signal that regulates various bacterial behaviors, such as biofilm formation and antibiotic resistance. To generate mechanistic probes of indole signaling and control indole-mediated pathogenic phenotypes in both Gram-positive and Gram-negative bacteria, we have investigated the use of desformylflustrabromine (dFBr) derivatives to generate highly active indole mimetics. We have developed non-microbicidal dFBr derivatives that are 27-2000 times more active than indole in modulating biofilm formation, motility, acid resistance, and antibiotic resistance. The activity of these analogues parallels indole, because they are dependent on temperature, the enzyme tryptophanase TnaA, and the transcriptional regulator SdiA. This investigation demonstrates that molecules based on the dFBr scaffold can alter pathogenic behaviors by mimicking indole-signaling pathways.

  7. Impurity Activation in MBE-Grown As-Doped HgCdTe by Modulated Photoluminescence Spectra

    Institute of Scientific and Technical Information of China (English)

    YUE Fang-Yu; CHEN Lu; WU Jun; HU Zhi-Gao; LI Ya-Wei; YANG Ping-Xiong; CHU Jun-Hao

    2009-01-01

    @@ Modulated photoluminescence spectra have been performed to investigate the impurity activation in MBE-grown As-doped Hg1-xCdxTe (x≈0.3). The results show that the doped As mainly acting as donors in the as-grown samples can be fully activated as AsTe by two-stage anneals of 285℃/16h + 240℃/48h, of which the ionization energy has been determined to be about 10.5 meV, slightly smaller than that of intrinsic VHg (about 14.5 meV). However, the higher activation temperature (e.g. 400℃) at the first-stage can produce large numbers of excessive VHg and seriously deteriorate the quality of epilayers. This could give a brief guideline for preparing extrinsic p-type HgCdTe materials or devices.

  8. Evaluation of Antibacterial Activity of Aminoglycosides and Modulating the Essential Oil of Cymbopogon citratus (DC. Stapf

    Directory of Open Access Journals (Sweden)

    Saulo R. TINTINO

    2014-05-01

    Full Text Available  Several works demonstrated the importance of the study of natural products as an alternative source for new antimicrobial drugs or for modulators for these ones. In this point, the aim of this was to investigate the antibacterial activity and the possible interactions between the essential oil of Cymbopogon citratus alone and in association with aminoglycosides against standard and clinically isolated strains of multidrug-resistant bacteria such as S. aureus, E. coli and P. aeruginosa by microdilution method. The results indicated a synergism between the antibiotics and the essential oil with a subinhibitory concentration (MIC/8, reducing the minimal inhibitory concentration (MIC sixteen times against the multidrug-resistant strains of S. aureus 358, E. coli 27 and P. aeruginosa 143, but none modulatory activity was observed against P. aeruginosa 78 and P. aeruginosa 91 strains. By our results, can be concluded that the essential oil of Cymbopogon citratus can be an interesting source of natural products with antibacterial and/or modulatory antibiotic activitieAVALIAÇÃO DA ATIVIDADE ANTIBACTERIANA E MODULADORA DE AMINOGLICOSÍDEOS DO ÓLEO ESSENCIAL DE Cymbopogon citratus (DC. STAPFVários trabalhos vêm demonstrando a importância do estudo de produtos naturais como fonte alternativa para novos antimicrobianos ou que venham potencializar os já existentes. Neste contexto este trabalho teve como objetivo investigar a atividade antibacteriana e as possíveis interações entre o óleo essencial de Cymbopogon citratus combinados a aminoglicosídeos frente a linhagens padrões e multirresistentes de S. aureus, E. coli e de P. aeruginosa provenientes de isolados clínicos. Um ensaio de microdiluição foi realizado para verificar a atividade antibacteriana e as possíveis interacções entre o produto natural e os antibióticos, utilizando uma concentração sub-inibitória. Através dos resultados foi constatado a interferência sinérgica dos

  9. Quaternary organization in a bifunctional prokaryotic FAD synthetase: Involvement of an arginine at its adenylyltransferase module on the riboflavin kinase activity.

    Science.gov (United States)

    Serrano, Ana; Sebastián, María; Arilla-Luna, Sonia; Baquedano, Silvia; Pallarés, María Carmen; Lostao, Anabel; Herguedas, Beatriz; Velázquez-Campoy, Adrián; Martínez-Júlvez, Marta; Medina, Milagros

    2015-08-01

    Prokaryotic FAD synthetases (FADSs) are bifunctional enzymes composed of two modules, the C-terminal module with ATP:riboflavin kinase (RFK) activity, and the N-terminus with ATP:FMN adenylyltransferase (FMNAT) activity. The FADS from Corynebacterium ammoniagenes, CaFADS, forms transient oligomers during catalysis. These oligomers are stabilized by several interactions between the RFK and FMNAT sites from neighboring protomers, which otherwise are separated in the monomeric enzyme. Among these inter-protomer interactions, the salt bridge between E268 at the RFK site and R66 at the FMNAT-module is particularly relevant, as E268 is the catalytic base of the kinase reaction. Here we have introduced point mutations at R66 to analyze the impact of the salt-bridge on ligand binding and catalysis. Interestingly, these mutations have only mild effects on ligand binding and kinetic properties of the FMNAT-module (where R66 is located), but considerably impair the RFK activity turnover. Substitutions of R66 also modulate the ratio between monomeric and oligomeric species and modify the quaternary arrangement observed by single-molecule methods. Therefore, our data further support the cross-talk between the RFK- and FMNAT-modules of neighboring protomers in the CaFADS enzyme, and establish the participation of R66 in the modulation of the geometry of the RFK active site during catalysis.

  10. Activation of PPARγ by a Natural Flavonoid Modulator, Apigenin Ameliorates Obesity-Related Inflammation Via Regulation of Macrophage Polarization

    Directory of Open Access Journals (Sweden)

    Xiujing Feng

    2016-07-01

    Full Text Available PPARγ has emerged as a master regulator of macrophage polarization and is the molecular target of the thiazolidinedione drugs. Here we show that apigenin binds and activates PPARγ by acting as a modulator. Activation of PPARγ by apigenin blocks p65 translocation into nuclei through inhibition of p65/PPARγ complex translocation into nuclei, thereby decreasing NF-κB activation and favoringM2 macrophage polarization. In HFD and ob/ob mice, apigenin significantly reverses M1 macrophage into M2 and reduces the infiltration of inflammatory cells in liver and adipose tissues, as well as decreases the levels of pro-inflammatory cytokines, thereby alleviating inflammation. Strikingly, apigenin reduces liver and muscular steatosis, decreases the levels of ALT, AST, TC and TG, improving glucose resistance obviously. Unlike rosiglitazone, apigenin does not cause significant weight gain, osteoporosis et al. Our findings identify apigenin as a modulator of PPARγ and a potential lead compound for treatment of metabolic disorders.

  11. Leukemia Mediated Endothelial Cell Activation Modulates Leukemia Cell Susceptibility to Chemotherapy through a Positive Feedback Loop Mechanism.

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    Bahareh Pezeshkian

    Full Text Available In acute myeloid leukemia (AML, the chances of achieving disease-free survival are low. Studies have demonstrated a supportive role of endothelial cells (ECs in normal hematopoiesis. Here we show that similar intercellular relationships exist in leukemia. We demonstrate that leukemia cells themselves initiate these interactions by directly modulating the behavior of resting ECs through the induction of EC activation. In this inflammatory state, activated ECs induce the adhesion of a sub-set of leukemia cells through the cell adhesion molecule E-selectin. These adherent leukemia cells are sequestered in a quiescent state and are unaffected by chemotherapy. The ability of adherent cells to later detach and again become proliferative following exposure to chemotherapy suggests a role of this process in relapse. Interestingly, differing leukemia subtypes modulate this process to varying degrees, which may explain the varied response of AML patients to chemotherapy and relapse rates. Finally, because leukemia cells themselves induce EC activation, we postulate a positive-feedback loop in leukemia that exists to support the growth and relapse of the disease. Together, the data defines a new mechanism describing how ECs and leukemia cells interact during leukemogenesis, which could be used to develop novel treatments for those with AML.

  12. Modulation of Pineal Melatonin Synthesis by Glutamate Involves Paracrine Interactions between Pinealocytes and Astrocytes through NF-κB Activation

    Directory of Open Access Journals (Sweden)

    Darine Villela

    2013-01-01

    Full Text Available The glutamatergic modulation of melatonin synthesis is well known, along with the importance of astrocytes in mediating glutamatergic signaling in the central nervous system. Pinealocytes and astrocytes are the main cell types in the pineal gland. The objective of this work was to investigate the interactions between astrocytes and pinealocytes as a part of the glutamate inhibitory effect on melatonin synthesis. Rat pinealocytes isolated or in coculture with astrocytes were incubated with glutamate in the presence of norepinephrine, and the melatonin content, was quantified. The expression of glutamate receptors, the intracellular calcium content and the NF-κB activation were analyzed in astrocytes and pinealocytes. TNF-α's possible mediation of the effect of glutamate was also investigated. The results showed that glutamate's inhibitory effect on melatonin synthesis involves interactions between astrocytes and pinealocytes, possibly through the release of TNF-α. Moreover, the activation of the astrocytic NF-κB seems to be a necessary step. In astrocytes and pinealocytes, AMPA, NMDA, and group I metabotropic glutamate receptors were observed, as well as the intracellular calcium elevation. In conclusion, there is evidence that the modulation of melatonin synthesis by glutamate involves paracrine interactions between pinealocytes and astrocytes through the activation of the astrocytic NF-κB transcription factor and possibly by subsequent TNF-α release.

  13. Mapping transmembrane residues of proteinase activated receptor 2 (PAR2) that influence ligand-modulated calcium signaling.

    Science.gov (United States)

    Suen, J Y; Adams, M N; Lim, J; Madala, P K; Xu, W; Cotterell, A J; He, Y; Yau, M K; Hooper, J D; Fairlie, D P

    2017-03-01

    Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor involved in metabolism, inflammation, and cancers. It is activated by proteolysis, which exposes a nascent N-terminal sequence that becomes a tethered agonist. Short synthetic peptides corresponding to this sequence also activate PAR2, while small organic molecules show promising PAR2 antagonism. Developing PAR2 ligands into pharmaceuticals is hindered by a lack of knowledge of how synthetic ligands interact with and differentially modulate PAR2. Guided by PAR2 homology modeling and ligand docking based on bovine rhodopsin, followed by cross-checking with newer PAR2 models based on ORL-1 and PAR1, site-directed mutagenesis of PAR2 was used to investigate the pharmacology of three agonists (two synthetic agonists and trypsin-exposed tethered ligand) and one antagonist for modulation of PAR2 signaling. Effects of 28 PAR2 mutations were examined for PAR2-mediated calcium mobilization and key mutants were selected for measuring ligand binding. Nineteen of twenty-eight PAR2 mutations reduced the potency of at least one ligand by >10-fold. Key residues mapped predominantly to a cluster in the transmembrane (TM) domains of PAR2, differentially influence intracellular Ca(2+) induced by synthetic agonists versus a native agonist, and highlight subtly different TM residues involved in receptor activation. This is the first evidence highlighting the importance of the PAR2 TM regions for receptor activation by synthetic PAR2 agonists and antagonists. The trypsin-cleaved N-terminus that activates PAR2 was unaffected by residues that affected synthetic peptides, challenging the widespread practice of substituting peptides for proteases to characterize PAR2 physiology.

  14. ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma.

    Science.gov (United States)

    Hutchinson, Katherine E; Johnson, Douglas B; Johnson, Adam S; Sanchez, Violeta; Kuba, Maria; Lu, Pengcheng; Chen, Xi; Kelley, Mark C; Wang, Qingguo; Zhao, Zhongming; Kris, Mark; Berger, Michael F; Sosman, Jeffrey A; Pao, William

    2015-09-08

    Melanomas are characterized by activating "driver" mutations in BRAF, NRAS, KIT, GNAQ, and GNA11. Resultant mitogen-activated protein kinase (MAPK) pathway signaling makes some melanomas susceptible to BRAF (BRAF V600 mutations), MEK1/2 (BRAF V600, L597, fusions; NRAS mutations), or other kinase inhibitors (KIT), respectively. Among driver-negative ("pan-negative") patients, an unexplained heterogeneity of response to MEK1/2 inhibitors has been observed. Analysis of 16 pan-negative melanoma cell lines revealed that 8 (50%; termed Class I) are sensitive to the MEK1/2 inhibitor, trametinib, similar to BRAF V600E melanomas. A second set (termed Class II) display reduced trametinib sensitivity, paradoxical activation of MEK1/2 and basal activation of ERBBs 1, 2, and 3 (4 lines, 25%). In 3 of these lines, PI3K/AKT and MAPK pathway signaling is abrogated using the ERBB inhibitor, afatinib, and proliferation is even further reduced upon the addition of trametinib. A potential mechanism of ERBB activation in Class II melanomas is minimal expression of the ERK1/2 phosphatase, DUSP4, as ectopic restoration of DUSP4 attenuated ERBB signaling through potential modulation of the ERBB ligand, amphiregulin (AREG). Consistent with these data, immunohistochemical analysis of patient melanomas revealed a trend towards lower overall DUSP4 expression in pan-negative versus BRAF- and NRAS-mutant tumors. This study is the first to demonstrate that differential ERBB activity in pan-negative melanoma may modulate sensitivity to clinically-available MEK1/2 inhibitors and provides rationale for the use of ERBB inhibitors, potentially in combination with MEK1/2 inhibitors, in subsets of this disease.

  15. Experience in judging intent to harm modulates parahippocampal activity: an fMRI study with experienced CCTV operators.

    Science.gov (United States)

    Petrini, Karin; McAleer, Phil; Neary, Catherine; Gillard, Julia; Pollick, Frank E

    2014-08-01

    Does visual experience in judging intent to harm change our brain responses? And if it does, what are the mechanisms affected? We addressed these questions by studying the abilities of Closed Circuit Television (CCTV) operators, who must identify the presence of hostile intentions using only visual cues in complex scenes. We used functional magnetic resonance imaging to assess which brain processes are modulated by CCTV experience. To this end we scanned 15 CCTV operators and 15 age and gender matched novices while they watched CCTV videos of 16 sec, and asked them to report whether each clip would end in violence or not. We carried out four separate whole-brain analyses including 3 model-based analyses and one analysis of intersubject correlation to examine differences between the two groups. The three model analyses were based on 1) experimentally pre-defined clip activity labels of fight, confrontation, playful, and neutral behaviour, 2) participants' reports of violent outcomes during the scan, and 3) visual saliency within each clip, as pre-assessed using eye-tracking. The analyses identified greater activation in the right superior frontal gyrus for operators than novices when viewing playful behaviour, and reduced activity for operators in comparison with novices in the occipital and temporal regions, irrespective of the type of clips viewed. However, in the parahippocampal gyrus, all three model-based analyses consistently showed reduced activity for experienced CCTV operators. Activity in the anterior part of the parahippocampal gyrus (uncus) was found to increase with years of CCTV experience. The intersubject correlation analysis revealed a further effect of experience, with CCTV operators showing correlated activity in fewer brain regions (superior and middle temporal gyrus, inferior parietal lobule and the ventral striatum) than novices. Our results indicate that long visual experience in action observation, aimed to predict harmful behaviour

  16. Modulation of spinal cord synaptic activity by tumor necrosis factor α in a model of peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Spicarova Diana

    2011-12-01

    Full Text Available Abstract Background The cytokine tumor necrosis factor α (TNFα is an established pain modulator in both the peripheral and central nervous systems. Modulation of nociceptive synaptic transmission in the spinal cord dorsal horn (DH is thought to be involved in the development and maintenance of several pathological pain states. Increased levels of TNFα and its receptors (TNFR in dorsal root ganglion (DRG cells and in the spinal cord DH have been shown to play an essential role in neuropathic pain processing. In the present experiments the effect of TNFα incubation on modulation of primary afferent synaptic activity was investigated in a model of peripheral neuropathy. Methods Spontaneous and miniature excitatory postsynaptic currents (sEPSC and mEPSCs were recorded in superficial DH neurons in acute spinal cord slices prepared from animals 5 days after sciatic nerve transection and in controls. Results In slices after axotomy the sEPSC frequency was 2.8 ± 0.8 Hz, while neurons recorded from slices after TNFα incubation had significantly higher sEPSC frequency (7.9 ± 2.2 Hz. The effect of TNFα treatment was smaller in the slices from the control animals, where sEPSC frequency was 1.2 ± 0.2 Hz in slices without and 2.0 ± 0.5 Hz with TNFα incubation. Tetrodotoxin (TTX application in slices from axotomized animals and after TNFα incubation decreased the mEPSC frequency to only 37.4 ± 6.9% of the sEPSC frequency. This decrease was significantly higher than in the slices without the TNFα treatment (64.4 ± 6.4%. TTX application in the control slices reduced the sEPSC frequency to about 80% in both TNFα untreated and treated slices. Application of low concentration TRPV1 receptors endogenous agonist N-oleoyldopamine (OLDA, 0.2 μM in slices after axotomy induced a significant increase in mEPSC frequency (175.9 ± 17.3%, similar to the group with TNFα pretreatment (158.1 ± 19.5%. Conclusions Our results indicate that TNFα may enhance

  17. Vitamin D modulation of the activity of estrogenic compounds in bone cells in vitro and in vivo.

    Science.gov (United States)

    Somjen, Dalia

    2007-01-01

    Vitamin D analogs modulate different organs, including modulation of energy metabolism, through the induction of creatine kinase (CK) activity. Skeletal organs from vitamin D-depleted rats showed lower constituent CK than those from vitamin D-replete rats. Moreover, estradiol-17beta (E2) or dihydrotestosterone (DHT), which increased CK in organs from intact female or male rats, respectively, stimulated much less CK in vitamin D-depleted rats. Treatment of intact female rats with noncalcemic vitamin D analogs significantly upregulated E2- and DHT-induced CKresponse. These analogs upregulated the CK response to selective estrogen receptor modulators (SERMs) in organs from intact or ovariectomized (Ovx) female rats but abolished SERMs' inhibitory effect on E2-induced CK. These analogs significantly increased estradiol receptor alpha (ERalpha) protein in skeletal organs as well as histomorphological and biochemical changes due to this treatment followed by E2 or DHT. The analogs alone markedly altered the growth plate and the trabeculae and increased trabecular bone volume (%TB V) and trabecular width. The addition of E2 or DHT to this treatment restored all parameters as well as increased %TBV and cell proliferation. Treatment of Ovx female rats with JK 1624 F2-2 (JKF) decreased growth-plate width and increased %TB V, whereas QW1624 F2-2 (QW) restored growth-plate width and %TB V. Treatment of E2 with JKF restored %TBV and growth-plate width, whereas E2 with QW restored all parameters, including cortical width. There was also upregulation of the response of CK to E2 in both combined treatments. Our human-derived osteoblast (hObs)-like cell cultures respond to estrogenic compounds, and pretreating them with JKF upregulated the CK response to E2, raloxifene (Ral), and some phytoestrogens. ERalpha and ERbeta proteins, as well as mRNA, were modulated by CB 1093 (CB) and JKF. JKF increased specific nuclear E2 binding in female hObs but inhibited specific membranal E2

  18. 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

    -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...... hydrochloride, anaesthetic blocking of sensory information from the foot with injections of lidocaine hydrochloride, and modulation of load feedback by increasing and decreasing the body load. The depression of the group II afferents significantly reduced the soleus response to the ankle trajectory...

  19. Normal aging in rats and pathological agin