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Sample records for ai-2 receptors suggests

  1. Lack of genomic evidence of AI-2 receptors suggests a non-quorum sensing role for luxS in most bacteria.

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    Rezzonico, Fabio; Duffy, Brion

    2008-09-20

    Great excitement accompanied discoveries over the last decade in several Gram-negative and Gram-positive bacteria of the LuxS protein, which catalyzes production of the AI-2 autoinducer molecule for a second quorum sensing system (QS-2). Since the luxS gene was found to be widespread among the most diverse bacterial taxa, it was hypothesized that AI-2 may constitute the basis of a universal microbial language, a kind of bacterial Esperanto. Many of the studies published in this field have drawn a direct correlation between the occurrence of the luxS gene in a given organism and the presence and functionality of a QS-2 therein. However, rarely hathe existence of potential AI-2 receptors been examined. This is important, since it is now well recognized that LuxS also holds a central role as a metabolic enzyme in the activated methyl cycle which is responsible for the generation of S-adenosyl-L-methionine, the major methyl donor in the cell. In order to assess whether the role of LuxS in these bacteria is indeed related to AI-2 mediated quorum sensing we analyzed genomic databases searching for established AI-2 receptors (i.e., LuxPQ-receptor of Vibrio harveyi and Lsr ABC-transporter of Salmonella typhimurium) and other presumed QS-related proteins and compared the outcome with published results about the role of QS-2 in these organisms. An unequivocal AI-2 related behavior was restricted primarily to organisms bearing known AI-2 receptor genes, while phenotypes of luxS mutant bacteria lacking these genes could often be explained simply by assuming deficiencies in sulfur metabolism. Genomic analysis shows that while LuxPQ is restricted to Vibrionales, the Lsr-receptor complex is mainly present in pathogenic bacteria associated with endotherms. This suggests that QS-2 may play an important role in interactions with animal hosts. In most other species, however, the role of LuxS appears to be limited to metabolism, although in a few cases the presence of yet unknown

  2. Lack of genomic evidence of AI-2 receptors suggests a non-quorum sensing role for luxS in most bacteria

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    Duffy Brion

    2008-09-01

    Full Text Available Abstract Background Great excitement accompanied discoveries over the last decade in several Gram-negative and Gram-positive bacteria of the LuxS protein, which catalyzes production of the AI-2 autoinducer molecule for a second quorum sensing system (QS-2. Since the luxS gene was found to be widespread among the most diverse bacterial taxa, it was hypothesized that AI-2 may constitute the basis of a universal microbial language, a kind of bacterial Esperanto. Many of the studies published in this field have drawn a direct correlation between the occurrence of the luxS gene in a given organism and the presence and functionality of a QS-2 therein. However, rarely hathe existence of potential AI-2 receptors been examined. This is important, since it is now well recognized that LuxS also holds a central role as a metabolic enzyme in the activated methyl cycle which is responsible for the generation of S-adenosyl-L-methionine, the major methyl donor in the cell. Results In order to assess whether the role of LuxS in these bacteria is indeed related to AI-2 mediated quorum sensing we analyzed genomic databases searching for established AI-2 receptors (i.e., LuxPQ-receptor of Vibrio harveyi and Lsr ABC-transporter of Salmonella typhimurium and other presumed QS-related proteins and compared the outcome with published results about the role of QS-2 in these organisms. An unequivocal AI-2 related behavior was restricted primarily to organisms bearing known AI-2 receptor genes, while phenotypes of luxS mutant bacteria lacking these genes could often be explained simply by assuming deficiencies in sulfur metabolism. Conclusion Genomic analysis shows that while LuxPQ is restricted to Vibrionales, the Lsr-receptor complex is mainly present in pathogenic bacteria associated with endotherms. This suggests that QS-2 may play an important role in interactions with animal hosts. In most other species, however, the role of LuxS appears to be limited to metabolism

  3. Thiophenone Attenuates Enteropathogenic Escherichia coli O103:H2 Virulence by Interfering with AI-2 Signaling.

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    Witsø, Ingun Lund; Valen Rukke, Håkon; Benneche, Tore; Aamdal Scheie, Anne

    2016-01-01

    Interference with bacterial quorum sensing communication provides an anti-virulence strategy to control pathogenic bacteria. Here, using the Enteropathogenic E. coli (EPEC) O103:H2, we showed for the first time that thiophenone TF101 reduced expression of lsrB; the gene encoding the AI-2 receptor. Combined results of transcriptional and phenotypic analyses suggested that TF101 interfere with AI-2 signalling, possibly by competing with AI-2 for binding to LsrB. This is supported by in silico docking prediction of thiophenone TF101 in the LsrB pocket. Transcriptional analyses furthermore showed that thiophenone TF101 interfered with expression of the virulence genes eae and fimH. In addition, TF101 reduced AI-2 induced E. coli adhesion to colorectal adenocarcinoma cells. TF101, on the other hand, did not affect epinephrine or norepinephrine enhanced E. coli adhesion. Overall, our results showed that thiophenone TF101 interfered with virulence expression in E. coli O103:H2, suggestedly by interfering with AI-2 mediated quorum sensing. We thus conclude that thiophenone TF101 might represent a promising future anti-virulence agent in the fight against pathogenic E. coli.

  4. Thiophenone Attenuates Enteropathogenic Escherichia coli O103:H2 Virulence by Interfering with AI-2 Signaling

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    Valen Rukke, Håkon; Benneche, Tore; Aamdal Scheie, Anne

    2016-01-01

    Interference with bacterial quorum sensing communication provides an anti-virulence strategy to control pathogenic bacteria. Here, using the Enteropathogenic E. coli (EPEC) O103:H2, we showed for the first time that thiophenone TF101 reduced expression of lsrB; the gene encoding the AI-2 receptor. Combined results of transcriptional and phenotypic analyses suggested that TF101 interfere with AI-2 signalling, possibly by competing with AI-2 for binding to LsrB. This is supported by in silico docking prediction of thiophenone TF101 in the LsrB pocket. Transcriptional analyses furthermore showed that thiophenone TF101 interfered with expression of the virulence genes eae and fimH. In addition, TF101 reduced AI-2 induced E. coli adhesion to colorectal adenocarcinoma cells. TF101, on the other hand, did not affect epinephrine or norepinephrine enhanced E. coli adhesion. Overall, our results showed that thiophenone TF101 interfered with virulence expression in E. coli O103:H2, suggestedly by interfering with AI-2 mediated quorum sensing. We thus conclude that thiophenone TF101 might represent a promising future anti-virulence agent in the fight against pathogenic E. coli. PMID:27309855

  5. Regulation of bacteria population behaviors by AI-2 "consumer cells" and "supplier cells".

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    Quan, Yufen; Meng, Fankang; Ma, Xinyu; Song, Xinhao; Liu, Xiao; Gao, Weixia; Dang, Yulei; Meng, Yao; Cao, Mingfeng; Song, Cunjiang

    2017-09-19

    Autoinducer-2 (AI-2) is a universal signal molecule and enables an individual bacteria to communicate with each other and ultimately control behaviors of the population. Harnessing the character of AI-2, two kinds of AI-2 "controller cells" ("consumer cells" and "supplier cells") were designed to "reprogram" the behaviors of entire population. For the consumer cells, genes associated with the uptake and processing of AI-2, which includes LsrACDB, LsrFG, LsrK, were overexpressed in varying combinations. Four consumer cell strains were constructed: Escherichia coli MG1655 pLsrACDB (NK-C1), MG1655 pLsrACDBK (NK-C2), MG1655 pLsrACDBFG (NK-C3) and MG1655 pLsrACDBFGK (NK-C4). The key enzymes responsible for production of AI-2, LuxS and Mtn, were also overexpressed, yielding strains MG1655 pLuxS (NK-SU1), and MG1655 pLuxS-Mtn (NK-SU2). All the consumer cells could decrease the environmental AI-2 concentration. NK-C2 and NK-C4 were most effective in AI-2 uptake and inhibited biofilm formation. While suppliers can increase the environmental AI-2 concentration and NK-SU2 was most effective in supplying AI-2 and facilitated biofilm formation. Further, reporter strain, MG1655 pLGFP was constructed. The expression of green fluorescent protein (GFP) in reporter cells was initiated and guided by AI-2. Mixture of consumer cells and reporter cells suggest that consumer cells can decrease the AI-2 concentration. And the supplier cells were co-cultured with reporter cells, indicating that supplier cells can provide more AI-2 compared to the control. The consumer cells and supplier cells could be used to regulate environmental AI-2 concentration and the biofilm formation. They can also modulate the AI-2 concentration when they were co-cultured with reporter cells. It can be envisioned that this system will become useful tools in synthetic biology and researching new antimicrobials.

  6. LuxS-independent formation of AI-2 from ribulose-5-phosphate

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    Hardie Kim R

    2008-06-01

    Full Text Available Abstract Background In many bacteria, the signal molecule AI-2 is generated from its precursor S-ribosyl-L-homocysteine in a reaction catalysed by the enzyme LuxS. However, generation of AI-2-like activity has also been reported for organisms lacking the luxS gene and the existence of alternative pathways for AI-2 formation in Escherichia coli has recently been predicted by stochastic modelling. Here, we investigate the possibility that spontaneous conversion of ribulose-5-phosphate could be responsible for AI-2 generation in the absence of luxS. Results Buffered solutions of ribulose-5-phosphate, but not ribose-5-phosphate, were found to contain high levels of AI-2 activity following incubation at concentrations similar to those reported in vivo. To test whether this process contributes to AI-2 formation by bacterial cells in vivo, an improved Vibrio harveyi bioassay was used. In agreement with previous studies, culture supernatants of E. coli and Staphylococcus aureus luxS mutants were found not to contain detectable levels of AI-2 activity. However, low activities were detected in an E. coli pgi-eda-edd-luxS mutant, a strain which degrades glucose entirely via the oxidative pentose phosphate pathway, with ribulose-5-phosphate as an obligatory intermediate. Conclusion Our results suggest that LuxS-independent formation of AI-2, via spontaneous conversion of ribulose-5-phosphate, may indeed occur in vivo. It does not contribute to AI-2 formation in wildtype E. coli and S. aureus under the conditions tested, but may be responsible for the AI-2-like activities reported for other organisms lacking the luxS gene.

  7. Integration of AI-2 Based Cell-Cell Signaling with Metabolic Cues in Escherichia coli.

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    Arindam Mitra

    Full Text Available The quorum sensing molecule Autoinducer-2 (AI-2 is generated as a byproduct of activated methyl cycle by the action of LuxS in Escherichia coli. AI-2 is synthesized, released and later internalized in a cell-density dependent manner. Here, by mutational analysis of the genes, uvrY and csrA, we describe a regulatory circuit of accumulation and uptake of AI-2. We constructed a single-copy chromosomal luxS-lacZ fusion in a luxS + merodiploid strain and evaluated its relative expression in uvrY and csrA mutants. At the entry of stationary phase, the expression of the fusion and AI-2 accumulation was positively regulated by uvrY and negatively regulated by csrA respectively. A deletion of csrA altered message stability of the luxS transcript and CsrA protein exhibited weak binding to 5' luxS regulatory region. DNA protein interaction and chromatin immunoprecipitation analysis confirmed direct interaction of UvrY with the luxS promoter. Additionally, reduced expression of the fusion in hfq deletion mutant suggested involvement of small RNA interactions in luxS regulation. In contrast, the expression of lsrA operon involved in AI-2 uptake, is negatively regulated by uvrY and positively by csrA in a cell-density dependent manner. The dual role of csrA in AI-2 synthesis and uptake suggested a regulatory crosstalk of cell signaling with carbon regulation in Escherichia coli. We found that the cAMP-CRP mediated catabolite repression of luxS expression was uvrY dependent. This study suggests that luxS expression is complex and regulated at the level of transcription and translation. The multifactorial regulation supports the notion that cell-cell communication requires interaction and integration of multiple metabolic signals.

  8. AI-2 of Aggregatibacter actinomycetemcomitans Inhibits Candida albicans Biofilm Formation

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    Endang W. Bachtiar

    2014-07-01

    Full Text Available Aggregatibacter actinomycetemcomitans, a Gram-negative bacterium, and Candida albicans, a polymorphic fungus, are both commensals of the oral cavity but both are opportunistic pathogens that can cause oral diseases. A. actinomycetemcomitans produces a quorum-sensing molecule called autoinducer-2 (AI-2, synthesized by LuxS, that plays an important role in expression of virulence factors, in intra- but also in interspecies communication. The aim of this study was to investigate the role of AI-2 based signaling in the interactions between C. albicans and A. actinomycetemcomitans. A. actinomycetemcomitans adhered to C. albicans and inhibited biofilm formation by means of a molecule that was secreted during growth. C. albicans biofilm formation increased significantly when co-cultured with A. actinomycetemcomitans luxS, lacking AI-2 production. Addition of wild-type-derived spent medium or synthetic AI-2 to spent medium of the luxS strain, restored inhibition of C. albicans biofilm formation to wild-type levels. Addition of synthetic AI-2 significantly inhibited hypha formation of C. albicans possibly explaining the inhibition of biofilm formation. AI-2 of A. actinomycetemcomitans is synthesized by LuxS, accumulates during growth and inhibits C. albicans hypha- and biofilm formation. Identifying the molecular mechanisms underlying the interaction between bacteria and fungi may provide important insight into the balance within complex oral microbial communities.

  9. Recent progresses on AI-2 bacterial quorum sensing inhibitors.

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    Zhu, Peng; Li, Minyong

    2012-01-01

    Quorum sensing (QS) is a communication procedure that predominates gene expression in response to cell density and fluctuations in the neighboring environment as a result of discerning molecules termed autoinducers (AIs). It has been embroiled that QS can govern bacterial behaviors such as the secretion of virulence factors, biofilm formation, bioluminescence production, conjugation, sporulation and swarming motility. Autoinducer 2 (AI-2), a QS signaling molecule brought up to be involved in interspecies communication, exists in both gram-negative and -positive bacteria. Therefore, novel approaches to interrupt AI-2 quorum sensing are being recognized as next generation antimicrobials. In the present review article, we summarized recent progresses on AI-2 bacterial quorum sensing inhibitors and discussed their potential as the antibacterial agents.

  10. Altering the communication networks of multispecies microbial systems using a diverse toolbox of AI-2 analogues.

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    Gamby, Sonja; Roy, Varnika; Guo, Min; Smith, Jacqueline A I; Wang, Jingxin; Stewart, Jessica E; Wang, Xiao; Bentley, William E; Sintim, Herman O

    2012-06-15

    There have been intensive efforts to find small molecule antagonists for bacterial quorum sensing (QS) mediated by the "universal" QS autoinducer, AI-2. Previous work has shown that linear and branched acyl analogues of AI-2 can selectively modulate AI-2 signaling in bacteria. Additionally, LsrK-dependent phosphorylated analogues have been implicated as the active inhibitory form against AI-2 signaling. We used these observations to synthesize an expanded and diverse array of AI-2 analogues, which included aromatic as well as cyclic C-1-alkyl analogues. Species-specific analogues that disrupted AI-2 signaling in Escherichia coli and Salmonella typhimurium were identified. Similarly, analogues that disrupted QS behaviors in Pseudomonas aeruginosa were found. Moreover, we observed a strong correlation between LsrK-dependent phosphorylation of these acyl analogues and their ability to suppress QS. Significantly, we demonstrate that these analogues can selectively antagonize QS in single bacterial strains in a physiologically relevant polymicrobial culture.

  11. Activity of autoinducer two (AI-2) in bacteria isolated from surface ripened cheeses

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    Gori, Klaus; Jespersen, Lene

    A large number of Gram-positive and Gram-negative bacteria have been found to produce the signaling molecule autoinducer two (AI-2), which is used for interspecies communication. In this study, AI-2 activity was for the first time determined in Arthrobacter nicotianae, Brevibacterium linens (BL2......). Corynebacterium casei, Microbacterium barkeri, Microbacterium gubbeenense and S. equorum subsp. linens (all isolated from the smear of surface ripened cheeses) using the AI-2 bioluminescence assay. This indicates that AI-2 signaling could take place between bacteria found in the smear of surface ripened cheeses....

  12. Coevolution of paired receptors in Xenopus carcinoembryonic antigen-related cell adhesion molecule families suggests appropriation as pathogen receptors.

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    Zimmermann, Wolfgang; Kammerer, Robert

    2016-11-16

    In mammals, CEACAM1 and closely related members represent paired receptors with similar extracellular ligand-binding regions and cytoplasmic domains with opposing functions. Human CEACAM1 and CEACAM3 which have inhibitory ITIM/ITSM and activating ITAM-like motifs, respectively, in their cytoplasmic regions are such paired receptors. Various bacterial pathogens bind to CEACAM1 on epithelial and immune cells facilitating both entry into the host and down-regulation of the immune response whereas interaction with granulocyte-specific CEACAM3 leads to their uptake and destruction. It is unclear whether paired CEACAM receptors also exist in other vertebrate clades. We identified more than 80 ceacam genes in Xenopus tropicalis and X. laevis. They consist of two subgroups containing one or two putative paired receptor pairs each. Analysis of genomic sequences of paired receptors provide evidence that their highly similar ligand binding domains were adjusted by recent gene conversion events. In contrast, selection for diversification is observed among inhibitory receptor orthologs of the two frogs which split some 60 million years ago. The allotetraploid X. laevis arose later by hybridization of two closely related species. Interestingly, despite the conservation of the genomic landscape surrounding the homeologous ceacam loci only one locus resembles the one found in X. tropicalis. From the second X. laevis locus more than 80 % of the ceacam genes were lost including 5 of the 6 paired receptor genes. This suggests that once the gene for one of the paired receptors is lost the remaining gene cluster degrades rapidly probably due to lack of selection pressure exerted by pathogens. The presence of paired receptors and selection for diversification suggests that also in amphibians CEACAM1-related inhibitory proteins are or were used as pathogen receptors.

  13. Regulation of Yersina pestis Virulence by AI-2 Mediated Quorum Sensing

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    Segelke, B; Hok, S; Lao, V; Corzett, M; Garcia, E

    2010-03-29

    The proposed research was motivated by an interest in understanding Y. pestis virulence mechanisms and bacteria cell-cell communication. It is expected that a greater understanding of virulence mechanisms will ultimately lead to biothreat countermeasures and novel therapeutics. Y. pestis is the etiological agent of plague, the most devastating disease in human history. Y. pestis infection has a high mortality rate and a short incubation before mortality. There is no widely available and effective vaccine for Y. pestis and multi-drug resistant strains are emerging. Y. pestis is a recognized biothreat agent based on the wide distribution of the bacteria in research laboratories around the world and on the knowledge that methods exist to produce and aerosolize large amounts of bacteria. We hypothesized that cell-cell communication via signaling molecules, or quorum sensing, by Y. pestis is important for the regulation of virulence factor gene expression during host invasion, though a causative link had never been established. Quorum sensing is a mode of intercellular communication which enables orchestration of gene expression for many bacteria as a function of population density and available evidence suggests there may be a link between quorum sensing and regulation of Y. pesits virulence. Several pathogenic bacteria have been shown to regulate expression of virulence factor genes, including genes encoding type III secretion, via quorum sensing. The Y. pestis genome encodes several cell-cell signaling pathways and the interaction of at least three of these are thought to be involved in one or more modes of host invasion. Furthermore, Y. pestis gene expression array studies carried out at LLNL have established a correlation between expression of known virulence factors and genes involved in processing of the AI-2 quorum sensing signal. This was a basic research project that was intended to provide new insights into bacterial intercellular communication and how it is

  14. Activity of autoinducer two (AI-2) in bacteria isolated from surface ripened cheeses

    DEFF Research Database (Denmark)

    Gori, Klaus; Jespersen, Lene

    2007-01-01

    ). Corynebacterium casei, Microbacterium barkeri, Microbacterium gubbeenense and S. equorum subsp. linens (all isolated from the smear of surface ripened cheeses) using the AI-2 bioluminescence assay. This indicates that AI-2 signaling could take place between bacteria found in the smear of surface ripened cheeses....

  15. LuxS/AI-2 system is involved in antibiotic susceptibility and autolysis in Staphylococcus aureus NCTC 8325.

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    Xue, Ting; Zhao, Liping; Sun, Baolin

    2013-01-01

    Current treatment for Staphylococcus aureus infections relies heavily upon the cell wall synthesis inhibitor antibiotics such as penicillin, oxacillin, vancomycin and teicoplanin. Increasing antibiotic resistance requires the development of new approaches to combating infection. Autoinducer-2 (AI-2) exists widely both in Gram-negative and Gram-positive pathogens and is suggested as a universal language for intraspecies and interspecies communication. This study demonstrates the association between AI-2 signalling and cell wall synthesis inhibitor antibiotic susceptibility in S. aureus. In addition, a luxS mutant exhibited decreased autolysis and upregulated vancomycin resistance-associated VraRS two-component regulatory system. This finding may provide novel clues for antimicrobial therapy in S. aureus infection. Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  16. Functional analysis of the group A streptococcal luxS/AI-2 system in metabolism, adaptation to stress and interaction with host cells

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    Zinkl Daniela

    2008-10-01

    Full Text Available Abstract Background The luxS/AI-2 signaling pathway has been reported to interfere with important physiological and pathogenic functions in a variety of bacteria. In the present study, we investigated the functional role of the streptococcal luxS/AI-2 system in metabolism and diverse aspects of pathogenicity including the adaptation of the organism to stress conditions using two serotypes of Streptococcus pyogenes, M1 and M19. Results Exposing wild-type and isogenic luxS-deficient strains to sulfur-limited media suggested a limited role for luxS in streptococcal activated methyl cycle metabolism. Interestingly, loss of luxS led to an increased acid tolerance in both serotypes. Accordingly, luxS expression and AI-2 production were reduced at lower pH, thus linking the luxS/AI-2 system to stress adaptation in S. pyogenes. luxS expression and AI-2 production also decreased when cells were grown in RPMI medium supplemented with 10% serum, considered to be a host environment-mimicking medium. Furthermore, interaction analysis with epithelial cells and macrophages showed a clear advantage of the luxS-deficient mutants to be internalized and survive intracellularly in the host cells compared to the wild-type parents. In addition, our data revealed that luxS influences the expression of two virulence-associated factors, the fasX regulatory RNA and the virulence gene sibA (psp. Conclusion Here, we suggest that the group A streptococcal luxS/AI-2 system is not only involved in the regulation of virulence factor expression but in addition low level of luxS expression seems to provide an advantage for bacterial survival in conditions that can be encountered during infections.

  17. Small Molecule Inhibitors of AI-2 Signaling in Bacteria: State-of-the-Art and Future Perspectives for Anti-Quorum Sensing Agents

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    Guo, Min; Gamby, Sonja; Zheng, Yue; Sintim, Herman O.

    2013-01-01

    Bacteria respond to different small molecules that are produced by other neighboring bacteria. These molecules, called autoinducers, are classified as intraspecies (i.e., molecules produced and perceived by the same bacterial species) or interspecies (molecules that are produced and sensed between different bacterial species). AI-2 has been proposed as an interspecies autoinducer and has been shown to regulate different bacterial physiology as well as affect virulence factor production and biofilm formation in some bacteria, including bacteria of clinical relevance. Several groups have embarked on the development of small molecules that could be used to perturb AI-2 signaling in bacteria, with the ultimate goal that these molecules could be used to inhibit bacterial virulence and biofilm formation. Additionally, these molecules have the potential to be used in synthetic biology applications whereby these small molecules are used as inputs to switch on and off AI-2 receptors. In this review, we highlight the state-of-the-art in the development of small molecules that perturb AI-2 signaling in bacteria and offer our perspective on the future development and applications of these classes of molecules. PMID:23994835

  18. AIS>2 in at least two body regions: a potential new anatomical definition of polytrauma.

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    Butcher, Nerida; Balogh, Zsolt J

    2012-02-01

    The term 'polytrauma' lacks a universally accepted, validated definition. In clinical trials the commonly applied injury severity based anatomical score cut-offs are ISS > 15, ISS > 17 and a recently recommended AIS > 2 in at least two body regions (2 × AIS > 2). To compare the outcomes of clinically defined polytrauma patients with those defined based on anatomical scores. A prospective observational study on all trauma team activation patients over a 7-month period presenting at a level-1 trauma centre were included in the study. The prospective data collection included AIS in each body region, ISS, ICU length of stay (LOS), multiple organ failure (MOF) and mortality. 336 patients met inclusion criteria (age: 41 ± 20, 74% male, ISS: 15 ± 11, NISS: 19 ± 15, MOF: 3%, mortality: 4%, 25% ICU admission). ISS > 15: 13 deaths (10%), 71 (54%) required ICU admission and 10 (8%) developed MOF. ISS > 17 captured 11 deaths (11%), with 63 (62%) requiring ICU admission and 10 (10%) developing MOF. Defining as (2 × AIS > 2): 8 deaths (13% of the group), with 43 patients requiring ICU admission (67%) and 9 (14%) developing MOF. When examining the performance of these three approaches, the ISS > 15 and the ISS > 17 captured statistically the same amount of clinically defined polytrauma patients (p = 0.4106), while the 2 × AIS > 2 definition captured significantly more polytrauma patients than ISS > 15 (p = 0.0251) and ISS > 17 (p = 0.0019). 2 × AIS > 2 captured the greatest percentage of the worst outcomes and significantly larger % of the clinically defined polytrauma patients. 2 × AIS > 2 has higher accuracy and precision in defining polytrauma than ISS > 15 and ISS > 17. This simple, retrospectively also reproducible criteria warrants larger scale validation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. AI-2 signalling is induced by acidic shock in probiotic strains of Lactobacillus spp.

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    Moslehi-Jenabian, Saloomeh; Gori, Klaus; Jespersen, Lene

    2009-11-15

    Survival and ability to respond to various environmental stresses such as low pH are important factors for lactobacilli for their function as probiotics. LuxS-mediated quorum sensing mechanism, which is based on the production of universal signal molecule called autoinducer-2 (AI-2), regulates important physiological traits and a variety of adaptive processes in different bacteria. The aim of this study was to investigate the effect of acidic stress on LuxS-mediated quorum sensing (AI-2 signalling) in four probiotic strains of different Lactobacillus species. Initially, the production of AI-2-like molecule was investigated in four strains of Lactobacillus spp. at standard growth conditions using Vibrio harveyi bioluminescence assay. Species variation in AI-2 activity was observed. AI-2 activity started at early-exponential growth phase and increased during the mid-exponential phase concomitant with the reduction of pH, reaching maximum at late exponential phase (L. rhamnosus GG) or at stationary phase (L. salivarius UCC118, L. acidophilus NCFM and L. johnsonii NCC533). Acidic shock experiments were conducted on L. rhamnosus GG and L. acidophilus NCFM after exposure to different acidic shocks (pH 5.0, 4.0 and 3.0) and to pH 6.5 as control, measuring AI-2 activity and transcription of the luxS gene. AI-2 activity increased by lowering the pH in a dose dependent manner and was negatively influenced by acid adaptation. In both species, the luxS gene was repressed after exposure to pH 6.5 as control. However, after acidic shock (pH 4.0) a transient response of luxS gene was observed and the transcription augmented over time, reaching a maximum level and decreased subsequently. Acid adaptation of cells attenuated the transcription of this gene. Based on the observations done in the present study, the luxS gene appears to have a clear role in acidic stress response in probiotic lactobacilli. This might be important in the survival of these bacteria during the passage

  20. Processing the Interspecies Quorum-sensing Signal Autoinducer-2 (AI-2)

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    J Marques; P Lamosa; C Russell; R Ventura; C Maycock; M Semmelhack; S Miller; K Xavier

    2011-12-31

    The molecule (S)-4,5-dihydroxy-2,3-pentanedione (DPD) is produced by many different species of bacteria and is the precursor of the signal molecule autoinducer-2 (AI-2). AI-2 mediates interspecies communication and facilitates regulation of bacterial behaviors such as biofilm formation and virulence. A variety of bacterial species have the ability to sequester and process the AI-2 present in their environment, thereby interfering with the cell-cell communication of other bacteria. This process involves the AI-2-regulated lsr operon, comprised of the Lsr transport system that facilitates uptake of the signal, a kinase that phosphorylates the signal to phospho-DPD (P-DPD), and enzymes (like LsrG) that are responsible for processing the phosphorylated signal. Because P-DPD is the intracellular inducer of the lsr operon, enzymes involved in P-DPD processing impact the levels of Lsr expression. Here we show that LsrG catalyzes isomerization of P-DPD into 3,4,4-trihydroxy-2-pentanone-5-phosphate. We present the crystal structure of LsrG, identify potential catalytic residues, and determine which of these residues affects P-DPD processing in vivo and in vitro. We also show that an lsrG deletion mutant accumulates at least 10 times more P-DPD than wild type cells. Consistent with this result, we find that the lsrG mutant has increased expression of the lsr operon and an altered profile of AI-2 accumulation and removal. Understanding of the biochemical mechanisms employed by bacteria to quench signaling of other species can be of great utility in the development of therapies to control bacterial behavior.

  1. Peroxisome proliferator-activated receptor α activation induces hepatic steatosis, suggesting an adverse effect.

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    Fang Yan

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is characterized by hepatic triglyceride accumulation, ranging from steatosis to steatohepatitis and cirrhosis. NAFLD is a risk factor for cardiovascular diseases and is associated with metabolic syndrome. Antihyperlipidemic drugs are recommended as part of the treatment for NAFLD patients. Although fibrates activate peroxisome proliferator-activated receptor α (PPARα, leading to the reduction of serum triglyceride levels, the effects of these drugs on NAFLD remain controversial. Clinical studies have reported that PPARα activation does not improve hepatic steatosis. In the present study, we focused on exploring the effect and mechanism of PPARα activation on hepatic triglyceride accumulation and hepatic steatosis. Male C57BL/6J mice, Pparα-null mice and HepG2 cells were treated with fenofibrate, one of the most commonly used fibrate drugs. Both low and high doses of fenofibrate were administered. Hepatic steatosis was detected through oil red O staining and electron microscopy. Notably, in fenofibrate-treated mice, the serum triglyceride levels were reduced and the hepatic triglyceride content was increased in a dose-dependent manner. Oil red O staining of liver sections demonstrated that fenofibrate-fed mice accumulated abundant neutral lipids. Fenofibrate also increased the intracellular triglyceride content in HepG2 cells. The expression of sterol regulatory element-binding protein 1c (SREBP-1c and the key genes associated with lipogenesis were increased in fenofibrate-treated mouse livers and HepG2 cells in a dose-dependent manner. However, the effect was strongly impaired in Pparα-null mice treated with fenofibrate. Fenofibrate treatment induced mature SREBP-1c expression via the direct binding of PPARα to the DR1 motif of the SREBP-1c gene. Taken together, these findings indicate the molecular mechanism by which PPARα activation increases liver triglyceride accumulation and suggest an

  2. Conditioned medium from Listeria innocua stimulates emergence from a resting state: not a response to E. coli quorum sensing autoinducer AI-2.

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    Yang, Li; Portugal, Frank; Bentley, William E

    2006-01-01

    The lag phase of the bacterial growth curve is an important determinant in speeding the detection of pathogens. It is affected by many factors including the prevailing growth environment and inoculum size, as well as specific signal molecules. The elucidation of growth-regulating signal molecules is further facilitated by culturing cells in defined growth media. In this study, a defined medium capable of supporting growth of Listeria innocua at similar levels as obtained using a complex brain heart infusion (BHI) media was developed. Further, the effects of conditioned medium (CM) on population lag time of L. innocua was investigated using a rapid parallel approach (with an automated microtiter plate reader). Importantly, the lag phase was shortened by up to approximately 50% by the addition of CM from L. innocua cultures obtained late in the exponential phase. Finally, while L. innocua were found to secrete bacterial signaling autoinducer, AI-2, tests using Escherichia coli based CM having a 90-fold difference in AI-2 level suggested that the observed decrease in lag phase was not due to E. coli-derived AI-2 and was instead due to elements specific to L. innocua. These findings indicate secreted signal molecules may be found in CM that speed detection of L. innocua.

  3. Anti-Inflammatory Chromatinscape Suggests Alternative Mechanisms of Glucocorticoid Receptor Action.

    Science.gov (United States)

    Oh, Kyu-Seon; Patel, Heta; Gottschalk, Rachel A; Lee, Wai Shing; Baek, Songjoon; Fraser, Iain D C; Hager, Gordon L; Sung, Myong-Hee

    2017-08-15

    Despite the widespread use of glucocorticoids (GCs), their anti-inflammatory effects are not understood mechanistically. Numerous investigations have examined the effects of glucocorticoid receptor (GR) activation prior to inflammatory challenges. However, clinical situations are emulated by a GC intervention initiated in the midst of rampant inflammatory responses. To characterize the effects of a late GC treatment, we profiled macrophage transcriptional and chromatinscapes with Dexamethasone (Dex) treatment before or after stimulation by lipopolysaccharide (LPS). The late activation of GR had a similar gene-expression profile as from GR pre-activation, while ameliorating the disruption of metabolic genes. Chromatin occupancy of GR was not predictive of Dex-regulated gene expression, contradicting the "trans-repression by tethering" model. Rather, GR activation resulted in genome-wide blockade of NF-κB interaction with chromatin and directly induced inhibitors of NF-κB and AP-1. Our investigation using GC treatments with clinically relevant timing highlights mechanisms underlying GR actions for modulating the "inflamed epigenome." Published by Elsevier Inc.

  4. Effects of aniracetam after LTP induction are suggestive of interactions on the kinetics of the AMPA receptor channel.

    Science.gov (United States)

    Kolta, A; Lynch, G; Ambros-Ingerson, J

    1998-03-30

    The modulatory influence of aniracetam, a drug which reversibly modifies the kinetic properties of AMPA-type glutamate receptors, on synaptic responses is reported to be detectably changed by the induction of long-term potentiation (LTP). The present study used hippocampal slices to examine three issues arising from this result. First, possible contributions of inhibitory currents and postsynaptic spiking to the aniracetam/LTP interaction were investigated with infusions of GABA receptor antagonists and topical applications of tetrodotoxin. Second, tests were carried out to determine if the altered response to aniracetam is sufficiently persistent to be a plausible substrate for the extremely stable LTP effect. Third, the nature of the change responsible for the aniracetam/LTP interaction was explored with waveform analyses and a kinetic model of the AMPA receptor. The following results were obtained. LTP reduced the effect of aniracetam on the amplitude but increased its effect on the decay time constant of field EPSPs recorded under conditions in which local spiking and inhibitory responses were blocked. The LTP-induced change in the effect of aniracetam was extremely stable in that it was still evident 75 min after induction of potentiation. Finally, the waveform distortions introduced by LTP and aniracetam could be corrected by uniform stretching of the responses, suggesting that the changes introduced by each of the manipulations are unitary in nature. These distortions and the interactions between them could be reproduced in the AMPA receptor model by representing LTP as an acceleration of channel gating kinetics. Copyright 1998 Elsevier Science B.V.

  5. Structure of Epstein-Barr Virus Glycoprotein 42 Suggests a Mechanism for Triggering Receptor-Activated Virus Entry

    Energy Technology Data Exchange (ETDEWEB)

    Kirschner, Austin N.; Sorem, Jessica; Longnecker, Richard; Jardetzky, Theodore S.; (NWU); (Stanford-MED)

    2009-05-26

    Epstein-Barr virus requires glycoproteins gH/gL, gB, and gp42 to fuse its lipid envelope with B cells. Gp42 is a type II membrane protein consisting of a flexible N-terminal region, which binds gH/gL, and a C-terminal lectin-like domain that binds to the B-cell entry receptor human leukocyte antigen (HLA) class II. Gp42 triggers membrane fusion after HLA binding, a process that requires simultaneous binding to gH/gL and a functional hydrophobic pocket in the lectin domain adjacent to the HLA binding site. Here we present the structure of gp42 in its unbound form. Comparisons to the previously determined structure of a gp42:HLA complex reveals additional N-terminal residues forming part of the gH/gL binding site and structural changes in the receptor binding domain. Although the core of the lectin domain remains similar, significant shifts in two loops and an {alpha} helix bordering the essential hydrophobic pocket suggest a structural mechanism for triggering fusion.

  6. AI-2 does not function as a quorum sensing molecule in Campylobacter jejuni during exponential growth in vitro

    Directory of Open Access Journals (Sweden)

    Winzer Klaus

    2009-10-01

    Full Text Available Abstract Background Campylobacter jejuni contains a homologue of the luxS gene shown to be responsible for the production of the signalling molecule autoinducer-2 (AI-2 in Vibrio harveyi and Vibrio cholerae. The aim of this study was to determine whether AI-2 acted as a diffusible quorum sensing signal controlling C. jejuni gene expression when it is produced at high levels during mid exponential growth phase. Results AI-2 activity was produced by the parental strain NCTC 11168 when grown in rich Mueller-Hinton broth (MHB as expected, but interestingly was not present in defined Modified Eagles Medium (MEM-α. Consistent with previous studies, the luxS mutant showed comparable growth rates to the parental strain and exhibited decreased motility halos in both MEM-α and MHB. Microarray analysis of genes differentially expressed in wild type and luxS mutant strains showed that many effects on mRNA transcript abundance were dependent on the growth medium and linked to metabolic functions including methionine metabolism. Addition of exogenously produced AI-2 to the wild type and the luxS mutant, growing exponentially in either MHB or MEM-α did not induce any transcriptional changes as analysed by microarray. Conclusion Taken together these results led us to conclude that there is no evidence for the role of AI-2 in cell-to-cell communication in C. jejuni strain NCTC 11168 under the growth conditions used, and that the effects of the luxS mutation on the transcriptome are related to the consequential loss of function in the activated methyl cycle.

  7. Development of a robust mapping between AIS 2+ and ICD-9 injury codes.

    Science.gov (United States)

    Barnard, Ryan T; Loftis, Kathryn L; Martin, R Shayn; Stitzel, Joel D

    2013-03-01

    Motor vehicle crashes result in millions of injuries and thousands of deaths each year in the United States. While most crash research datasets use Abbreviated Injury Scale (AIS) codes to identify injuries, most hospital datasets use the International Classification of Diseases, version 9 (ICD-9) codes. The objective of this research was to establish a one-to-one mapping between AIS and ICD-9 codes for use with motor vehicle crash injury research. This paper presents results from investigating different mapping approaches using the most common AIS 2+ injuries from the National Automotive Sampling System-Crashworthiness Data System (NASS-CDS). The mapping approaches were generated from the National Trauma Data Bank (NTDB) (428,637 code pairs), ICDMAP (2500 code pairs), and the Crash Injury Research and Engineering Network (CIREN) (4125 code pairs). Each approach may pair given AIS code with more than one ICD-9 code (mean number of pairs per AIS code: NTDB=211, ICDMAP=7, CIREN=5), and some of the potential pairs are unrelated. The mappings were evaluated using two comparative metrics coupled with qualitative inspection by an expert physician. Based on the number of false mappings and correct pairs, the best mapping was derived from CIREN. AIS and ICD-9 codes in CIREN are both manually coded, leading to more proper mappings between the two. Using the mapping presented herein, data from crash and hospital datasets can be used together to better understand and prevent motor vehicle crash injuries in the future. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Reconstitution of Torso signaling in cultured cells suggests a role for both Trunk and Torso-like in receptor activation.

    Science.gov (United States)

    Amarnath, Smita; Stevens, Leslie M; Stein, David S

    2017-02-15

    Formation of the Drosophila embryonic termini is controlled by the localized activation of the receptor tyrosine kinase Torso. Both Torso and Torso's presumed ligand, Trunk, are expressed uniformly in the early embryo. Polar activation of Torso requires Torso-like, which is expressed by follicle cells adjacent to the ends of the developing oocyte. We find that Torso expressed at high levels in cultured Drosophila cells is activated by individual application of Trunk, Torso-like or another known Torso ligand, Prothoracicotropic Hormone. In addition to assays of downstream signaling activity, Torso dimerization was detected using bimolecular fluorescence complementation. Trunk and Torso-like were active when co-transfected with Torso and when presented to Torso-expressing cells in conditioned medium. Trunk and Torso-like were also taken up from conditioned medium specifically by cells expressing Torso. At low levels of Torso, similar to those present in the embryo, Trunk and Torso-like alone were ineffective but acted synergistically to stimulate Torso signaling. Our results suggest that Torso interacts with both Trunk and Torso-like, which cooperate to mediate dimerization and activation of Torso at the ends of the Drosophila embryo. © 2017. Published by The Company of Biologists Ltd.

  9. AI-2 signalling is induced by acidic shock in probiotic strains of Lactobacillus spp

    DEFF Research Database (Denmark)

    Moslehi Jenabian, Saloomeh; Gori, Klaus; Jespersen, Lene

    2009-01-01

    Survival and ability to respond to various environmental stresses such as low pH are important factors for lactobacilli for their function as probiotics. LuxS-mediated quorum sensing mechanism, which is based on the production of universal signal molecule called autoinducer-2 (AI-2), regulates...... study, the luxS gene appears to have a clear role in acidic stress response in probiotic lactobacilli. This might be important in the survival of these bacteria during the passage through the gastrointestinal tract, and further influence the cell-to-cell communication among bacteria in the intestinal...

  10. Analysis and modeling of heat-labile enterotoxins of Escherichia coli suggests a novel space with insights into receptor preference.

    Science.gov (United States)

    Krishna Raja, M; Ghosh, Asit Ranjan; Vino, S; Sajitha Lulu, S

    2015-01-01

    Features of heat-labile enterotoxins of Escherichia coli which make them fit to use as novel receptors for antidiarrheals are not completely explored. Data-set of 14 different serovars of enterotoxigenic Escherichia coli producing heat-labile toxins were taken from NCBI Genbank database and used in the study. Sequence analysis showed mutations in different subunits and also at their interface residues. As these toxins lack crystallography structures, homology modeling using Modeller 9.11 led to the structural approximation for the E. coli producing heat-labile toxins. Interaction of modeled toxin subunits with proanthocyanidin, an antidiarrheal showed several strong hydrogen bonding interactions at the cost of minimized energy. The hits were subsequently characterized by molecular dynamics simulation studies to monitor their binding stabilities. This study looks into novel space where the ligand can choose the receptor preference not as a whole but as an individual subunit. Mutation at interface residues and interaction among subunits along with the binding of ligand to individual subunits would help to design a non-toxic labile toxin and also to improve the therapeutics.

  11. The expression of a novel receptor-type tyrosine phosphatase suggests a role in morphogenesis and plasticity of the nervous system

    DEFF Research Database (Denmark)

    Canoll, P D; Barnea, G; Levy, J B

    1993-01-01

    . In the adult, high levels of RPTP-beta are seen in regions of the brain where there is continued neurogenesis and neurite outgrowth. The spatial and temporal patterns of RPTP-beta expression suggest that this receptor phosphatase plays a role in morphogenesis and plasticity of the nervous system....

  12. Comprehensive Immunolocalization Studies of a Putative Serotonin Receptor from the Alimentary Canal of Aedes aegypti Larvae Suggest Its Diverse Roles in Digestion and Homeostasis.

    Directory of Open Access Journals (Sweden)

    Adelina Petrova

    Full Text Available Serotonin regulates key processes including digestion and homeostasis in insects. Serotonin effects are mediated by serotonin receptors that transduce information through initiation of second messenger signaling pathways. Lack of information on serotonin receptors associated with the alimentary canal impedes the understanding of the serotonergic role in insect physiology. To address this void, the present study has cloned and identified a putative serotonin receptor (hereafter AaSeR-1 from the alimentary canal of Aedes aegypti (yellow fever mosquito larvae. In addition to in-silico analyses of AaSeR-1 primary sequence, immunohistochemical investigations were carried out to elucidate receptor expression patterns. Specific AaSeR-1 immunofluorescence was detected in the caeca, the mid- and hindgut, including the Malpighian tubules. These findings point out not only receptor ubiquitous nature but also its involvement in regulation of different stages of nutrient processing and homeostasis. Furthermore, AaSeR-1 may mediate an array of effects through its differential expression at various cell compartments. While AaSeR-1 specific immunofluorescence was depicted in the nucleus and nucleolus of principal cells of the anterior midgut, in the posterior, analyses suggest receptor association with the plasma membrane of both principal and regenerative cells. In addition, AaSeR-1 immunofluorescence was also found in some enteroendocrine cells and in both circular and longitudinal muscles that innervate the alimentary canal. Overall, immunohistochemical analyses of AaSeR-1 expression indicate that this receptor exercises multiple roles in digestion- and homeostasis-related mechanisms.

  13. Analysis on Actinobacillus pleuropneumoniae LuxS regulated genes reveals pleiotropic roles of LuxS/AI-2 on biofilm formation, adhesion ability and iron metabolism.

    Science.gov (United States)

    Li, Lu; Xu, Zhuofei; Zhou, Yang; Li, Tingting; Sun, Lili; Chen, Huanchun; Zhou, Rui

    2011-06-01

    LuxS is an enzyme involved in the activated methyl cycle and the by-product autoinducer-2 (AI-2) was a quorum sensing signal in some species. In our previous study, the functional LuxS in AI-2 production was verified in the porcine respiratory pathogen Actinobacillus pleuropneumoniae. Enhanced biofilm formation and reduced virulence were observed in the luxS mutant. To comprehensively understand the luxS function, in this study, the transcriptional profiles were compared between the A. pleuropneumoniae luxS mutant and its parental strain in four different growth phases using microarray. Many genes associated with infection were differentially expressed. The biofilm formation genes pgaABC in the luxS mutant were up-regulated in early exponential phase, while 9 genes associated with adhesion were down-regulated in late exponential phase. A group of genes involved in iron acquisition and metabolism were regulated in four growth phases. Phenotypic investigations using luxS mutant and both genetic and chemical (AI-2) complementation on these virulence traits were performed. The results demonstrated that the luxS mutant showed enhanced biofilm formation and reduced adhesion ability and these effects were not due to lack of AI-2. But AI-2 could increase biofilm formation and adhesion of A. pleuropneumoniae independent of LuxS. Growth under iron restricted condition could be controlled by LuxS through AI-2 production. These results revealed pleiotropic roles of LuxS and AI-2 on A. pleuropneumoniae virulence traits. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Expression of hepatocyte growth factor/scatter factor and its receptor, MET, suggests roles in human embryonic organogenesis.

    Science.gov (United States)

    Kolatsi-Joannou, M; Moore, R; Winyard, P J; Woolf, A S

    1997-05-01

    Hepatocyte growth factor/scatter factor (HGF/SF) is secreted by mesenchymal cells and elicits proliferation, motility, differentiation, and morphogenesis of epithelia and other cells. These effects are mediated by binding to MET, a receptor tyrosine kinase. Genetically engineered mice lacking HGF/SF die in utero due to a failure of placental and hepatocyte differentiation, but little information exists regarding the expression of this signaling system in human development. Using reverse transcriptase-polymerase chain reaction, Western blots, and immunohistochemistry, we report that HGF/SF and MET are expressed during critical early periods of human organogenesis from 6 to 13 wk of gestation. Organs that expressed both genes included liver, metanephric kidney, intestine, and lung, each of which develop by inductive interactions between mesenchyme and epithelia. Of all organs studied, the placenta contained the highest levels of HGF/SF protein, and MET was detected in trophoblastic cells of chorionic villi as early as the 5th wk of gestation. Finally, examination of a human multicystic dysplastic kidney demonstrated that malformed, hyperproliferative tubules expressed MET, whereas HGF/SF protein was immunolocalized to the same epithelia and also to the surrounding undifferentiated cells. Hence HGF/SF might be an important growth factor in normal human embryogenesis and may additionally play a role in human organ malformations.

  15. Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding

    Energy Technology Data Exchange (ETDEWEB)

    Guu, Tom S.Y.; Liu, Zheng; Ye, Qiaozhen; Mata, Douglas A.; Li, Kunpeng; Yin, Changcheng; Zhang, Jingqiang; Tao, Yizhi Jane; (Sun Yat-Sen); (Rice); (Peking)

    2009-08-25

    Hepatitis E virus (HEV), a small, non-enveloped RNA virus in the family Hepeviridae, is associated with endemic and epidemic acute viral hepatitis in developing countries. Our 3.5-{angstrom} structure of a HEV-like particle (VLP) shows that each capsid protein contains 3 linear domains that form distinct structural elements: S, the continuous capsid; P1, 3-fold protrusions; and P2, 2-fold spikes. The S domain adopts a jelly-roll fold commonly observed in small RNA viruses. The P1 and P2 domains both adopt {beta}-barrel folds. Each domain possesses a potential polysaccharide-binding site that may function in cell-receptor binding. Sugar binding to P1 at the capsid protein interface may lead to capsid disassembly and cell entry. Structural modeling indicates that native T = 3 capsid contains flat dimers, with less curvature than those of T = 1 VLP. Our findings significantly advance the understanding of HEV molecular biology and have application to the development of vaccines and antiviral medications.

  16. The expression of a novel receptor-type tyrosine phosphatase suggests a role in morphogenesis and plasticity of the nervous system

    DEFF Research Database (Denmark)

    Canoll, P D; Barnea, G; Levy, J B

    1993-01-01

    of glial cells that play an important role during development. The immunoreactivity localizes to the radial processes of these cells, which act as guides during neuronal migration and axonal elongation. The pattern of RPTP-beta expression changes with the progression of glial cell differentiation......Analysis of the localization of receptor-type protein tyrosine phosphatase-beta (RPTP-beta) by in situ hybridization and immunocytochemistry indicates that it is predominantly expressed in the developing central nervous system (CNS). RPTP-beta is highly expressed in radial glia and other forms....... In the adult, high levels of RPTP-beta are seen in regions of the brain where there is continued neurogenesis and neurite outgrowth. The spatial and temporal patterns of RPTP-beta expression suggest that this receptor phosphatase plays a role in morphogenesis and plasticity of the nervous system....

  17. Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive–Compulsive Disorder

    Directory of Open Access Journals (Sweden)

    Michelle M. Rodriguez

    2017-05-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are the only effective pharmacological treatments for obsessive–compulsive disorder (OCD. Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C receptor agonist ((3S-3-Methyl-1-[4-(trifluoromethyl-7-benzofuranyl]-piperazine (CPD 1 with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats and non-consummatory behaviors (marble-burying and nestlet-shredding in mice that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia. The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors

  18. AI-2 quorum-sensing inhibitors affect the starvation response and reduce virulence in several Vibrio species, most likely by interfering with LuxPQ.

    Science.gov (United States)

    Brackman, Gilles; Celen, Shari; Baruah, Kartik; Bossier, Peter; Van Calenbergh, Serge; Nelis, Hans J; Coenye, Tom

    2009-12-01

    The increase of disease outbreaks caused by Vibrio species in aquatic organisms as well as in humans, together with the emergence of antibiotic resistance in Vibrio species, has led to a growing interest in alternative disease control measures. Quorum sensing (QS) is a mechanism for regulating microbial gene expression in a cell density-dependent way. While there is good evidence for the involvement of auto-inducer 2 (AI-2)-based interspecies QS in the control of virulence in multiple Vibrio species, only few inhibitors of this system are known. From the screening of a small panel of nucleoside analogues for their ability to disturb AI-2-based QS, an adenosine derivative with a p-methoxyphenylpropionamide moiety at C-3' emerged as a promising hit. Its mechanism of inhibition was elucidated by measuring the effect on bioluminescence in a series of Vibrio harveyi AI-2 QS mutants. Our results indicate that this compound, as well as a truncated analogue lacking the adenine base, block AI-2-based QS without interfering with bacterial growth. The active compounds affected neither the bioluminescence system as such nor the production of AI-2, but most likely interfered with the signal transduction pathway at the level of LuxPQ in V. harveyi. The most active nucleoside analogue (designated LMC-21) was found to reduce the Vibrio species starvation response, to affect biofilm formation in Vibrio anguillarum, Vibrio vulnificus and Vibrio cholerae, to reduce pigment and protease production in V. anguillarum, and to protect gnotobiotic Artemia from V. harveyi-induced mortality.

  19. Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggests Dentate Gyrus Pathology Linked to N-Methyl-D-Aspartate Receptor Hypofunction.

    Science.gov (United States)

    Kraguljac, Nina Vanessa; Carle, Matthew; Frölich, Michael A; Tran, Steve; Yassa, Michael A; White, David Matthew; Reddy, Abhishek; Lahti, Adrienne Carol

    2018-03-01

    Converging evidence from neuroimaging and postmortem studies suggests that hippocampal subfields are differentially affected in schizophrenia. Recent studies report dentate gyrus dysfunction in chronic schizophrenia, but the underlying mechanisms remain to be elucidated. Here we sought to examine if this deficit is already present in first-episode psychosis, and if N-methyl-D-aspartate receptor hypofunction, a putative central pathophysiological mechanism in schizophrenia, experimentally induced by ketamine, would result in a similar abnormality. We applied a mnemonic discrimination task selectively taxing pattern separation in two experiments: 1) a group of 23 first-episode psychosis patients and 23 matched healthy volunteers and 2) a group of 19 healthy volunteers before and during a ketamine challenge (0.27 mg/kg over 10 minutes, then 0.25 mg/kg/hour for 50 minutes, 0.01 mL/s). We calculated response bias-corrected pattern separation and recognition scores. We also examined the relationships between task performance and symptom severity as well as ketamine levels. We report a deficit in pattern separation but not recognition performance in first-episode psychosis patients compared with healthy volunteers (p = .04) and in volunteers during the ketamine challenge compared with baseline (p = .003). Exploratory analyses revealed no correlation between task performance and Repeatable Battery for the Assessment of Neuropsychological Status total scores or positive symptoms in first-episode psychosis patients, or with ketamine serum levels. We observed a mnemonic discrimination deficit but intact recognition in both datasets. Our findings suggest a tentative mechanistic link between dentate gyrus dysfunction in first-episode psychosis and N-methyl-D-aspartate receptor hypofunction. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  20. S-aryl-L-cysteine sulphoxides and related organosulphur compounds alter oral biofilm development and AI-2-based cell-cell communication.

    Science.gov (United States)

    Kasper, S H; Samarian, D; Jadhav, A P; Rickard, A H; Musah, R A; Cady, N C

    2014-11-01

    To design and synthesize a library of structurally related, small molecules related to homologues of compounds produced by the plant Petiveria alliacea and determine their ability to interfere with AI-2 cell-cell communication and biofilm formation by oral bacteria. Many human diseases are associated with persistent bacterial biofilms. Oral biofilms (dental plaque) are problematic as they are often associated with tooth decay, periodontal disease and systemic disorders such as heart disease and diabetes. Using a microplate-based approach, a bio-inspired small molecule library was screened for anti-biofilm activity against the oral species Streptococcus mutans UA159, Streptococcus sanguis 10556 and Actinomyces oris MG1. To complement the static screen, a flow-based BioFlux microfluidic system screen was also performed under conditions representative of the human oral cavity. Several compounds were found to display biofilm inhibitory activity in all three of the oral bacteria tested. These compounds were also shown to inhibit bioluminescence by Vibrio harveyi and were thus inferred to be quorum sensing (QS) inhibitors. Due to the structural similarity of these compounds to each other, and to key molecules in AI-2 biosynthetic pathways, we propose that these molecules potentially reduce biofilm formation via antagonism of QS or QS-related pathways. This study highlights the potential for a non-antimicrobial-based strategy, focused on AI-2 cell-cell signalling, to control the development of dental plaque. Considering that many bacterial species use AI-2 cell-cell signalling, as well as the increased concern of the use of antimicrobials in healthcare products, such an anti-biofilm approach could also be used to control biofilms in environments beyond the human oral cavity. © 2014 The Society for Applied Microbiology.

  1. Oxidative burst and nitric oxide responses in carp macrophages induced by zymosan, MacroGard® and selective dectin-1 agonists suggest recognition by multiple pattern recognition receptors

    DEFF Research Database (Denmark)

    Pietretti, D.; Jiménez, Natalia Ivonne Vera; Hoole, D.

    2013-01-01

    β-Glucans are glucose polymers that are found in the cell walls of plants, bacteria, certain fungi, mushrooms and the cell wall of baker's yeast. In mammals, myeloid cells express several receptors capable of recognizing β-glucans, with the C-type lectin receptor dectin-1 in conjunction with Toll...

  2. Oxidative and nitric oxide responses in carp macrophages induced by zymosan, MacroGard and selective dectin-1 agonists suggest recognition by multiple pattern recognition receptors

    NARCIS (Netherlands)

    Pietretti, D.; Vera-Jimenez, N.I.; Hoole, D.; Wiegertjes, G.F.

    2013-01-01

    ß-Glucans are glucose polymers that are found in the cell walls of plants, bacteria, certain fungi, mushrooms and the cell wall of baker's yeast. In mammals, myeloid cells express several receptors capable of recognizing ß-glucans, with the C-type lectin receptor dectin-1 in conjunction with

  3. Immunotoxicity of nanoparticles: a computational study suggests that CNTs and C60 fullerenes might be recognized as pathogens by Toll-like receptors

    Science.gov (United States)

    Turabekova, M.; Rasulev, B.; Theodore, M.; Jackman, J.; Leszczynska, D.; Leszczynski, J.

    2014-03-01

    Over the last decade, a great deal of attention has been devoted to study the inflammatory response upon exposure to multi/single-walled carbon nanotubes (CNTs) and different fullerene derivatives. In particular, carbon nanoparticles are reported to provoke substantial inflammation in alveolar and bronchial epithelial cells, epidermal keratinocytes, cultured monocyte-macrophage cells, etc. We suggest a hypothetical model providing the potential mechanistic explanation for immune and inflammatory responses observed upon exposure to carbon nanoparticles. Specifically, we performed a theoretical study to analyze CNT and C60 fullerene interactions with the available X-ray structures of Toll-like receptors (TLRs) homo- and hetero-dimer extracellular domains. This assumption was based on the fact that similar to the known TLR ligands both CNTs and fullerenes induce, in cells, the secretion of certain inflammatory protein mediators, such as interleukins and chemokines. These proteins are observed within inflammation downstream processes resulted from the ligand molecule dependent inhibition or activation of TLR-induced signal transduction. Our computational studies have shown that the internal hydrophobic pockets of some TLRs might be capable of binding small-sized carbon nanostructures (5,5 armchair SWCNTs containing 11 carbon atom layers and C60 fullerene). High binding scores and minor structural alterations induced in TLR ectodomains upon binding C60 and CNTs further supported our hypothesis. Additionally, the proposed hypothesis is strengthened by the indirect experimental findings indicating that CNTs and fullerenes induce an excessive expression of specific cytokines and chemokines (i.e. IL-8 and MCP1).Over the last decade, a great deal of attention has been devoted to study the inflammatory response upon exposure to multi/single-walled carbon nanotubes (CNTs) and different fullerene derivatives. In particular, carbon nanoparticles are reported to provoke

  4. Restricted Cell Surface Expression of Receptor Tyrosine Kinase ROR1 in Pediatric B-Lineage Acute Lymphoblastic Leukemia Suggests Targetability with Therapeutic Monoclonal Antibodies

    Science.gov (United States)

    Dave, Hema; Anver, Miriam R.; Butcher, Donna O.; Brown, Patrick; Khan, Javed; Wayne, Alan S.; Baskar, Sivasubramanian; Rader, Christoph

    2012-01-01

    Background Despite high cure rates for pediatric B-lineage acute lymphoblastic leukemia (B-ALL), short-term and long-term toxicities and chemoresistance are shortcomings of standard chemotherapy. Immunotherapy and chemoimmunotherapy based on monoclonal antibodies (mAbs) that target cell surface antigens with restricted expression in pediatric B-ALL may offer the potential to reduce toxicities and prevent or overcome chemoresistance. The receptor tyrosine kinase ROR1 has emerged as a candidate for mAb targeting in select B-cell malignancies. Methodology and Principal Findings Using flow cytometry, Western blotting, immunohistochemistry, and confocal immunofluorescence microscopy, we analyzed the cell surface expression of ROR1 across major pediatric ALL subtypes represented by 14 cell lines and 56 primary blasts at diagnosis or relapse as well as in normal adult and pediatric tissues. Cell surface ROR1 expression was found in 45% of pediatric ALL patients, all of which were B-ALL, and was not limited to any particular genotype. All cell lines and primary blasts with E2A-PBX1 translocation and a portion of patients with other high risk genotypes, such as MLL rearrangement, expressed cell surface ROR1. Importantly, cell surface ROR1 expression was found in many of the pediatric B-ALL patients with multiply relapsed and refractory disease and normal karyotype or low risk cytogenetics, such as hyperdiploidy. Notably, cell surface ROR1 was virtually absent in normal adult and pediatric tissues. Conclusions and Significance Collectively, this study suggests that ROR1 merits preclinical and clinical investigations as a novel target for mAb-based therapies in pediatric B-ALL. We propose cell surface expression of ROR1 detected by flow cytometry as primary inclusion criterion for pediatric B-ALL patients in future clinical trials of ROR1-targeted therapies. PMID:23285131

  5. Restricted cell surface expression of receptor tyrosine kinase ROR1 in pediatric B-lineage acute lymphoblastic leukemia suggests targetability with therapeutic monoclonal antibodies.

    Directory of Open Access Journals (Sweden)

    Hema Dave

    Full Text Available Despite high cure rates for pediatric B-lineage acute lymphoblastic leukemia (B-ALL, short-term and long-term toxicities and chemoresistance are shortcomings of standard chemotherapy. Immunotherapy and chemoimmunotherapy based on monoclonal antibodies (mAbs that target cell surface antigens with restricted expression in pediatric B-ALL may offer the potential to reduce toxicities and prevent or overcome chemoresistance. The receptor tyrosine kinase ROR1 has emerged as a candidate for mAb targeting in select B-cell malignancies.Using flow cytometry, Western blotting, immunohistochemistry, and confocal immunofluorescence microscopy, we analyzed the cell surface expression of ROR1 across major pediatric ALL subtypes represented by 14 cell lines and 56 primary blasts at diagnosis or relapse as well as in normal adult and pediatric tissues. Cell surface ROR1 expression was found in 45% of pediatric ALL patients, all of which were B-ALL, and was not limited to any particular genotype. All cell lines and primary blasts with E2A-PBX1 translocation and a portion of patients with other high risk genotypes, such as MLL rearrangement, expressed cell surface ROR1. Importantly, cell surface ROR1 expression was found in many of the pediatric B-ALL patients with multiply relapsed and refractory disease and normal karyotype or low risk cytogenetics, such as hyperdiploidy. Notably, cell surface ROR1 was virtually absent in normal adult and pediatric tissues.Collectively, this study suggests that ROR1 merits preclinical and clinical investigations as a novel target for mAb-based therapies in pediatric B-ALL. We propose cell surface expression of ROR1 detected by flow cytometry as primary inclusion criterion for pediatric B-ALL patients in future clinical trials of ROR1-targeted therapies.

  6. Stopping AI-2 chatter by means of an indigenous bacterium ( Acinetobacter sp. DKY-1): A new anti-biofouling strategy in an MBR for wastewater treatment.

    Science.gov (United States)

    Lee, Kibaek; Kim, Yea-Won; Lee, Seonki; Lee, Sang Hyun; Nahm, Chang Hyun; Kwon, Hyeokpil; Park, Pyung-Kyu; Choo, Kwang-Ho; Koyuncu, Ismail; Drews, Anja; Lee, Chung-Hak; Lee, Jung-Kee

    2018-05-01

    Bacterial quorum quenching (QQ) by means of degrading signaling molecules has been applied to anti-biofouling strategy in a membrane bioreactor (MBR) for wastewater treatment. However, the target signaling molecules have been limited to N-acyl homoserine lactones participating in intra-species quorum sensing. Here, an approach to disrupt autoinducer-2 (AI-2) signaling molecules participating in inter-species quorum sensing, was pursued as a next-generation anti-biofouling strategy in an MBR for wastewater treatment. We isolated an indigenous QQ bacterium ( Acinetobacter sp. DKY-1) that can attenuate the expression of quorum sensing (QS) response through inactivation of autoinducer-2 signaling molecule, 4,5-dihydroxy-2,3-pentanedione (DPD) among four kinds of autoinducer-2 QS bacteria. DKY-1 released AI-2 QQ compound(s), which was verified to be hydrophilic with a molecular weight biofouling. This new approach, combining molecular biology with wastewater engineering, could enlarge the range of QQ-MBR for anti-biofouling and energy savings in the field of wastewater treatment.

  7. The Identification of Phytohormone Receptor Homologs in Early Diverging Fungi Suggests a Role for Plant Sensing in Land Colonization by Fungi

    Directory of Open Access Journals (Sweden)

    Anais Hérivaux

    2017-01-01

    Full Text Available Histidine kinases (HKs are among the most prominent sensing proteins studied in the kingdom Fungi. Their distribution and biological functions in early diverging fungi (EDF, however, remain elusive. We have taken advantage of recent genomic resources to elucidate whether relationships between the occurrence of specific HKs in some EDF and their respective habitat/lifestyle could be established. This led to the unexpected discovery of fungal HKs that share a high degree of similarity with receptors for plant hormones (ethylene and cytokinin. Importantly, these phytohormone receptor homologs are found not only in EDF that behave as plant root symbionts or endophytes but also in EDF species that colonize decaying plant material. We hypothesize that these particular sensing proteins promoted the interaction of EDF with plants, leading to the conquest of land by these ancestral fungi.

  8. The Identification of Phytohormone Receptor Homologs in Early Diverging Fungi Suggests a Role for Plant Sensing in Land Colonization by Fungi.

    Science.gov (United States)

    Hérivaux, Anaïs; Dugé de Bernonville, Thomas; Roux, Christophe; Clastre, Marc; Courdavault, Vincent; Gastebois, Amandine; Bouchara, Jean-Philippe; James, Timothy Y; Latgé, Jean-Paul; Martin, Francis; Papon, Nicolas

    2017-01-31

    Histidine kinases (HKs) are among the most prominent sensing proteins studied in the kingdom Fungi. Their distribution and biological functions in early diverging fungi (EDF), however, remain elusive. We have taken advantage of recent genomic resources to elucidate whether relationships between the occurrence of specific HKs in some EDF and their respective habitat/lifestyle could be established. This led to the unexpected discovery of fungal HKs that share a high degree of similarity with receptors for plant hormones (ethylene and cytokinin). Importantly, these phytohormone receptor homologs are found not only in EDF that behave as plant root symbionts or endophytes but also in EDF species that colonize decaying plant material. We hypothesize that these particular sensing proteins promoted the interaction of EDF with plants, leading to the conquest of land by these ancestral fungi. Copyright © 2017 Hérivaux et al.

  9. Residues essential for Panton-Valentine leukocidin S component binding to its cell receptor suggest both plasticity and adaptability in its interaction surface.

    Directory of Open Access Journals (Sweden)

    Benoit-Joseph Laventie

    Full Text Available Panton-Valentine leukocidin (PVL, a bicomponent staphylococcal leukotoxin, is involved in the poor prognosis of necrotizing pneumonia. The present study aimed to elucidate the binding mechanism of PVL and in particular its cell-binding domain. The class S component of PVL, LukS-PV, is known to ensure cell targeting and exhibits the highest affinity for the neutrophil membrane (Kd∼10(-10 M compared to the class F component of PVL, LukF-PV (Kd∼10(-9 M. Alanine scanning mutagenesis was used to identify the residues involved in LukS-PV binding to the neutrophil surface. Nineteen single alanine mutations were performed in the rim domain previously described as implicated in cell membrane interactions. Positions were chosen in order to replace polar or exposed charged residues and according to conservation between leukotoxin class S components. Characterization studies enabled to identify a cluster of residues essential for LukS-PV binding, localized on two loops of the rim domain. The mutations R73A, Y184A, T244A, H245A and Y250A led to dramatically reduced binding affinities for both human leukocytes and undifferentiated U937 cells expressing the C5a receptor. The three-dimensional structure of five of the mutants was determined using X-ray crystallography. Structure analysis identified residues Y184 and Y250 as crucial in providing structural flexibility in the receptor-binding domain of LukS-PV.

  10. Early postnatal maternal separation causes alterations in the expression of β3-adrenergic receptor in rat adipose tissue suggesting long-term influence on obesity

    Energy Technology Data Exchange (ETDEWEB)

    Miki, Takanori, E-mail: mikit@med.kagawa-u.ac.jp [Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University (Japan); Liu, Jun-Qian; Ohta, Ken-ichi; Suzuki, Shingo [Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University (Japan); Kusaka, Takashi [Department of Pediatrics, Faculty of Medicine, Kagawa University (Japan); Warita, Katsuhiko [Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University (Japan); Yokoyama, Toshifumi [Department of Bioresource and Agrobiosciences, Graduate School of Science and Technology, Kobe University (Japan); Jamal, Mostofa [Department of Forensic Medicine, Faculty of Medicine, Kagawa University (Japan); Ueki, Masaaki [Department of Anesthesia, Nishiwaki Municipal Hospital (Japan); Yakura, Tomiko; Tamai, Motoki [Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University (Japan); Sumitani, Kazunori [Department of Medical Education, Faculty of Medicine, Kagawa University (Japan); Hosomi, Naohisa [Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical Sciences (Japan); Takeuchi, Yoshiki [Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University (Japan)

    2013-12-06

    Highlights: •High-fat diet intake following maternal separation did not cause body weight gain. •However, levels of metabolism-related molecules in adipose tissue were altered. •Increased levels of prohibitin mRNA in white fat were observed. •Attenuated levels of β3-adrenergic receptor mRNA were observed in brown fat. •Such alterations in adipose tissue may contribute to obesity later in life. -- Abstract: The effects of early postnatal maternal deprivation on the biological characteristics of the adipose tissue later in life were investigated in the present study. Sprague–Dawley rats were classified as either maternal deprivation (MD) or mother-reared control (MRC) groups. MD was achieved by separating the rat pups from their mothers for 3 h each day during the 10–15 postnatal days. mRNA levels of mitochondrial uncoupling protein 1 (UCP-1), β3-adrenergic receptor (β3-AR), and prohibitin (PHB) in the brown and white adipose tissue were determined using real-time RT-PCR analysis. UCP-1, which is mediated through β3-AR, is closely involved in the energy metabolism and expenditure. PHB is highly expressed in the proliferating tissues/cells. At 10 weeks of age, the body weight of the MRC and MD rats was similar. However, the levels of the key molecules in the adipose tissue were substantially altered. There was a significant increase in the expression of PHB mRNA in the white adipose tissue, while the β3-AR mRNA expression decreased significantly, and the UCP-1 mRNA expression remained unchanged in the brown adipose tissue. Given that these molecules influence the mitochondrial metabolism, our study indicates that early postnatal maternal deprivation can influence the fate of adipose tissue proliferation, presumably leading to obesity later in life.

  11. Early postnatal maternal separation causes alterations in the expression of β3-adrenergic receptor in rat adipose tissue suggesting long-term influence on obesity

    International Nuclear Information System (INIS)

    Miki, Takanori; Liu, Jun-Qian; Ohta, Ken-ichi; Suzuki, Shingo; Kusaka, Takashi; Warita, Katsuhiko; Yokoyama, Toshifumi; Jamal, Mostofa; Ueki, Masaaki; Yakura, Tomiko; Tamai, Motoki; Sumitani, Kazunori; Hosomi, Naohisa; Takeuchi, Yoshiki

    2013-01-01

    Highlights: •High-fat diet intake following maternal separation did not cause body weight gain. •However, levels of metabolism-related molecules in adipose tissue were altered. •Increased levels of prohibitin mRNA in white fat were observed. •Attenuated levels of β3-adrenergic receptor mRNA were observed in brown fat. •Such alterations in adipose tissue may contribute to obesity later in life. -- Abstract: The effects of early postnatal maternal deprivation on the biological characteristics of the adipose tissue later in life were investigated in the present study. Sprague–Dawley rats were classified as either maternal deprivation (MD) or mother-reared control (MRC) groups. MD was achieved by separating the rat pups from their mothers for 3 h each day during the 10–15 postnatal days. mRNA levels of mitochondrial uncoupling protein 1 (UCP-1), β3-adrenergic receptor (β3-AR), and prohibitin (PHB) in the brown and white adipose tissue were determined using real-time RT-PCR analysis. UCP-1, which is mediated through β3-AR, is closely involved in the energy metabolism and expenditure. PHB is highly expressed in the proliferating tissues/cells. At 10 weeks of age, the body weight of the MRC and MD rats was similar. However, the levels of the key molecules in the adipose tissue were substantially altered. There was a significant increase in the expression of PHB mRNA in the white adipose tissue, while the β3-AR mRNA expression decreased significantly, and the UCP-1 mRNA expression remained unchanged in the brown adipose tissue. Given that these molecules influence the mitochondrial metabolism, our study indicates that early postnatal maternal deprivation can influence the fate of adipose tissue proliferation, presumably leading to obesity later in life

  12. Ecdysteroid receptor docking suggests that dibenzoylhydrazine-based insecticides are devoid of any deleterious effect on the parasitic wasp Psyttalia concolor (Hym. Braconidae).

    Science.gov (United States)

    Bengochea, Paloma; Christiaens, Olivier; Amor, Fermín; Viñuela, Elisa; Rougé, Pierre; Medina, Pilar; Smagghe, Guy

    2012-07-01

    The moulting accelerating compounds (MACs) or ecdysteroid agonists represent a selective group of insecticides acting upon binding to the ecdysteroid receptor (EcR) and leading to lethal premature moulting in larval stages and aborted reproduction in adults. Psyttalia concolor Szèpl. is a useful parasitic wasp attacking important tephritid pests such as the medfly and olive fruit fly. Contact and oral exposure in the laboratory of female parasitic wasps to the dibenzoylhydrazine-based methoxyfenozide, tebufenozide and RH-5849 did not provoke negative effects. No mortality and no reduction in beneficial capacity were observed. The ligand-binding domain (LBD) of the EcR of P. concolor was sequenced, and a homology protein model was constructed which confirmed a cavity structure with 12 α-helices, harbouring the natural insect moulting hormone 20-hydroxyecdysone. However, a steric clash occurred for the MAC insecticides owing to a restricted extent of the ligand-binding cavity of the PcLBD-EcR, while they did dock well in that of susceptible insects. The insect toxicity assays demonstrated that MACs are selective for P. concolor. The modelling/docking experiments are indications that these insecticides do not bind with the LBD-EcR of P. concolor and support the theory that they show no biological effects in the parasitic wasp. These data may help in explaining the compatible use of MACs together with parasitic wasps in IPM programmes. Copyright © 2012 Society of Chemical Industry.

  13. Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction.

    Science.gov (United States)

    Cunningham, Kathryn A; Anastasio, Noelle C; Fox, Robert G; Stutz, Sonja J; Bubar, Marcy J; Swinford, Sarah E; Watson, Cheryl S; Gilbertson, Scott R; Rice, Kenner C; Rosenzweig-Lipson, Sharon; Moeller, F Gerard

    2013-01-16

    Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT(2A)R antagonist M100907 plus the 5-HT(2C)R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT(2A)R antagonist plus a 5-HT(2C)R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules.

  14. Progesterone Exerts a Neuromodulatory Effect on Turning Behavior of Hemiparkinsonian Male Rats: Expression of 3α-Hydroxysteroid Oxidoreductase and Allopregnanolone as Suggestive of GABAA Receptors Involvement

    Directory of Open Access Journals (Sweden)

    Roberto Yunes

    2015-01-01

    Full Text Available There is a growing amount of evidence for a neuroprotective role of progesterone and its neuroactive metabolite, allopregnanolone, in animal models of neurodegenerative diseases. By using a model of hemiparkinsonism in male rats, injection of the neurotoxic 6-OHDA in left striatum, we studied progesterone’s effects on rotational behavior induced by amphetamine or apomorphine. Also, in order to find potential explanatory mechanisms, we studied expression and activity of nigrostriatal 3α-hydroxysteroid oxidoreductase, the enzyme that catalyzes progesterone to its active metabolite allopregnanolone. Coherently, we tested allopregnanolone for a possible neuromodulatory effect on rotational behavior. Also, since allopregnanolone is known as a GABAA modulator, we finally examined the action of GABAA antagonist bicuculline. We found that progesterone, in addition to an apparent neuroprotective effect, also increased ipsilateral expression and activity of 3α-hydroxysteroid oxidoreductase. It was interesting to note that ipsilateral administration of allopregnanolone reversed a clear sign of motor neurodegeneration, that is, contralateral rotational behavior. A possible GABAA involvement modulated by allopregnanolone was shown by the blocking effect of bicuculline. Our results suggest that early administration of progesterone possibly activates genomic mechanisms that promote neuroprotection subchronically. This, in turn, could be partially mediated by fast, nongenomic, actions of allopregnanolone acting as an acute modulator of GABAergic transmission.

  15. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  16. Hypnosis, suggestion, and suggestibility: an integrative model.

    Science.gov (United States)

    Lynn, Steven Jay; Laurence, Jean-Roch; Kirsch, Irving

    2015-01-01

    This article elucidates an integrative model of hypnosis that integrates social, cultural, cognitive, and neurophysiological variables at play both in and out of hypnosis and considers their dynamic interaction as determinants of the multifaceted experience of hypnosis. The roles of these variables are examined in the induction and suggestion stages of hypnosis, including how they are related to the experience of involuntariness, one of the hallmarks of hypnosis. It is suggested that studies of the modification of hypnotic suggestibility; cognitive flexibility; response sets and expectancies; the default-mode network; and the search for the neurophysiological correlates of hypnosis, more broadly, in conjunction with research on social psychological variables, hold much promise to further understanding of hypnosis.

  17. Open to Suggestion.

    Science.gov (United States)

    Journal of Reading, 1987

    1987-01-01

    Offers (1) suggestions for improving college students' study skills; (2) a system for keeping track of parent, teacher, and community contacts; (3) suggestions for motivating students using tic tac toe; (4) suggestions for using etymology to improve word retention; (5) a word search grid; and (6) suggestions for using postcards in remedial reading…

  18. Structure-activity relationship of cinnamaldehyde analogs as inhibitors of AI-2 based quorum sensing and their effect on virulence of Vibrio spp.

    Science.gov (United States)

    Brackman, Gilles; Celen, Shari; Hillaert, Ulrik; Van Calenbergh, Serge; Cos, Paul; Maes, Louis; Nelis, Hans J; Coenye, Tom

    2011-01-13

    Many bacteria, including Vibrio spp., regulate virulence gene expression in a cell-density dependent way through a communication process termed quorum sensing (QS). Hence, interfering with QS could be a valuable novel antipathogenic strategy. Cinnamaldehyde has previously been shown to inhibit QS-regulated virulence by decreasing the DNA-binding ability of the QS response regulator LuxR. However, little is known about the structure-activity relationship of cinnamaldehyde analogs. By evaluating the QS inhibitory activity of a series of cinnamaldehyde analogs, structural elements critical for autoinducer-2 QS inhibition were identified. These include an α,β unsaturated acyl group capable of reacting as Michael acceptor connected to a hydrophobic moiety and a partially negative charge. The most active cinnamaldehyde analogs were found to affect the starvation response, biofilm formation, pigment production and protease production in Vibrio spp in vitro, while exhibiting low cytotoxicity. In addition, these compounds significantly increased the survival of the nematode Caenorhabditis elegans infected with Vibrio anguillarum, Vibrio harveyi and Vibrio vulnificus. Several new and more active cinnamaldehyde analogs were discovered and they were shown to affect Vibrio spp. virulence factor production in vitro and in vivo. Although ligands for LuxR have not been identified so far, the nature of different cinnamaldehyde analogs and their effect on the DNA binding ability of LuxR suggest that these compounds act as LuxR-ligands.

  19. Structure-activity relationship of cinnamaldehyde analogs as inhibitors of AI-2 based quorum sensing and their effect on virulence of Vibrio spp.

    Directory of Open Access Journals (Sweden)

    Gilles Brackman

    Full Text Available BACKGROUND: Many bacteria, including Vibrio spp., regulate virulence gene expression in a cell-density dependent way through a communication process termed quorum sensing (QS. Hence, interfering with QS could be a valuable novel antipathogenic strategy. Cinnamaldehyde has previously been shown to inhibit QS-regulated virulence by decreasing the DNA-binding ability of the QS response regulator LuxR. However, little is known about the structure-activity relationship of cinnamaldehyde analogs. METHODOLOGY/PRINCIPAL FINDINGS: By evaluating the QS inhibitory activity of a series of cinnamaldehyde analogs, structural elements critical for autoinducer-2 QS inhibition were identified. These include an α,β unsaturated acyl group capable of reacting as Michael acceptor connected to a hydrophobic moiety and a partially negative charge. The most active cinnamaldehyde analogs were found to affect the starvation response, biofilm formation, pigment production and protease production in Vibrio spp in vitro, while exhibiting low cytotoxicity. In addition, these compounds significantly increased the survival of the nematode Caenorhabditis elegans infected with Vibrio anguillarum, Vibrio harveyi and Vibrio vulnificus. CONCLUSIONS/SIGNIFICANCE: Several new and more active cinnamaldehyde analogs were discovered and they were shown to affect Vibrio spp. virulence factor production in vitro and in vivo. Although ligands for LuxR have not been identified so far, the nature of different cinnamaldehyde analogs and their effect on the DNA binding ability of LuxR suggest that these compounds act as LuxR-ligands.

  20. Solitary expression of CD7 among T-cell antigens in acute myeloid leukemia: identification of a group of patients with similar T-cell receptor beta and delta rearrangements and course of disease suggestive of poor prognosis

    DEFF Research Database (Denmark)

    Jensen, A W; Hokland, M; Jørgensen, H

    1991-01-01

    to the French-American-British type M4, and four were under the age of 40. Despite intensive chemotherapy, four never obtained a complete remission and the fifth died of relapse after an allogenic bone marrow transplantation. While 12 randomly selected T-cell antigen negative AML patients showed only few...... rearrangements in Ig- or T-cell receptor (TCR) genes, such genetic alterations were demonstrated in four of five patients for the TCR delta gene and in all patients for the TCR beta gene. Interestingly, DNA fragments of similar size were demonstrated in three of five patients for both the beta and delta genes...

  1. Crystal Structures of Mouse CD1d-IGb3 Complex And Its Cognate Valpha14 T Cell Receptor Suggest a Model for Dual Recognition of Foreign And Self Glycolipids

    Energy Technology Data Exchange (ETDEWEB)

    Zajonc, D.M.; Saveage, P.B.; Bendelac, A.; Wilson, I.A.; Teyton, L.

    2009-05-28

    The semi-invariant Valpha14Jalpha18 T cell receptor (TCR) is expressed by regulatory NKT cells and has the unique ability to recognize chemically diverse ligands presented by CD1d. The crystal structure of CD1d complexed to a natural, endogenous ligand, isoglobotrihexosylceramide (iGb3), illustrates the extent of this diversity when compared to the binding of potent, exogenous ligands, such as alpha-galactosylceramide (alpha-GalCer). A single mode of recognition for these two classes of ligands would then appear problematic for a single T cell receptor. However, the Valpha14 TCR adopts two different conformations in the crystal where, in one configuration, the presence of a larger cavity between the two CDR3 regions could accommodate iGb3 and, in the other, a smaller cavity fits alpha-GalCer more snugly. Alternatively, the extended iGb3 headgroup could be 'squashed' upon docking of the TCR and accommodated between the CD1 and TCR surfaces. Thus, the same TCR may adopt alternative modes of recognition for these foreign and self-ligands for NKT cell activation.

  2. The frequencies of Killer immunoglobulin-like receptors and their HLA ligands in chronic inflammatory demyelinating polyradiculoneuropathy are similar to those in Guillian Barre syndrome but differ from those of controls, suggesting a role for NK cells in pathogenesis.

    Science.gov (United States)

    Blum, Stefan; Csurhes, Peter; McCombe, Pamela

    2015-08-15

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired inflammatory neuropathy, which has similar clinical and pathological features to Guillain-Barré Syndrome (GBS), but differs in time course. We investigated the frequency of genes encoding Killer immunoglobulin-like receptors and their HLA ligands in subjects with CIDP, in subjects with GBS and in healthy controls. There were no differences in KIR gene frequency among the 3 groups. The gene frequencies for HLA-B Bw4-I were significantly greater in CIDP than HC, but did not differ from GBS. The frequency of the combination of 3DL1/HLA-B Bw4I was greater in CIDP than HC, but did not differ from that of GBS. These data raise the possibility of NK cell function being an important factor in the pathogenesis of CIDP. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Deepening sleep by hypnotic suggestion.

    Science.gov (United States)

    Cordi, Maren J; Schlarb, Angelika A; Rasch, Björn

    2014-06-01

    Slow wave sleep (SWS) plays a critical role in body restoration and promotes brain plasticity; however, it markedly declines across the lifespan. Despite its importance, effective tools to increase SWS are rare. Here we tested whether a hypnotic suggestion to "sleep deeper" extends the amount of SWS. Within-subject, placebo-controlled crossover design. Sleep laboratory at the University of Zurich, Switzerland. Seventy healthy females 23.27 ± 3.17 y. Participants listened to an auditory text with hypnotic suggestions or a control tape before napping for 90 min while high-density electroencephalography was recorded. After participants listened to the hypnotic suggestion to "sleep deeper" subsequent SWS was increased by 81% and time spent awake was reduced by 67% (with the amount of SWS or wake in the control condition set to 100%). Other sleep stages remained unaffected. Additionally, slow wave activity was significantly enhanced after hypnotic suggestions. During the hypnotic tape, parietal theta power increases predicted the hypnosis-induced extension of SWS. Additional experiments confirmed that the beneficial effect of hypnotic suggestions on SWS was specific to the hypnotic suggestion and did not occur in low suggestible participants. Our results demonstrate the effectiveness of hypnotic suggestions to specifically increase the amount and duration of slow wave sleep (SWS) in a midday nap using objective measures of sleep in young, healthy, suggestible females. Hypnotic suggestions might be a successful tool with a lower risk of adverse side effects than pharmacological treatments to extend SWS also in clinical and elderly populations.

  4. Insulin receptors

    International Nuclear Information System (INIS)

    Kahn, C.R.; Harrison, L.C.

    1988-01-01

    This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

  5. Deepening Sleep by Hypnotic Suggestion

    Science.gov (United States)

    Cordi, Maren J.; Schlarb, Angelika A.; Rasch, Björn

    2014-01-01

    Study Objectives: Slow wave sleep (SWS) plays a critical role in body restoration and promotes brain plasticity; however, it markedly declines across the lifespan. Despite its importance, effective tools to increase SWS are rare. Here we tested whether a hypnotic suggestion to “sleep deeper” extends the amount of SWS. Design: Within-subject, placebo-controlled crossover design. Setting: Sleep laboratory at the University of Zurich, Switzerland. Participants: Seventy healthy females 23.27 ± 3.17 y. Intervention: Participants listened to an auditory text with hypnotic suggestions or a control tape before napping for 90 min while high-density electroencephalography was recorded. Measurements and Results: After participants listened to the hypnotic suggestion to “sleep deeper” subsequent SWS was increased by 81% and time spent awake was reduced by 67% (with the amount of SWS or wake in the control condition set to 100%). Other sleep stages remained unaffected. Additionally, slow wave activity was significantly enhanced after hypnotic suggestions. During the hypnotic tape, parietal theta power increases predicted the hypnosis-induced extension of SWS. Additional experiments confirmed that the beneficial effect of hypnotic suggestions on SWS was specific to the hypnotic suggestion and did not occur in low suggestible participants. Conclusions: Our results demonstrate the effectiveness of hypnotic suggestions to specifically increase the amount and duration of slow wave sleep (SWS) in a midday nap using objective measures of sleep in young, healthy, suggestible females. Hypnotic suggestions might be a successful tool with a lower risk of adverse side effects than pharmacological treatments to extend SWS also in clinical and elderly populations. Citation: Cordi MJ, Schlarb AA, Rasch B. Deepening sleep by hypnotic suggestion. SLEEP 2014;37(6):1143-1152. PMID:24882909

  6. Legal Education Reform: Modest Suggestions.

    Science.gov (United States)

    Watson, Alan

    2001-01-01

    Based on harsh criticism of legal education by students, offers suggestions for improvement that do not require additional time for law studies, will increase the exposure of students both to law as practice and to law as an intellectual discipline, and involve no greater burden on law schools. A main suggestion involves elimination of teaching…

  7. Infant Care Suggestions for Parents

    Science.gov (United States)

    ... bones, that are in various stages of healing. Handling Suggestions • All movements should be slow, methodical and ... holding, lifting, diapering, and general infant care. The return demonstration will ensure that the parents are comfortable ...

  8. Classification of hadith into positive suggestion, negative suggestion, and information

    Science.gov (United States)

    Faraby, Said Al; Riviera Rachmawati Jasin, Eliza; Kusumaningrum, Andina; Adiwijaya

    2018-03-01

    As one of the Muslim life guidelines, based on the meaning of its sentence(s), a hadith can be viewed as a suggestion for doing something, or a suggestion for not doing something, or just information without any suggestion. In this paper, we tried to classify the Bahasa translation of hadith into the three categories using machine learning approach. We tried stemming and stopword removal in preprocessing, and TF-IDF of unigram, bigram, and trigram as the extracted features. As the classifier, we compared between SVM and Neural Network. Since the categories are new, so in order to compare the results of the previous pipelines, we created a baseline classifier using simple rule-based string matching technique. The rule-based algorithm conditions on the occurrence of words such as “janganlah, sholatlah, and so on” to determine the category. The baseline method achieved F1-Score of 0.69, while the best F1-Score from the machine learning approach was 0.88, and it was produced by SVM model with the linear kernel.

  9. Hypnotic suggestion and cognitive neuroscience.

    Science.gov (United States)

    Oakley, David A; Halligan, Peter W

    2009-06-01

    The growing acceptance of consciousness as a legitimate field of enquiry and the availability of functional imaging has rekindled research interest in the use of hypnosis and suggestion to manipulate subjective experience and to gain insights into healthy and pathological cognitive functioning. Current research forms two strands. The first comprises studies exploring the cognitive and neural nature of hypnosis itself. The second employs hypnosis to explore known psychological processes using specifically targeted suggestions. An extension of this second approach involves using hypnotic suggestion to create clinically informed analogues of established structural and functional neuropsychological disorders. With functional imaging, this type of experimental neuropsychopathology offers a productive means of investigating brain activity involved in many symptom-based disorders and their related phenomenology.

  10. Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease

    Directory of Open Access Journals (Sweden)

    Luigi F. Agnati

    2007-01-01

    Full Text Available It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers, but clusters of receptors (receptor mosaics, altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.

  11. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing....... The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  12. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing......- and heterodimerisation, let alone oligomerisation. Theoretically, this phenomenon adds a novel series of functional megareceptors/super-receptors, with varied pharmacological profiles, to the catalogue of monomeric receptor subtypes isolated and cloned in the past. SRIF analogues include both peptides and non......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  13. Genetics Home Reference: leptin receptor deficiency

    Science.gov (United States)

    ... People with leptin receptor deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production ... weight gain associated with this disorder. Because hypogonadotropic hypogonadism occurs in leptin receptor deficiency , researchers suggest that ...

  14. Prostaglandin Receptor Signaling in Disease

    Directory of Open Access Journals (Sweden)

    Toshiyuki Matsuoka

    2007-01-01

    Full Text Available Prostanoids, consisting of the prostaglandins (PGs and the thromboxanes (TXs, are a group of lipid mediators formed in response to various stimuli. They include PGD2, PGE2, PGF2α, PGI2, and TXA2. They are released outside of the cells immediately after synthesis, and exert their actions by binding to a G-protein coupled rhodopsin-type receptor on the surface of target cells. There are eight types of the prostanoid receptors conserved in mammals from mouse to human. They are the PGD receptor (DP, four subtypes of the PGE receptor (EP1, EP2, EP3, and EP4, the PGF receptor (FP, PGI receptor (IP, and TXA receptor (TP. Recently, mice deficient in each of these prostanoid receptors were generated and subjected to various experimental models of disease. These studies have revealed the roles of PG receptor signaling in various pathological conditions, and suggest that selective manipulation of the prostanoid receptors may be beneficial in treatment of the pathological conditions. Here we review these recent findings of roles of prostanoid receptor signaling and their therapeutic implications.

  15. Hydrocarbon Receptor Pathway in Dogs

    NARCIS (Netherlands)

    Steenbeek, F.G. van; Spee, B.; Penning, L.C.; Kummeling, A.; Gils, I.H.M.; Grinwis, G.C.M.; Leenen, D. van; Holstege, F.C.P.; Vos-Loohuis, M.; Rothuizen, J.; Leegwater, P.A.J.

    The aryl hydrocarbon receptor (AHR) mediates biological responses to toxic chemicals. An unexpected role for AHR in vascularization was suggested when mice lacking AHR displayed impaired closure of the ductus venosus after birth, as did knockout mice for aryl hydrocarbon receptor interacting

  16. Evolutionary analysis of functional divergence among chemokine receptors, decoy receptors and viral receptors

    Directory of Open Access Journals (Sweden)

    Hiromi eDaiyasu

    2012-07-01

    Full Text Available Chemokine receptors (CKRs function in the inflammatory response and in vertebrate homeostasis. Decoy and viral receptors are two types of CKR homologues with modified functions from those of the typical CKRs. The decoy receptors are able to bind ligands without signaling. On the other hand, the viral receptors show constitutive signaling without ligands. We examined the sites related to the functional difference. At first, the decoy and viral receptors were each classified into five groups, based on the molecular phylogenetic analysis. A multiple amino acid sequence alignment between each group and the CKRs was then constructed. The difference in the amino acid composition between the group and the CKRs was evaluated as the Kullback-Leibler (KL information value at each alignment site. The KL information value is considered to reflect the difference in the functional constraints at the site. The sites with the top 5% of KL information values were selected and mapped on the structure of a CKR. The comparisons with decoy receptor groups revealed that the detected sites were biased on the intracellular side. In contrast, the sites detected from the comparisons with viral receptor groups were found on both the extracellular and intracellular sides. More sites were found in the ligand-binding pocket in the analyses of the viral receptor groups, as compared to the decoy receptor groups. Some of the detected sites were located in the GPCR motifs. For example, the DRY motif of the decoy receptors was often degraded, although the motif of the viral receptors was basically conserved. The observations for the viral receptor groups suggested that the constraints in the pocket region are loose and that the sites on the intracellular side are different from those for the decoy receptors, which may be related to the constitutive signaling activity of the viral receptors.

  17. Ionotropic crustacean olfactory receptors.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Corey

    Full Text Available The nature of the olfactory receptor in crustaceans, a major group of arthropods, has remained elusive. We report that spiny lobsters, Panulirus argus, express ionotropic receptors (IRs, the insect chemosensory variants of ionotropic glutamate receptors. Unlike insects IRs, which are expressed in a specific subset of olfactory cells, two lobster IR subunits are expressed in most, if not all, lobster olfactory receptor neurons (ORNs, as confirmed by antibody labeling and in situ hybridization. Ligand-specific ORN responses visualized by calcium imaging are consistent with a restricted expression pattern found for other potential subunits, suggesting that cell-specific expression of uncommon IR subunits determines the ligand sensitivity of individual cells. IRs are the only type of olfactory receptor that we have detected in spiny lobster olfactory tissue, suggesting that they likely mediate olfactory signaling. Given long-standing evidence for G protein-mediated signaling in activation of lobster ORNs, this finding raises the interesting specter that IRs act in concert with second messenger-mediated signaling.

  18. Flavivirus Entry Receptors: An Update

    Directory of Open Access Journals (Sweden)

    Manuel Perera-Lecoin

    2013-12-01

    Full Text Available Flaviviruses enter host cells by endocytosis initiated when the virus particles interact with cell surface receptors. The current model suggests that flaviviruses use at least two different sets of molecules for infectious entry: attachment factors that concentrate and/or recruit viruses on the cell surface and primary receptor(s that bind to virions and direct them to the endocytic pathway. Here, we present the currently available knowledge regarding the flavivirus receptors described so far with specific attention to C-type lectin receptors and the phosphatidylserine receptors, T-cell immunoglobulin and mucin domain (TIM and TYRO3, AXL and MER (TAM. Their role in flavivirus attachment and entry as well as their implication in the virus biology will be discussed in depth.

  19. CANNABINOID RECEPTOR AGONISTS UPREGULATE AND ENHANCE SEROTONIN 2A (5-HT2A) RECEPTOR ACTIVITY VIA ERK1/2 SIGNALING

    OpenAIRE

    Franklin, Jade M.; Carrasco, Gonzalo A.

    2012-01-01

    Recent behavioral studies suggest that non-selective agonists of cannabinoid receptors may regulate serotonin 2A (5-HT2A) receptor neurotransmission. Two cannabinoids receptors are found in brain, CB1 and CB2 receptors, but the molecular mechanism by which cannabinoid receptors would regulate 5-HT2A receptor neurotransmission remains unknown. Interestingly, we have recently found that certain cannabinoid receptor agonists can specifically upregulate 5-HT2A receptors. Here, we present experime...

  20. Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor

    Directory of Open Access Journals (Sweden)

    Hiroki Ide

    2015-01-01

    Full Text Available There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression.

  1. Reinventing suggestion systems for continuous improvement

    NARCIS (Netherlands)

    Schuring, R.W.; Luijten, Harald

    2001-01-01

    This article reports an experiment to increase the effectiveness of a suggestion system by deliberately applying principles of the kaizen and performance management. Design rules for suggestion systems are derived from these theories. The suggestion system that resulted differs from traditional

  2. The relationships between suggestibility, influenceability, and relaxability.

    Science.gov (United States)

    Polczyk, Romuald; Frey, Olga; Szpitalak, Malwina

    2013-01-01

    This research explores the relationships between relaxability and various aspects of suggestibility and influenceability. The Jacobson Progressive Muscle Relaxation procedure was used to induce relaxation. Tests of direct suggestibility, relating to the susceptibility of overt suggestions, and indirect suggestibility, referring to indirect hidden influence, as well as self-description questionnaires on suggestibility and the tendency to comply were used. Thayer's Activation-Deactivation Adjective Check List, measuring various kinds of activation and used as a pre- and posttest, determined the efficacy of the relaxation procedure. Indirect, direct, and self-measured suggestibility proved to be positively related to the ability to relax, measured by Thayer's subscales relating to emotions. Compliance was not related to relaxability. The results are discussed in terms of the aspects of relaxation training connected with suggestibility.

  3. Hypnotic suggestion: opportunities for cognitive neuroscience.

    Science.gov (United States)

    Oakley, David A; Halligan, Peter W

    2013-08-01

    Hypnosis uses the powerful effects of attention and suggestion to produce, modify and enhance a broad range of subjectively compelling experiences and behaviours. For more than a century, hypnotic suggestion has been used successfully as an adjunctive procedure to treat a wide range of clinical conditions. More recently, hypnosis has attracted a growing interest from a cognitive neuroscience perspective. Recent studies using hypnotic suggestion show how manipulating subjective awareness in the laboratory can provide insights into brain mechanisms involved in attention, motor control, pain perception, beliefs and volition. Moreover, they indicate that hypnotic suggestion can create informative analogues of clinical conditions that may be useful for understanding these conditions and their treatments.

  4. Asymmetric regulation of quorum-sensing receptors drives autoinducer-specific gene expression programs in Vibrio cholerae.

    Science.gov (United States)

    Hurley, Amanda; Bassler, Bonnie L

    2017-05-01

    Quorum sensing (QS) is a mechanism of chemical communication that bacteria use to monitor cell-population density and coordinate group behaviors. QS relies on the production, detection, and group-wide response to extracellular signal molecules called autoinducers. Vibrio cholerae employs parallel QS circuits that converge into a shared signaling pathway. At high cell density, the CqsS and LuxPQ QS receptors detect the intra-genus and inter-species autoinducers CAI-1 and AI-2, respectively, to repress virulence factor production and biofilm formation. We show that positive feedback, mediated by the QS pathway, increases CqsS but not LuxQ levels during the transition into QS-mode, which amplifies the CAI-1 input into the pathway relative to the AI-2 input. Asymmetric feedback on CqsS enables responses exclusively to the CAI-1 autoinducer. Because CqsS exhibits the dominant QS signaling role in V. cholerae, agonism of CqsS with synthetic compounds could be used to control pathogenicity and host dispersal. We identify nine compounds that share no structural similarity to CAI-1, yet potently agonize CqsS via inhibition of CqsS autokinase activity.

  5. Electrocardiographic features suggestive of a left. ventricular ...

    African Journals Online (AJOL)

    Abstract. Electrocardiographic features suggestive of a transmural anterior myocardial infarction with resultant left ventricular aneurysm formation were found in a 22-year-old man who had sustained a ballistic missile injury to his chest.

  6. LSD enhances suggestibility in healthy volunteers.

    Science.gov (United States)

    Carhart-Harris, R L; Kaelen, M; Whalley, M G; Bolstridge, M; Feilding, A; Nutt, D J

    2015-02-01

    Lysergic acid diethylamide (LSD) has a history of use as a psychotherapeutic aid in the treatment of mood disorders and addiction, and it was also explored as an enhancer of mind control. The present study sought to test the effect of LSD on suggestibility in a modern research study. Ten healthy volunteers were administered with intravenous (i.v.) LSD (40-80 μg) in a within-subject placebo-controlled design. Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale (CIS) and a mental imagery test (MIT). CIS and MIT items were split into two versions (A and B), balanced for 'efficacy' (i.e. A ≈ B) and counterbalanced across conditions (i.e. 50 % completed version 'A' under LSD). The MIT and CIS were issued 110 and 140 min, respectively, post-infusion, corresponding with the peak drug effects. Volunteers gave significantly higher ratings for the CIS (p = 0.018), but not the MIT (p = 0.11), after LSD than placebo. The magnitude of suggestibility enhancement under LSD was positively correlated with trait conscientiousness measured at baseline (p = 0.0005). These results imply that the influence of suggestion is enhanced by LSD. Enhanced suggestibility under LSD may have implications for its use as an adjunct to psychotherapy, where suggestibility plays a major role. That cued imagery was unaffected by LSD implies that suggestions must be of a sufficient duration and level of detail to be enhanced by the drug. The results also imply that individuals with high trait conscientiousness are especially sensitive to the suggestibility-enhancing effects of LSD.

  7. A recipe for ridding synapses of the ubiquitous AMPA receptor.

    Science.gov (United States)

    Turrigiano, Gina G

    2002-12-01

    Getting AMPA receptors into and out of synapses represents an important mechanism for changing synaptic strength, but the signals that target AMPA receptors for removal from the synaptic membrane are incompletely understood. A recent study in Ceanorhabditis elegans suggests that ubiquitination of AMPA receptors is one important signal that targets these receptors for endocytosis.

  8. Glutamate receptors

    DEFF Research Database (Denmark)

    Kristensen, Anders S; Geballe, Matthew T; Snyder, James P

    2006-01-01

    Fast excitatory synaptic transmission in the CNS relies almost entirely on the neurotransmitter glutamate and its family of ion channel receptors. An appreciation of the coupling between agonist binding and channel opening has advanced rapidly during the past five years, largely as a result of ne...

  9. The functional anatomy of suggested limb paralysis.

    Science.gov (United States)

    Deeley, Quinton; Oakley, David A; Toone, Brian; Bell, Vaughan; Walsh, Eamonn; Marquand, Andre F; Giampietro, Vincent; Brammer, Michael J; Williams, Steven C R; Mehta, Mitul A; Halligan, Peter W

    2013-02-01

    Suggestions of limb paralysis in highly hypnotically suggestible subjects have been employed to successfully model conversion disorders, revealing similar patterns of brain activation associated with attempted movement of the affected limb. However, previous studies differ with regard to the executive regions involved during involuntary inhibition of the affected limb. This difference may have arisen as previous studies did not control for differences in hypnosis depth between conditions and/or include subjective measures to explore the experience of suggested paralysis. In the current study we employed functional magnetic resonance imaging (fMRI) to examine the functional anatomy of left and right upper limb movements in eight healthy subjects selected for high hypnotic suggestibility during (i) hypnosis (NORMAL) and (ii) attempted movement following additional left upper limb paralysis suggestions (PARALYSIS). Contrast of left upper limb motor function during NORMAL relative to PARALYSIS conditions revealed greater activation of contralateral M1/S1 and ipsilateral cerebellum, consistent with the engagement of these regions in the completion of movements. By contrast, two significant observations were noted in PARALYSIS relative to NORMAL conditions. In conjunction with reports of attempts to move the paralysed limb, greater supplementary motor area (SMA) activation was observed, a finding consistent with the role of SMA in motor intention and planning. The anterior cingulate cortex (ACC, BA 24) was also significantly more active in PARALYSIS relative to NORMAL conditions - suggesting that ACC (BA 24) may be implicated in involuntary, as well as voluntary inhibition of prepotent motor responses. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Overview of the SBS 2016 Suggestion Track

    DEFF Research Database (Denmark)

    Koolen, Marijn; Bogers, Toine; Jaap, Kamps

    2016-01-01

    The goal of the SBS 2016 Suggestion Track is to evaluate approaches for supporting users in searching collections of books who express their information needs both in a query and through example books. The track investigates the complex nature of relevance in book search and the role of traditional...... and user-generated book metadata in retrieval. We consolidated last year’s investigation into the nature of book suggestions from the LibraryThing forums and how they compare to book relevance judgements. Participants were encouraged to incorporate rich user profiles of both topic creators and other...

  11. Studies and Suggestions on Prewriting Activities

    Science.gov (United States)

    Zheng, Shigao; Dai, Weiping

    2012-01-01

    This paper studies and suggests the need for writing instruction by which students can experience writing as a creative process in exploring and communicating meaning. The prewriting activities generate ideas which can encourage a free flow of thoughts and help students discover both what they want to say and how to say it on paper. Through the…

  12. Qualitative Research Articles: Guidelines, Suggestions and Needs

    Science.gov (United States)

    Crescentini, Alberto; Mainardi, Giuditta

    2009-01-01

    Purpose: The purpose of this paper is to give ideas and suggestions to avoid some typical problems of qualitative articles. The aim is not to debate quality in qualitative research but to indicate some practical solutions. Design/methodology/approach: The paper discusses the design of qualitative research and the structure of a qualitative article…

  13. Leadership Theories--Managing Practices, Challenges, Suggestions

    Science.gov (United States)

    Hawkins, Cheryl

    2009-01-01

    A shortage of community college executives due to the number of retirements occurring among current leaders is predicted. An examination of three leadership theories--servant-leadership, business leadership and transformational leadership--suggests techniques for potential community college leaders. Servant-leaders focus on the needs of their…

  14. Suggestions for Structuring a Research Article

    Science.gov (United States)

    Klein, James D.; Reiser, Robert A.

    2014-01-01

    Researchers often experience difficulty as they attempt to prepare journal articles that describe their work. The purpose of this article is to provide researchers in the field of education with a series of suggestions as to how to clearly structure each section of a research manuscript that they intend to submit for publication in a scholarly…

  15. IRIT at TREC 2014 Contextual Suggestion Track

    Science.gov (United States)

    2014-11-01

    both criteria users preferences and geographical location criteria. 1 Introduction TREC3 2014 Contextual Suggestion track examines search techniques...Contextual Retrieval Framework We address here the contextual retrieval problem as a multi-criteria decision making ( MCDM ) problem. The difficulty here

  16. Family Living: Suggestions for Effective Parenting.

    Science.gov (United States)

    Katz, Lilian G.; And Others

    Suggestions for effective parenting of preschool children are provided in 33 brief articles on children's feelings concerning self-esteem; fear; adopted children; the birth of a sibling; death; depression; and coping with stress, trauma, and divorce. Children's behavior is discussed in articles on toddlers' eating habits, punishment and…

  17. Didactic Experiments Suggest Enhanced Learning Outcomes

    DEFF Research Database (Denmark)

    Pals Svendsen, Lisbet

    2011-01-01

    and presenting material in the language studied, just as they were encouraged to systematically use evaluation processes to enhance learning outcomes. Eventually, increased grade point averages suggested that the experiment was successful. The article also mentions subsequent revisions to the original format...... and points the way for further research....

  18. Membrane proteomics of phagosomes suggests a connection to autophagy

    Energy Technology Data Exchange (ETDEWEB)

    Shui, Wenqing; Sheu, Leslie; Liu, Jun; Smart, Brian; Petzold, Christopher J.; Hsieh, Tsung-yen; Pitcher, Austin; Keasling*, Jay D.; Bertozzi*, Carolyn R.

    2008-11-25

    Phagocytosis is the central process by which macrophage cellsinternalize and eliminate infectious microbes as well as apoptoticcells. During maturation, phagosomes containing engulfed particlesfuse with various endosomal compartments through theaction of regulatory molecules on the phagosomal membrane. Inthis study, we performed a proteomic analysis of the membranefraction from latex bead-containing (LBC) phagosomes isolatedfrom macrophages. The profile, which comprised 546 proteins,suggests diverse functions of the phagosome and potential connectionsto secretory processes, toll-like receptor signaling, andautophagy. Many identified proteins were not previously knownto reside in the phagosome. We characterized several proteins inLBC phagosomes that change in abundance on induction of autophagy,a process that has been previously implicated in the hostdefense against microbial pathogens. These observations suggestcrosstalk between autophagy and phagocytosis that may be relevantto the innate immune response of macrophages.

  19. Personalized and not general suggestion produces false autobiographical memories and suggestion-consistent behavior.

    Science.gov (United States)

    Scoboria, Alan; Mazzoni, Giuliana; Jarry, Josée L; Bernstein, Daniel M

    2012-01-01

    Suggesting false childhood events produces false autobiographical beliefs, memories and suggestion-consistent behavior. The mechanisms by which suggestion affects behavior are not understood, and whether false beliefs and memories are necessary for suggestions to impact behavior remains unexplored. We examined the relative effects of providing a personalized suggestion (suggesting that an event occurred to the person in the past), and/or a general suggestion (suggesting that an event happened to others in the past). Participants (N=122) received a personalized suggestion, a general suggestion, both or neither, about childhood illness due to spoiled peach yogurt. The personalized suggestion resulted in false beliefs, false memories, and suggestion-consistent behavioral intentions immediately after the suggestion. One week or one month later participants completed a taste test that involved eating varieties of crackers and yogurts. The personalized suggestion led to reduced consumption of only peach yogurt, and those who reported a false memory showed the most eating suppression. This effect on behavior was equally strong after one week and one month, showing a long lived influence of the personalized suggestion. The general suggestion showed no effects. Suggestions that convey personal information about a past event produce false autobiographical memories, which in turn impact behavior. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. Suggestion of a conventional Islamic calendar

    Directory of Open Access Journals (Sweden)

    M.G. Rashed

    2017-12-01

    Full Text Available There is a complexity of the problem concerning the first sighting of the new lunar crescent, which is attributed to various astronomical, astrophysical and geographical factors. Therefore, Astronomers adopted various criteria for the new crescent visibility. Muslims around the world differ in the beginning of the Hijric months. In fact the differences are not due to different methodology of astronomical calculations, which in turn the variations of the calendar at different countries gives. Farewell Hajj of Prophet Mohamed was on Friday, the ninth of Thul'hejja of the tenth year of immigration (Biography of the Prophet Mohamed. Therefor; the beginning of the month of Thul'hejja 10 A.H is on Thursday. Our suggested calendar takes Farewell Hajj of the Prophet Mohammad to be the base of this calendar. The advantage of our suggested calendar far away from any criteria; where the adoption of criteria for the new crescent visibility is often misleading.

  1. Suggestion of a conventional Islamic calendar

    Science.gov (United States)

    Rashed, M. G.; Moklof, M. G.

    2017-12-01

    There is a complexity of the problem concerning the first sighting of the new lunar crescent, which is attributed to various astronomical, astrophysical and geographical factors. Therefore, Astronomers adopted various criteria for the new crescent visibility. Muslims around the world differ in the beginning of the Hijric months. In fact the differences are not due to different methodology of astronomical calculations, which in turn the variations of the calendar at different countries gives. Farewell Hajj of Prophet Mohamed was on Friday, the ninth of Thul'hejja of the tenth year of immigration (Biography of the Prophet Mohamed). Therefor; the beginning of the month of Thul'hejja 10 A.H is on Thursday. Our suggested calendar takes Farewell Hajj of the Prophet Mohammad to be the base of this calendar. The advantage of our suggested calendar far away from any criteria; where the adoption of criteria for the new crescent visibility is often misleading.

  2. Does neuroimaging of suggestion elucidate hypnotic trance?

    Science.gov (United States)

    Raz, Amir

    2011-07-01

    Contemporary studies in the cognitive neuroscience of attention and suggestion shed new light on the underlying neural mechanisms that operationalize these effects. Without adhering to important caveats inherent to imaging of the living human brain, however, findings from brain imaging studies may enthrall more than explain. Scholars, practitioners, professionals, and consumers must realize that the influence words exert on focal brain activity is measurable but that these measurements are often difficult to interpret. While recent brain imaging research increasingly incorporates variations of suggestion and hypnosis, correlating overarching hypnotic experiences with specific brain substrates remains tenuous. This article elucidates the mounting role of cognitive neuroscience, including the relative merits and intrinsic limitations of neuroimaging, in better contextualizing trance-like concepts.

  3. Application for Suggesting Restaurants Using Clustering Algorithms

    Directory of Open Access Journals (Sweden)

    Iulia Alexandra IANCU

    2014-10-01

    Full Text Available The aim of this article is to present an application whose purpose is to make suggestions of restaurants to users. The application uses as input the descriptions of restaurants, reviews, user reviews available on the specialized Internet sites and blogs. In the application there are used processing techniques of natural language implemented using parsers, clustering algorithms and techniques for data collection from the Internet through web crawlers.

  4. Ontology Learning - Suggesting Associations from Text

    OpenAIRE

    Kvarv, Gøran Sveia

    2007-01-01

    In many applications, large-scale ontologies have to be constructed and maintained. A manual construction of an ontology is a time consuming and resource demanding process, often involving some domain experts. It would therefore be beneficial to support this process with tools that automates the construction of an ontology. This master thesis has examined the use of association rules for suggesting associations between words in text. In ontology learning, concepts are often extracted from d...

  5. [Suggestions to improve dentist-endodontist collaboration].

    Science.gov (United States)

    Zabalegui, B; Zabalegui, I; Flores, L

    1989-01-01

    Referrals from the general dentist to the endodontist are in some occasions complicated with lack of proper communication among dentist-patient-specialist, resulting in the loss of confidence or even the patient. Suggestions to improve this communication are discussed, which will provide the patient a higher confidence in the indicated endodontic treatment and a better dental service. It will also enhance the prestige of the general dentists' and specialists' practice.

  6. Aberrant DR5 transport through disruption of lysosomal function suggests a novel mechanism for receptor activation

    Czech Academy of Sciences Publication Activity Database

    Akpinar, B.; Šafaříková, Barbora; Lauková, Jarmila; Debnath, S.; Vaculová, Alena; Zhivotovsky, B.; Olsson, M.

    2016-01-01

    Roč. 7, č. 36 (2016), s. 58286-58301 ISSN 1949-2553 R&D Projects: GA ČR GA15-06650S Institutional support: RVO:68081707 Keywords : death ligand trail * dependent apoptosis * cancer-cells * autophagy Subject RIV: BO - Biophysics Impact factor: 5.168, year: 2016

  7. Preventing motor training through nocebo suggestions.

    Science.gov (United States)

    Pollo, Antonella; Carlino, Elisa; Vase, Lene; Benedetti, Fabrizio

    2012-11-01

    Although placebos have repeatedly been shown to increase physical performance and endurance, much less is known about the effect of their negative counterpart, nocebos. Here, we employ negative suggestions and a sham electrical stimulation as a nocebo conditioning procedure in healthy subjects performing a leg extension exercise to total exhaustion. Using two different protocols, we analyze the contribution of expectation alone or the combination of conditioning and expectation to the nocebo effect evaluated as the change of work performed and rate of perceived exertion. We find that it is possible to negatively modulate the physical performance in both cases, and we argue that this effect can effectively offset the outcome of training programs.

  8. Dinosaur Peptides Suggest Mechanisms of Protein Survival

    Energy Technology Data Exchange (ETDEWEB)

    San Antonio, James D.; Schweitzer, Mary H.; Jensen, Shane T.; Kalluri, Raghu; Buckley, Michael; Orgel, Joseph P.R.O. (Harvard-Med); (IIT); (NCSU); (UPENN); (Manchester); (Orthovita)

    2011-09-16

    Eleven collagen peptide sequences recovered from chemical extracts of dinosaur bones were mapped onto molecular models of the vertebrate collagen fibril derived from extant taxa. The dinosaur peptides localized to fibril regions protected by the close packing of collagen molecules, and contained few acidic amino acids. Four peptides mapped to collagen regions crucial for cell-collagen interactions and tissue development. Dinosaur peptides were not represented in more exposed parts of the collagen fibril or regions mediating intermolecular cross-linking. Thus functionally significant regions of collagen fibrils that are physically shielded within the fibril may be preferentially preserved in fossils. These results show empirically that structure-function relationships at the molecular level could contribute to selective preservation in fossilized vertebrate remains across geological time, suggest a 'preservation motif', and bolster current concepts linking collagen structure to biological function. This non-random distribution supports the hypothesis that the peptides are produced by the extinct organisms and suggests a chemical mechanism for survival.

  9. Dinosaur peptides suggest mechanisms of protein survival.

    Directory of Open Access Journals (Sweden)

    James D San Antonio

    Full Text Available Eleven collagen peptide sequences recovered from chemical extracts of dinosaur bones were mapped onto molecular models of the vertebrate collagen fibril derived from extant taxa. The dinosaur peptides localized to fibril regions protected by the close packing of collagen molecules, and contained few acidic amino acids. Four peptides mapped to collagen regions crucial for cell-collagen interactions and tissue development. Dinosaur peptides were not represented in more exposed parts of the collagen fibril or regions mediating intermolecular cross-linking. Thus functionally significant regions of collagen fibrils that are physically shielded within the fibril may be preferentially preserved in fossils. These results show empirically that structure-function relationships at the molecular level could contribute to selective preservation in fossilized vertebrate remains across geological time, suggest a 'preservation motif', and bolster current concepts linking collagen structure to biological function. This non-random distribution supports the hypothesis that the peptides are produced by the extinct organisms and suggests a chemical mechanism for survival.

  10. Radioiodinated ligands for dopamine receptors

    International Nuclear Information System (INIS)

    Kung, H.F.

    1994-01-01

    The dopamine receptor system is important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other metal disorders. In the past few years radioiodinated ligands for single photon emission tomography (SPECT) have been successfully developed and tested in humans: [ 123 I]TISCH for D1 dopamine receptors; [ 123 I]IBZM, epidepride, IBF and FIDA2, four iodobenzamide derivatives, for D2/D3 dopamine receptors. In addition, [ 123 I]β-CIT (RTI-55) and IPT, cocaine derivatives, for the dopamine reuptake site are potentially useful for diagnosis of loss of dopamine neurons. The first iodinated ligand, (R)trans-7-OH-PIPAT, for D3 dopamine receptors, was synthesized and characterized with cloned cell lines (Spodoptera frugiperda, Sf9) expressing the D2 and D3 dopamine receptors and with rat basal forebrain membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to both D2 and D3 dopamine receptors expressed in the cell lines. Initial studies appear to suggest that by fine tuning the structures it may be possible to develop agents specific for D2 and D3 dopamine receptors. It is important to investigate D2/D3 selectivity for this series of potent ligands

  11. Chest magnetic resonance imaging: a protocol suggestion

    Directory of Open Access Journals (Sweden)

    Bruno Hochhegger

    2015-12-01

    Full Text Available Abstract In the recent years, with the development of ultrafast sequences, magnetic resonance imaging (MRI has been established as a valuable diagnostic modality in body imaging. Because of improvements in speed and image quality, MRI is now ready for routine clinical use also in the study of pulmonary diseases. The main advantage of MRI of the lungs is its unique combination of morphological and functional assessment in a single imaging session. In this article, the authors review most technical aspects and suggest a protocol for performing chest MRI. The authors also describe the three major clinical indications for MRI of the lungs: staging of lung tumors; evaluation of pulmonary vascular diseases; and investigation of pulmonary abnormalities in patients who should not be exposed to radiation.

  12. Elastic wave scattering methods: assessments and suggestions

    International Nuclear Information System (INIS)

    Gubernatis, J.E.

    1985-01-01

    The author was asked by the meeting organizers to review and assess the developments over the past ten or so years in elastic wave scattering methods and to suggest areas of future research opportunities. He highlights the developments, focusing on what he feels were distinct steps forward in our theoretical understanding of how elastic waves interact with flaws. For references and illustrative figures, he decided to use as his principal source the proceedings of the various annual Reviews of Progress in Quantitative Nondestructive Evaluation (NDE). These meetings have been the main forum not only for presenting results of theoretical research but also for demonstrating the relevance of the theoretical research for the design and interpretation of experiment. In his opinion a quantitative NDE is possible only if this relevance exists, and his major objective is to discuss and illustrate the degree to which relevance has developed

  13. Health service marketing: a suggested model.

    Science.gov (United States)

    Zaltman, G; Vertinsky, I

    1971-07-01

    Focus is on social marketing in a health context, and attention is directed to the development of a psychosocial model of health-related behavior with emphasis on developing countries. Each component of the model is identified and defined, with some of the interactions among its components noted. There are both advantages and limitations to using the model in a social marketing context. The model's primary contribution at this stage of its development is in structuring and organizing diverse sources of knowledge and data. New relationships are suggested which were not previously considered in the literature. The relationship between risk-taking and perceived susceptibility is 1 example. The model also provides a basis for simulating health processes, providing a testing ground for health policies before their actual implementation. The model's perspective is uniquely appropriate for the development of social marketing strategies, and it promises to encompass health market behavior in various cultural settings.

  14. Limits of quantitation — Yet another suggestion

    Energy Technology Data Exchange (ETDEWEB)

    Carlson, Jill; Wysoczanski, Artur; Voigtman, Edward, E-mail: voigtman@chem.umass.edu

    2014-06-01

    The work presented herein suggests that the limit of quantitation concept may be rendered substantially less ambiguous and ultimately more useful as a figure of merit by basing it upon the significant figure and relative measurement error ideas due to Coleman, Auses and Gram, coupled with the correct instantiation of Currie's detection limit methodology. Simple theoretical results are presented for a linear, univariate chemical measurement system with homoscedastic Gaussian noise, and these are tested against both Monte Carlo computer simulations and laser-excited molecular fluorescence experimental results. Good agreement among experiment, theory and simulation is obtained and an easy extension to linearly heteroscedastic Gaussian noise is also outlined. - Highlights: • True Currie detection limits are estimated. • Experimental results validate previous 2008 theory. • Linearly heteroscedastic system is correctly modeled.

  15. Ultrasonographic findings of early abortion: suggested predictors

    International Nuclear Information System (INIS)

    Jun, Soon Ae; Ahn, Myoung Ock; Cha, Kwang Yul; Lee, Young Doo

    1992-01-01

    To investigate predictable ultrasonographic findings of early abortion. To investigate objective rules for the screening of abortion. Ultrasonographic examination of 111 early pregnancies between the sixth and ninth week in women who had regular 28 day menstrual cycles was performed. Ultrasonographic measurements of the gestational sac, crown rump length and fetal heart rate were performed using a linear array real time transducer with doppler ultrasonogram. All measurements of 17 early abortions were compared to those of 94 normal pregnancies. Most of early aborted pregnancies were classified correctly by discriminant analysis with G-SAC and CRL (G-SAC=0.5 CRL + 15, sensitivity 76.5%, specificity 96.8%). With the addition of FHR, 94.1% of early abortions could be predicted. In conclusion, ultrasonographic findings of early intrauterine growth retardation, small gestational sac and bradycardia can be predictable signs suggestive of poor prognosis of early pregnancies

  16. Chest magnetic resonance imaging: a protocol suggestion*

    Science.gov (United States)

    Hochhegger, Bruno; de Souza, Vinícius Valério Silveira; Marchiori, Edson; Irion, Klaus Loureiro; Souza Jr., Arthur Soares; Elias Junior, Jorge; Rodrigues, Rosana Souza; Barreto, Miriam Menna; Escuissato, Dante Luiz; Mançano, Alexandre Dias; Araujo Neto, César Augusto; Guimarães, Marcos Duarte; Nin, Carlos Schuler; Santos, Marcel Koenigkam; Silva, Jorge Luiz Pereira e

    2015-01-01

    In the recent years, with the development of ultrafast sequences, magnetic resonance imaging (MRI) has been established as a valuable diagnostic modality in body imaging. Because of improvements in speed and image quality, MRI is now ready for routine clinical use also in the study of pulmonary diseases. The main advantage of MRI of the lungs is its unique combination of morphological and functional assessment in a single imaging session. In this article, the authors review most technical aspects and suggest a protocol for performing chest MRI. The authors also describe the three major clinical indications for MRI of the lungs: staging of lung tumors; evaluation of pulmonary vascular diseases; and investigation of pulmonary abnormalities in patients who should not be exposed to radiation. PMID:26811555

  17. PEER SUGGESTIVE FEEDBACK IN ENGLISH SPEAKING CLASS

    Directory of Open Access Journals (Sweden)

    Agnes Widyaningrum

    2017-12-01

    Full Text Available Students learn English in Speaking Class should get enjoyable learning atmosphere in order to help them improve their speaking skill. Teacher‘s role as facilitator contributes in reducing students‘ anxiety when they have chance to speak. Nunan (1995 and Richards (2008 argue that speaking is an important skill in language learning whether it is as EFL or ESL that enable language learners to communicate not only in expressing view point but also in giving responses in their communication. This classroom study supports the idea to give positive suggestion as students‘ feedback given by their peers. Each student has their own chance to review and to be reviewed so that they can perform better in speaking class. This study is conducted in order to improve students‘ speaking skill in speaking class.

  18. Suggested use of vaccines in diabetes

    Directory of Open Access Journals (Sweden)

    Jothydev Kesavadev

    2012-01-01

    Full Text Available Diabetes has emerged as a disease of major public health importance in India affecting the rich and the poor alike. Conventionally, comprehensive diabetes management is aimed at preventing micro and macro vascular complications. However, morbidity and mortality due to infections are also significant. In developing countries like India, the concept of adult immunization is far from reality. Recently the H1N1 pandemic has triggered the necessity for considering immunization in all age groups for the prevention of vaccine-preventable fatal infectious diseases. Considering the economics of immunization in a developing country, providing free vaccines to all adults may not be a practical solution, although the free universal immunization program for children is in existence for several decades. There is no consensus on the use of vaccines in diabetes subjects in India. However, there are some clinics offering routine pneumococcal, influenza and other vaccinations. Patients with diabetes have a deranged immune system making them more prone for infections. Hospitalization and death due to pneumococcal disease and influenza are higher in diabetes patients. They, like other healthy individuals, have a normal humoral response to vaccination with clinically significant benefits. The American Diabetes Association, Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention, World Health Organization, United Kingdom Guidelines and a number of other scientific organizations have well defined guidelines for vaccination in diabetes. In this article we make some suggestions for clinicians in India, regarding use of vaccines in subjects with diabetes.

  19. [Evidence that suggest the reality of reincarnation].

    Science.gov (United States)

    Bonilla, Ernesto

    2015-06-01

    Worldwide, children can be found who reported that they have memories of a previous life. More than 2,500 cases have been studied and their specifications have been published and preserved in the archives of the Division of Perceptual Studies at the University of Virginia (United States). Many of those children come from countries where the majority of the inhabitants believe in reincarnation, but others come from countries with different cultures and religions that reject it. In many cases, the revelations of the children have been verified and have corresponded to a particular individual, already dead. A good number of these children have marks and birth defects corresponding to wounds on the body of his previous personality. Many have behaviors related to their claims to their former life: phobias, philias, and attachments. Others seem to recognize people and places of his supposed previous life, and some of their assertions have been made under controlled conditions. The hypothesis of reincarnation is controversial. We can never say that it does not occur, or will obtain conclusive evidence that it happens. The cases that have been described so far, isolated or combined, do not provide irrefutable proof of reincarnation, but they supply evidence that suggest its reality.

  20. Triheteromeric NMDA Receptors at Hippocampal Synapses

    Science.gov (United States)

    Tovar, Kenneth R.; McGinley, Matthew J.; Westbrook, Gary L.

    2013-01-01

    NMDA receptors are composed of two GluN1 (N1) and two GluN2 (N2) subunits. Constituent N2 subunits control the pharmacological and kinetic characteristics of the receptor. NMDA receptors in hippocampal or cortical neurons are often thought of as diheteromeric, i.e., containing only one type of N2 subunit. However, triheteromeric receptors with more than one type of N2 subunit also have been reported and the relative contribution of di- and triheteromeric NMDA receptors at synapses has been difficult to assess. Because wild-type hippocampal principal neurons express N1, N2A and N2B, we used cultured hippocampal principal neurons from N2A and N2B-knockout mice as templates for diheteromeric synaptic receptors. Summation of N1/N2B and N1/N2A excitatory postsynaptic currents could not account for the deactivation kinetics of wild-type excitatory postsynaptic currents (EPSCs) however. To make a quantitative estimate of NMDA receptor subtypes at wild-type synapses, we used the deactivation kinetics, as well as the effects of the competitive antagonist NVP-AAM077. Our results indicate that three types of NMDA receptors contribute to the wild-type EPSC, with at least two-thirds being triheteromeric receptors. Functional isolation of synaptic triheteromeric receptors revealed deactivation kinetics and pharmacology distinct from either diheteromeric receptor subtype. Because of differences in open probability, synaptic triheteromeric receptors outnumbered N1/N2A receptors by 5.8 to 1 and N1/N2B receptors by 3.2 to 1. Our results suggest that triheteromeric NMDA receptors must be either preferentially assembled or preferentially localized at synapses. PMID:23699525

  1. Protein Connectivity in Chemotaxis Receptor Complexes.

    Directory of Open Access Journals (Sweden)

    Stephan Eismann

    2015-12-01

    Full Text Available The chemotaxis sensory system allows bacteria such as Escherichia coli to swim towards nutrients and away from repellents. The underlying pathway is remarkably sensitive in detecting chemical gradients over a wide range of ambient concentrations. Interactions among receptors, which are predominantly clustered at the cell poles, are crucial to this sensitivity. Although it has been suggested that the kinase CheA and the adapter protein CheW are integral for receptor connectivity, the exact coupling mechanism remains unclear. Here, we present a statistical-mechanics approach to model the receptor linkage mechanism itself, building on nanodisc and electron cryotomography experiments. Specifically, we investigate how the sensing behavior of mixed receptor clusters is affected by variations in the expression levels of CheA and CheW at a constant receptor density in the membrane. Our model compares favorably with dose-response curves from in vivo Förster resonance energy transfer (FRET measurements, demonstrating that the receptor-methylation level has only minor effects on receptor cooperativity. Importantly, our model provides an explanation for the non-intuitive conclusion that the receptor cooperativity decreases with increasing levels of CheA, a core signaling protein associated with the receptors, whereas the receptor cooperativity increases with increasing levels of CheW, a key adapter protein. Finally, we propose an evolutionary advantage as explanation for the recently suggested CheW-only linker structures.

  2. Cannabinoid 2 Receptor- and Beta Arrestin 2-Dependent Upregulation of Serotonin 2A Receptors

    OpenAIRE

    Franklin, J.M.; Vasiljevik, T.; Prisinzano, T.E.; Carrasco, G.A.

    2012-01-01

    Recent evidence suggests that cannabinoid receptor agonists may regulate serotonin 2A (5-HT2A) receptor neurotransmission in the brain, although no molecular mechanism has been identified. Here, we present experimental evidence that sustained treatment with a non-selective cannabinoid agonist (CP 55,940) or selective CB2 receptor agonists (JWH 133 or GP 1a) upregulate 5-HT2A receptors in a neuronal cell line. Furthermore, this cannabinoid receptor agonist-induced upregulation of 5-HT2A recept...

  3. New horizons for lipoprotein receptors

    DEFF Research Database (Denmark)

    Andersen, Olav M.; Dagil, Robert; Kragelund, Birthe Brandt

    2013-01-01

    , this dogma has transformed with the observation that β-propellers of some LRs actively engage in complex formation too. Based on an in-depth decomposition of current structures and sequences, we suggest that exploitation of the β-propellers as binding targets depends on receptor subgroups. In particular, we...

  4. Localization of mineralocorticoid receptors at mammalian synapses.

    Directory of Open Access Journals (Sweden)

    Eric M Prager

    Full Text Available In the brain, membrane associated nongenomic steroid receptors can induce fast-acting responses to ion conductance and second messenger systems of neurons. Emerging data suggest that membrane associated glucocorticoid and mineralocorticoid receptors may directly regulate synaptic excitability during times of stress when adrenal hormones are elevated. As the key neuron signaling interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. The lateral amygdala is a key site for synaptic plasticity underlying conditioned fear, which can both trigger and be coincident with the stress response. A large body of electrophysiological data shows rapid regulation of neuronal excitability by steroid hormone receptors. Despite the importance of these receptors, to date, only the glucocorticoid receptor has been anatomically localized to the membrane. We investigated the subcellular sites of mineralocorticoid receptors in the lateral amygdala of the Sprague-Dawley rat. Immunoblot analysis revealed the presence of mineralocorticoid receptors in the amygdala. Using electron microscopy, we found mineralocorticoid receptors expressed at both nuclear including: glutamatergic and GABAergic neurons and extra nuclear sites including: presynaptic terminals, neuronal dendrites, and dendritic spines. Importantly we also observed mineralocorticoid receptors at postsynaptic membrane densities of excitatory synapses. These data provide direct anatomical evidence supporting the concept that, at some synapses, synaptic transmission is regulated by mineralocorticoid receptors. Thus part of the stress signaling response in the brain is a direct modulation of the synapse itself by adrenal steroids.

  5. Enhanced sensitivity of muscarinic cholinergic receptor associated with dopaminergic receptor subsensitivity after chronic antidepressant treatment

    International Nuclear Information System (INIS)

    Koide, T.; Matsushita, H.

    1981-01-01

    The chronic effects of antidepressant treatment on striatal dopaminergic (DA) and muscarinic cholinergic (mACh) receptors of the rat brain have been examined comparatively in this study using 3 H-spiroperidol ( 3 H-SPD) and 3 H-quinuclidinyl benzilate ( 3 H-QNB) as the respective radioactive ligands. Imipramine and desipramine were used as prototype antidepressants. Although a single administration of imipramine or desipramine did not affect each receptor sensitivity, chronic treatment with each drug caused a supersensitivity of mACh receptor subsequent to DA receptor subsensitivity. Furthermore, it has been suggested that anti-mACh properties of imipramine or desipramine may not necessarily be related to the manifestation of mACh receptor supersensitivity and that sustained DA receptor subsensitivity may play some role in the alterations of mACh receptor sensitivity

  6. Production of antibodies which recognize opiate receptors on murine leukocytes

    Energy Technology Data Exchange (ETDEWEB)

    Carr, D.J.J.; Bost, K.L.; Blalock, J.E.

    1988-01-01

    An antibody has been developed which recognizes opiate receptors on cells of the immune system. This antibody blocks specific binding of the radiolabeled opiate receptor ligand, /sup 3/H-dihydromorphine, to receptors on murine splenocytes. Additionally, the anti-receptor antibody competes with ..beta..-endorphin, meta-enkephalin, and naloxone for the same binding site on the leukocytes. Moreover, the anti-receptor antibody possesses agonist activity similar to ..beta..-endorphin in suppressing cAMP production by lymphocytes. These results suggest the development of an antibody which recognizes classical opiate receptors on cells of the immune system.

  7. G-protein-coupled receptors for free fatty acids

    DEFF Research Database (Denmark)

    Milligan, Graeme; Ulven, Trond; Murdoch, Hannah

    2014-01-01

    that communicate cellular signals initiated by hormones and neurotransmitters. Recently, based on tissue expression patterns of these receptors and the concept that they may elicit the production of a range of appetite- and hunger-regulating peptides, such nutrient sensing GPCRs are attracting considerable...... of these receptors. However, ongoing clinical trials of agonists of free fatty acid receptor 1 suggest that this receptor and other receptors for free fatty acids may provide a successful strategy for controlling hyperglycaemia and providing novel approaches to treat diabetes. Receptors responsive to free fatty acid...

  8. Molecular Mechanisms of Dopamine Receptor Mediated Neuroprotection

    National Research Council Canada - National Science Library

    Sealfon, Stuart

    2000-01-01

    ... of the cellular changes characteristic of this process. Evidence from our laboratory and others suggest that activation of dopamine receptors can oppose the induction of apoptosis in dopamine neurons...

  9. Molecular pharmacology of human NMDA receptors

    DEFF Research Database (Denmark)

    Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard

    2012-01-01

    current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side......-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest...... that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human...

  10. Expression of GABAergic receptors in mouse taste receptor cells.

    Directory of Open Access Journals (Sweden)

    Margaret R Starostik

    Full Text Available BACKGROUND: Multiple excitatory neurotransmitters have been identified in the mammalian taste transduction, with few studies focused on inhibitory neurotransmitters. Since the synthetic enzyme glutamate decarboxylase (GAD for gamma-aminobutyric acid (GABA is expressed in a subset of mouse taste cells, we hypothesized that other components of the GABA signaling pathway are likely expressed in this system. GABA signaling is initiated by the activation of either ionotropic receptors (GABA(A and GABA(C or metabotropic receptors (GABA(B while it is terminated by the re-uptake of GABA through transporters (GATs. METHODOLOGY/PRINCIPAL FINDINGS: Using reverse transcriptase-PCR (RT-PCR analysis, we investigated the expression of different GABA signaling molecules in the mouse taste system. Taste receptor cells (TRCs in the circumvallate papillae express multiple subunits of the GABA(A and GABA(B receptors as well as multiple GATs. Immunocytochemical analyses examined the distribution of the GABA machinery in the circumvallate papillae. Both GABA(A-and GABA(B- immunoreactivity were detected in the peripheral taste receptor cells. We also used transgenic mice that express green fluorescent protein (GFP in either the Type II taste cells, which can respond to bitter, sweet or umami taste stimuli, or in the Type III GAD67 expressing taste cells. Thus, we were able to identify that GABAergic receptors are expressed in some Type II and Type III taste cells. Mouse GAT4 labeling was concentrated in the cells surrounding the taste buds with a few positively labeled TRCs at the margins of the taste buds. CONCLUSIONS/SIGNIFICANCE: The presence of GABAergic receptors localized on Type II and Type III taste cells suggests that GABA is likely modulating evoked taste responses in the mouse taste bud.

  11. Intracellular insulin-receptor dissociation and segregation in a rat fibroblast cell line transfected with a human insulin receptor gene

    International Nuclear Information System (INIS)

    Levy, J.R.; Olefsky, J.M.

    1988-01-01

    The cellular processing of insulin and insulin receptors was studied using a rat fibroblast cell line that had been transfected with a normal human insulin receptor gene, expressing approximately 500 times the normal number of native fibroblasts insulin receptors. These cells bind and internalize insulin normally. Biochemically assays based on the selective precipitation by polyethylene glycol of intact insulin-receptor complexes but not of free intracellular insulin were developed to study the time course of intracellular insulin-receptor dissociation. Fibroblasts were incubated with radiolabeled insulin at 4 0 C, and internalization of insulin-receptor complexes was initiated by warming the cells to 37 0 C. Within 2 min, 90% of the internalized radioactivity was composed of intact insulin-receptor complexes. The dissociation of insulin from internalized insulin-receptor complexes was markedly inhibited by monensin and chloroquine. Furthermore, chloroquine markedly increased the number of cross-linkable intracellular insulin-receptor complexes, as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography. These findings suggest that acidification of intracellular vesicles is responsible for insulin-receptor dissociation. Physical segregation of dissociated intracellular insulin from its receptor was monitored. The results are consistent with the view that segregation of insulin and receptor occurs 5-10 min after initiation of dissociation. These studies demonstrate the intracellular itinerary of insulin-receptor complexes, including internalization, dissociation of insulin from the internalized receptor within an acidified compartment, segregation of insulin from the receptor, and subsequent ligand degradation

  12. Vasoactive Intestinal Polypeptide and Muscarinic Receptors: Supersensitivity Induced by Long-Term Atropine Treatment

    Science.gov (United States)

    Hedlund, Britta; Abens, Janis; Bartfai, Tamas

    1983-04-01

    Long-term treatment of rats with atropine induced large increases in the numbers of muscarinic receptors and receptors for vasoactive intestinal polypeptide in the salivary glands. Since receptors for vasoactive intestinal polypeptide coexist with muscarinic receptors on the same neurons in this preparation, the results suggest that a drug that alters the sensitivity of one receptor may also affect the sensitivity of the receptor for a costored transmitter and in this way contribute to the therapeutic or side effects of the drug.

  13. Children's Memory for Their Mother's Murder: Accuracy, Suggestibility, and Resistance to Suggestion.

    Science.gov (United States)

    McWilliams, Kelly; Narr, Rachel; Goodman, Gail S; Ruiz, Sandra; Mendoza, Macaria

    2013-01-31

    From its inception, child eyewitness memory research has been guided by dramatic legal cases that turn on the testimony of children. Decades of scientific research reveal that, under many conditions, children can provide veracious accounts of traumatic experiences. Scientific studies also document factors that lead children to make false statements. In this paper we describe a legal case in which children testified about their mother's murder. We discuss factors that may have influenced the accuracy of the children's eyewitness memory. Children's suggestibility and resistance to suggestion are illustrated. Expert testimony, based on scientific research, can aid the trier of fact when children provide crucial evidence in criminal investigations and courtroom trials about tragic events.

  14. Insulin causes insulin-receptor internalization in human erythrocyte ghosts.

    OpenAIRE

    Kelleher, R S; Murray, E F; Peterson, S W

    1987-01-01

    The effect of incubation with insulin on insulin-receptor internalization by erythrocyte ghosts was investigated. The number of surface insulin receptors decreased by 30-40% after incubation of ghosts with insulin. Total insulin-receptor binding to solubilized ghosts was the same in insulin-incubated and control ghosts, whereas insulin binding to an internal vesicular fraction was substantially increased in insulin-incubated ghosts. Our findings suggest that erythrocyte-ghost insulin receptor...

  15. Evolution of Class I cytokine receptors

    Science.gov (United States)

    Liongue, Clifford; Ward, Alister C

    2007-01-01

    Background The Class I cytokine receptors have a wide range of actions, including a major role in the development and function of immune and blood cells. However, the evolution of the genes encoding them remains poorly understood. To address this we have used bioinformatics to analyze the Class I receptor repertoire in sea squirt (Ciona intestinalis) and zebrafish (Danio rerio). Results Only two Class I receptors were identified in sea squirt, one with homology to the archetypal GP130 receptor, and the other with high conservation with the divergent orphan receptor CLF-3. In contrast, 36 Class I cytokine receptors were present in zebrafish, including representative members for each of the five structural groups found in mammals. This allowed the identification of 27 core receptors belonging to the last common ancestor of teleosts and mammals. Conclusion This study suggests that the majority of diversification of this receptor family occurred after the divergence of urochordates and vertebrates approximately 794 million years ago (MYA), but before the divergence of ray-finned from lobe-finned fishes around 476 MYA. Since then, only relatively limited lineage-specific diversification within the different Class I receptor structural groups has occurred. PMID:17640376

  16. Purinergic Receptors in Ocular Inflammation

    Directory of Open Access Journals (Sweden)

    Ana Guzman-Aranguez

    2014-01-01

    Full Text Available Inflammation is a complex process that implies the interaction between cells and molecular mediators, which, when not properly “tuned,” can lead to disease. When inflammation affects the eye, it can produce severe disorders affecting the superficial and internal parts of the visual organ. The nucleoside adenosine and nucleotides including adenine mononucleotides like ADP and ATP and dinucleotides such as P1,P4-diadenosine tetraphosphate (Ap4A, and P1,P5-diadenosine pentaphosphate (Ap5A are present in different ocular locations and therefore they may contribute/modulate inflammatory processes. Adenosine receptors, in particular A2A adenosine receptors, present anti-inflammatory action in acute and chronic retinal inflammation. Regarding the A3 receptor, selective agonists like N6-(3-iodobenzyl-5′-N-methylcarboxamidoadenosine (CF101 have been used for the treatment of inflammatory ophthalmic diseases such as dry eye and uveoretinitis. Sideways, diverse stimuli (sensory stimulation, large intraocular pressure increases can produce a release of ATP from ocular sensory innervation or after injury to ocular tissues. Then, ATP will activate purinergic P2 receptors present in sensory nerve endings, the iris, the ciliary body, or other tissues surrounding the anterior chamber of the eye to produce uveitis/endophthalmitis. In summary, adenosine and nucleotides can activate receptors in ocular structures susceptible to suffer from inflammatory processes. This involvement suggests the possible use of purinergic agonists and antagonists as therapeutic targets for ocular inflammation.

  17. Involvement of direct inhibition of NMDA receptors in the effects of sigma-receptor ligands on glutamate neurotoxicity in vitro.

    Science.gov (United States)

    Nishikawa, H; Hashino, A; Kume, T; Katsuki, H; Kaneko, S; Akaike, A

    2000-09-15

    This study was performed to examine the roles of the N-methyl-D-aspartate (NMDA) receptor/phencyclidine (PCP) channel complex in the protective effects of sigma-receptor ligands against glutamate neurotoxicity in cultured cortical neurons derived from fetal rats. A 1-h exposure of cultures to glutamate caused a marked loss of viability, as determined by Trypan blue exclusion. This acute neurotoxicity of glutamate was prevented by NMDA receptor antagonists. Expression of sigma(1) receptor mRNA in cortical cultures was confirmed by reverse transcription polymerase chain reaction (RT-PCR). sigma Receptor ligands with affinity for NMDA receptor channels including the PCP site, such as (+)-N-allylnormetazocine ((+)-SKF10,047), haloperidol, and R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane ((-)-PPAP), prevented glutamate neurotoxicity in a concentration-dependent manner. In contrast, other sigma-receptor ligands without affinity for NMDA receptors, such as carbetapentane and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP), did not show neuroprotective effects. Putative endogenous sigma receptor ligands such as pregnenolone, progesterone, and dehydroepiandrosterone did not affect glutamate neurotoxicity. The protective effects of (+)-SKF10,047, haloperidol, and (-)-PPAP were not affected by the sigma(1) receptor antagonist rimcazole. These results suggested that a direct interaction with NMDA receptors but not with sigma receptors plays a crucial role in the neuroprotective effects of sigma receptor ligands with affinity for NMDA receptors.

  18. Hypoxia Induces Internalization of κ-Opioid Receptor.

    Science.gov (United States)

    Xi, Chunhua; Liang, Xuan; Chen, Chunhua; Babazada, Hasan; Li, Tianzuo; Liu, Renyu

    2017-05-01

    It has been demonstrated that κ-opioid receptor agonists can reduce hypoxia-ischemia brain injury in animal models. However, it is unclear how the κ-opioid receptor responds to hypoxia-ischemia. In the current study, the authors used an in vitro model of oxygen-glucose deprivation and reoxygenation to explore how κ-opioid receptors respond to hypoxia and reoxygenation. Mouse neuroblastoma Neuro2A cells were stably transfected with mouse κ-opioid receptor-tdTomato fusion protein or Flag-tagged mouse κ-opioid receptor, divided into several groups (n = 6 to 12), and used to investigate the κ-opioid receptor movement. Observations were performed under normal oxygen, at 30 min to 1 h after oxygen-glucose deprivation and at 1 h after reoxygenation using high-resolution imaging techniques including immunoelectronmicroscopy in the presence and absence of κ-opioid receptor antagonist, dynamin inhibitors, potassium channel blockers, and dopamine receptor inhibitor. Hypoxic conditions caused the κ-opioid receptor to be internalized into the cells. Inhibition of dynamin by Dyngo-4a prevented the receptor internalization. Interestingly, a specific κ-opioid receptor antagonist norbinaltorphimine blocked internalization, suggesting the involvement of activation of a specific κ-opioid receptor. κ-Opioid receptor internalization appears to be reversed by reoxygenation. Quantities of intracellular κ-opioid receptor-associated gold particles as demonstrated by immunoelectron microscopy were increased from 37 to 85% (P internalization. Hypoxia induces reversible κ-opioid receptor internalization, which was inhibited by selective κ-opioid receptor antagonists or dynamin inhibitor, and can be reversed by reoxygenation in neuroblastoma cells, indicating the modulating effects between κ-opioid receptor and hypoxia via κ-opioid receptor activation and the dynamin-dependent mechanism.

  19. Lipophorin Receptor: The Insect Lipoprotein Receptor

    Indian Academy of Sciences (India)

    IAS Admin

    physiology and develop- mental biology of silkworms, and use of silk in industrial applications. The low-density lipoprotein receptor (LDLR), one of the best characterized cell-surface receptors, mediates cholesterol ho- meostasis and other functions in mammals. The members of the LDLR superfamily are structurally related ...

  20. Lipophorin Receptor: The Insect Lipoprotein Receptor

    Indian Academy of Sciences (India)

    Permanent link: http://www.ias.ac.in/article/fulltext/reso/018/08/0748-0755. Keywords. Low-density lipoprotein receptor; lipophorin; lipophorin receptor; insects. Author Affiliations. G Ravikumar1 N B Vijayaprakash1. Seri-biotech Research Laboratory Central Silk Board Kodathi, Carmelaram Post Bangalore 560 035, India.

  1. Computer modeling of Cannabinoid receptor type 1

    Directory of Open Access Journals (Sweden)

    Sapundzhi Fatima

    2018-01-01

    Full Text Available Cannabinoid receptors are important class of receptors as they are involved in various physiological processes such as appetite, pain-sensation, mood, and memory. It is important to design receptor-selective ligands in order to treat a particular disorder. The aim of the present study is to model the structure of cannabinoid receptor CB1 and to perform docking between obtained models and known ligands. Two models of CBR1 were prepared with two different methods (Modeller of Chimera and MOE. They were used for docking with GOLD 5.2. It was established a high correlation between inhibitory constant Ki of CB1 cannabinoid ligands and the ChemScore scoring function of GOLD, which concerns both models. This suggests that the models of the CB1 receptors obtained could be used for docking studies and in further investigation and design of new potential, selective and active cannabinoids with the desired effects.

  2. Acetylcholine receptor antibody

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003576.htm Acetylcholine receptor antibody To use the sharing features on this page, please enable JavaScript. Acetylcholine receptor antibody is a protein found in the blood ...

  3. Androgen receptor abnormalities

    NARCIS (Netherlands)

    A.O. Brinkmann (Albert); G.G.J.M. Kuiper (George); C. Ris-Stalpers (Carolyn); H.C.J. van Rooij (Henri); G. Romalo (G.); G. Trifiro (Gianluca); E. Mulder (Eppo); L. Pinsky (L.); H.U. Schweikert (H.); J. Trapman (Jan)

    1991-01-01

    markdownabstract__Abstract__ The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of

  4. Androgen receptor abnormalities

    NARCIS (Netherlands)

    Brinkmann, A. O.; Kuiper, G. G.; Ris-Stalpers, C.; van Rooij, H. C.; Romalo, G.; Trifiro, M.; Mulder, E.; Pinsky, L.; Schweikert, H. U.; Trapman, J.

    1991-01-01

    The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of the genomic organization of the

  5. Cannabinoid receptor localization in brain

    Energy Technology Data Exchange (ETDEWEB)

    Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. (National Institute of Mental Health, Bethesda, MD (USA))

    1990-03-01

    (3H)CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of (3H)CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

  6. Clinical and Genomic Crosstalk between Glucocorticoid Receptor and Estrogen Receptor α In Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Jeffery M. Vahrenkamp

    2018-03-01

    Full Text Available Summary: Steroid hormone receptors are simultaneously active in many tissues and are capable of altering each other’s function. Estrogen receptor α (ER and glucocorticoid receptor (GR are expressed in the uterus, and their ligands have opposing effects on uterine growth. In endometrial tumors with high ER expression, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic-binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is altered significantly by estradiol with GR recruited to ER-bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol but with additional regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer. : Estrogen receptor α (ER and glucocorticoid receptor (GR are expressed in the uterus and have differential effects on growth. Vahrenkamp et al. find that expression of both receptors is associated with poor outcome in endometrial cancer and that simultaneous induction of ER and GR leads to molecular interplay between the receptors. Keywords: estrogen receptor, glucocorticoid receptor, endometrial cancer

  7. GABA receptor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Doo [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA{sub A}-receptor that allows chloride to pass through a ligand gated ion channel and GABA{sub B}-receptor that uses G-proteins for signaling. The GABA{sub A}-receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA{sub A}-receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with {sup 11}C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, {sup 18}F-fluoroflumazenil (FFMZ) has been developed to overcome {sup 11}C's short half-life. {sup 18}F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1{sup 1}C-FMZ PET instead of {sup 18}F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA{sub A} receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas.

  8. GABA receptor imaging

    International Nuclear Information System (INIS)

    Lee, Jong Doo

    2007-01-01

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA A -receptor that allows chloride to pass through a ligand gated ion channel and GABA B -receptor that uses G-proteins for signaling. The GABA A -receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA A -receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with 11 C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, 18 F-fluoroflumazenil (FFMZ) has been developed to overcome 11 C's short half-life. 18 F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1 1 C-FMZ PET instead of 18 F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA A receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas

  9. PAF receptor structure: a hypothesis.

    Science.gov (United States)

    Godfroid, J J; Dive, G; Lamotte-Brasseur, J; Batt, J P; Heymans, F

    1991-12-01

    Different hypotheses of the structure of platelet-activating factor (PAF) receptor based on structure-activity relationships of agonists and antagonists are reviewed. For an agonistic effect, strong hydrophobic interactions and an ether function are required in position-1 of the glycerol backbone; chain length limitations and steric hindrance demand a small group in position-2. The unusual structural properties of non-PAF-like antagonists required 3-D electrostatic potential calculations. This method applied to seven potent antagonists suggests a strong "Cache-orielles" (ear-muff) effect, i.e., two strong electronegative wells (isocontour at -10 Kcal/mole) are located at 180 degrees to each other and at a relatively constant distance. Initial consideration of the "Cache-oreilles" effect implied the structure of a bipolarized cylinder of 10-12 A diameter for the receptor. However, very recent results on studies with agonists and antagonists structurally similar to PAF suggest that the receptor may in fact be a multi-polarized cylinder.

  10. Tachykinins and tachykinin receptors in bone.

    Science.gov (United States)

    Goto, Tetsuya; Tanaka, Teruo

    2002-07-15

    Tachykinins are neuropeptides that are widely distributed in the body and function as neurotransmitters and neuromodulators. Five tachykinin subtypes: substance P (SP), neurokinin A, neurokinin B, neuropeptide K, and neuropeptide gamma; and three receptor subtypes: neurokinin-1, -2, and -3 receptors, have been identified. SP was the first peptide of the tachykinin family to be identified. It is considered to be an important neuropeptide, and to function in the nervous system and intestine. However, recent advances in the analysis of SP receptors, particularly neurokinin-1 receptors (NK(1)-Rs) that have high affinity for SP, have demonstrated that NK(1)-Rs are distributed not only in neurons and immune cells, but also in other peripheral cells, including bone cells. This article reviews the current understanding of the distribution of SP and other tachykinins in bone, and the function of tachykinins, through neurokinin receptors. The distribution of tachykinin-immunoreactive axons and neurokinin receptors suggests that tachykinins may directly modulate bone metabolism through neurokinin receptors. Copyright 2002 Wiley-Liss, Inc.

  11. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity.

    Science.gov (United States)

    Kawai, Taro; Akira, Shizuo

    2011-05-27

    Toll-like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that play a central role in host cell recognition and responses to microbial pathogens. TLR-mediated recognition of components derived from a wide range of pathogens and their role in the subsequent initiation of innate immune responses is widely accepted; however, the recent discovery of non-TLR PRRs, such as C-type lectin receptors, NOD-like receptors, and RIG-I-like receptors, suggests that many aspects of innate immunity are more sophisticated and complex. In this review, we will focus on the role played by TLRs in mounting protective immune responses against infection and their crosstalk with other PRRs with respect to pathogen recognition. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Dengue virus receptor

    OpenAIRE

    Hidari, Kazuya I.P.J.; Suzuki, Takashi

    2011-01-01

    Dengue virus is an arthropod-borne virus transmitted by Aedes mosquitoes. Dengue virus causes fever and hemorrhagic disorders in humans and non-human primates. Direct interaction of the virus introduced by a mosquito bite with host receptor molecule(s) is crucial for virus propagation and the pathological progression of dengue diseases. Therefore, elucidation of the molecular mechanisms underlying the interaction between dengue virus and its receptor(s) in both humans and mosquitoes is essent...

  13. Therapeutic androgen receptor ligands

    Science.gov (United States)

    Allan, George F.; Sui, Zhihua

    2003-01-01

    In the past several years, the concept of tissue-selective nuclear receptor ligands has emerged. This concept has come to fruition with estrogens, with the successful marketing of drugs such as raloxifene. The discovery of raloxifene and other selective estrogen receptor modulators (SERMs) has raised the possibility of generating selective compounds for other pathways, including androgens (that is, selective androgen receptor modulators, or SARMs). PMID:16604181

  14. G-protein Receptor Kinase 5 Regulates the Cannabinoid Receptor 2-induced Up-regulation of Serotonin 2A Receptors*

    Science.gov (United States)

    Franklin, Jade M.; Carrasco, Gonzalo A.

    2013-01-01

    We have recently reported that cannabinoid agonists can up-regulate and enhance the activity of serotonin 2A (5-HT2A) receptors in the prefrontal cortex (PFCx). Increased expression and activity of cortical 5-HT2A receptors has been associated with neuropsychiatric disorders, such as anxiety and schizophrenia. Here we report that repeated CP55940 exposure selectively up-regulates GRK5 proteins in rat PFCx and in a neuronal cell culture model. We sought to examine the mechanism underlying the regulation of GRK5 and to identify the role of GRK5 in the cannabinoid agonist-induced up-regulation and enhanced activity of 5-HT2A receptors. Interestingly, we found that cannabinoid agonist-induced up-regulation of GRK5 involves CB2 receptors, β-arrestin 2, and ERK1/2 signaling because treatment with CB2 shRNA lentiviral particles, β-arrestin 2 shRNA lentiviral particles, or ERK1/2 inhibitor prevented the cannabinoid agonist-induced up-regulation of GRK5. Most importantly, we found that GRK5 shRNA lentiviral particle treatment prevented the cannabinoid agonist-induced up-regulation and enhanced 5-HT2A receptor-mediated calcium release. Repeated cannabinoid exposure was also associated with enhanced phosphorylation of CB2 receptors and increased interaction between β-arrestin 2 and ERK1/2. These latter phenomena were also significantly inhibited by GRK5 shRNA lentiviral treatment. Our results suggest that sustained activation of CB2 receptors, which up-regulates 5-HT2A receptor signaling, enhances GRK5 expression; the phosphorylation of CB2 receptors; and the β-arrestin 2/ERK interactions. These data could provide a rationale for some of the adverse effects associated with repeated cannabinoid agonist exposure. PMID:23592773

  15. On the Effects of Suggested Prices in Gasoline Markets

    NARCIS (Netherlands)

    R.P. Faber (Riemer); M.C.W. Janssen (Maarten)

    2008-01-01

    textabstractThis article analyzes the role of suggested prices in the Dutch retail market for gasoline. Suggested prices are announced by large oil companies with the suggestion that retailers follow them. There are at least two competing rationales for the existence of suggested prices: they may

  16. Acetylcholine Receptor: Complex of Homologous Subunits

    Science.gov (United States)

    Raftery, Michael A.; Hunkapiller, Michael W.; Strader, Catherine D.; Hood, Leroy E.

    1980-06-01

    The acetylcholine receptor from the electric ray Torpedo californica is composed of five subunits; two are identical and the other three are structurally related to them. Microsequence analysis of the four polypeptides demonstrates amino acid homology among the subunits. Further sequence analysis of both membrane-bound and Triton-solubilized, chromatographically purified receptor gave the stoichiometry of the four subunits (40,000:50,000:60,000:65,000 daltons) as 2:1:1:1, indicating that this protein is a pentameric complex with a molecular weight of 255,000 daltons. Genealogical analysis suggests that divergence from a common ancestral gene occurred early in the evolution of the receptor. This shared ancestry argues that each of the four subunits plays a functional role in the receptor's physiological action.

  17. Tachykinins and tachykinin receptors: a growing family.

    Science.gov (United States)

    Pennefather, Jocelyn N; Lecci, Alessandro; Candenas, M Luz; Patak, Eva; Pinto, Francisco M; Maggi, Carlo Alberto

    2004-02-06

    The peptides of the tachykinin family are widely distributed within the mammalian peripheral and central nervous systems and play a well-recognized role as excitatory neurotransmitters. Currently, the concept that tachykinins act exclusively as neuropeptides is being challenged, since the best known members of the family, substance P, neurokinin A and neurokinin B, are also present in non-neuronal cells and in non-innervated tissues. Moreover, the recently cloned mammalian tachykinins hemokinin-1 and endokinins are primarily expressed in non-neuronal cells, suggesting a widespread distribution and important role for these peptides as intercellular signaling molecules. The biological actions of tachykinins are mediated through three types of receptors denoted NK(1), NK(2) and NK(3) that belong to the family of G protein-coupled receptors. The identification of additional tachykinins has reopened the debate of whether more tachykinin receptors exist. In this review, we summarize the current knowledge of tachykinins and their receptors.

  18. Agonist induction, conformational selection, and mutant receptors.

    Science.gov (United States)

    Giraldo, Jesús

    2004-01-02

    Current models of receptor activation are based on either of two basic mechanisms: agonist induction or conformational selection. The importance of one pathway relative to the other is controversial. In this article, the impossibility of distinguishing between the two mechanisms under a thermodynamic approach is shown. The effect of receptor mutation on the constants governing ligand-receptor equilibria is discussed. The two-state model of agonism both in its original formulation (one cycle) and including multiple active states (multiple cycles) is used. Pharmacological equations for the double (two cycles) two-state model are derived. The simulations performed suggest that the double two-state model of agonism can be a useful model for assessing quantitatively the changes in pharmacological activity following receptor mutation.

  19. Scavenger receptors and β-glucan receptors participate in the recognition of yeasts by murine macrophages.

    Science.gov (United States)

    Józefowski, Szczepan; Yang, Zhiping; Marcinkiewicz, Janusz; Kobzik, Lester

    2012-02-01

    Numerous receptors have been implicated in recognition of pathogenic fungi by macrophages, including the β-glucan receptor dectin-1. The role of scavenger receptors (SRs) in anti-fungal immunity is not well characterized. We studied uptake of unopsonized Saccharomycetes cerevisiae (zymosan) and live Candida albicans yeasts as well as zymosan-stimulated H(2)O(2) production in J774 macrophage-like cells and peritoneal exudate macrophages (PEMs). The role of different receptors was assessed with the use of competitive ligands, transfected cells and receptor-deficient macrophages. The uptake of zymosan by untreated J774 cells was mediated approximately half by SRs and half by a β-glucan receptor which was distinct from dectin-1 and not linked to stimulation of H(2)O(2) production. Ligands of β-glucan receptors and of SRs also inhibited uptake of C. albicans by macrophages (J774 cells and PEMs). In macrophages pretreated with a CpG motif-containing oligodeoxynucleotide (CpG-ODN) the relative contribution of SRs to yeast uptake increased and that of β-glucan receptors decreased. Whereas the class A SR MARCO participated in the uptake of both zymosan and C. albicans by CpG-ODN-pretreated, but not untreated macrophages, the related receptor SR-A/CD204 was involved in the uptake of zymosan, but not of C. albicans. The reduction of zymosan-stimulated H(2)O(2) production observed in DS-pretreated J774 cells and in class A SRs-deficient PEMs suggest that class A SRs mediate part of this process. Our results revealed that SRs belong to a redundant system of receptors for yeasts. Binding of yeasts to different receptors in resting versus CpG-ODN-pre-exposed macrophages may differentially affect polarization of adaptive immune responses.

  20. Pharmacological and autoradiographic characterization of sigma receptors

    International Nuclear Information System (INIS)

    Largent, B.L.

    1986-01-01

    The existence of three types of opioid receptors - μ, kappa, and sigma - was postulated to explain the effects of different opioids in the chronic spinal dog. Sigma receptors, named for the prototypic agonist SKF 10,047 (N-allylnormetazocine), were suggested to mediate the psychotomimetic-like effects of SKF 10,047 in the dog. 3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) has been proposed as a selective dopamine autoreceptor agonist. However, the drug specificity of (+)[ 3 H]3-PPP binding in brain is identical to that of sigma receptor binding sites which may mediate psychotomimetic effects of some opioids. Pharmacological and autoradiographic analyses reveal that (+)[ 3 H]SKF 10,047, the prototypic sigma agonist, labels two sites in brain. The drug specificity of the high affinity site for (+)[ 3 H]SKF 10,047 resembles that of putative sigma receptors labeled with (+)[ 3 H]3-PPP, being potently inhibited by (+)3-PPP, haloperidol, and (+/-)pentazocine, and demonstrating stereoselectivity for the (+) isomer of SKF 10,047. Autoradiographic localizations of high affinity (+)[ 3 H]SKF 10,047 binding sites closely resemble those of (+)[ 3 H]3-PPP labeled sites with high levels of binding in the hippocampal pyramidal cell layer, hypothalamus, and pontine and cranial nerve nuclei. Thus, putative sigma receptors and PCP receptors represent distinct receptor populations in brain. This proposal is supported by the presence of sigma binding sites - and absence of PCP receptors - on NCB-20 cell membranes, a hybrid neurotumor cell line that provides a model system for the physiological and biochemical study of sigma receptors

  1. Steroid receptors and their ligands: effects on male gamete functions.

    Science.gov (United States)

    Aquila, Saveria; De Amicis, Francesca

    2014-11-01

    In recent years a new picture of human sperm biology is emerging. It is now widely recognized that sperm contain nuclear encoded mRNA, mitochondrial encoded RNA and different transcription factors including steroid receptors, while in the past sperm were considered incapable of transcription and translation. One of the main targets of steroid hormones and their receptors is reproductive function. Expression studies on Progesterone Receptor, estrogen receptor, androgen receptor and their specific ligands, demonstrate the presence of these systems in mature spermatozoa as surface but also as nuclear conventional receptors, suggesting that both systemic and local steroid hormones, through sperm receptors, may influence male reproduction. However, the relationship between the signaling events modulated by steroid hormones and sperm fertilization potential as well as the possible involvement of the specific receptors are still controversial issues. The main line of this review highlights the current research in human sperm biology examining new molecular systems of response to the hormones as well as specific regulatory pathways controlling sperm cell fate and biological functions. Most significant studies regarding the identification of steroid receptors are reported and the mechanistic insights relative to signaling pathways, together with the change in sperm metabolism energy influenced by steroid hormones are discussed.The reviewed evidences suggest important effects of Progesterone, Estrogen and Testosterone and their receptors on spermatozoa and implicate the involvement of both systemic and local steroid action in the regulation of male fertility potential. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, X. Edward; Suino-Powell, Kelly M.; Xu, Yong; Chan, Cee-Wah; Tanabe, Osamu; Kruse, Schoen W.; Reynolds, Ross; Engel, James Douglas; Xu, H. Eric (Michigan-Med); (Van Andel)

    2015-11-30

    Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.

  3. The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor.

    Science.gov (United States)

    Ciana, Paolo; Fumagalli, Marta; Trincavelli, Maria Letizia; Verderio, Claudia; Rosa, Patrizia; Lecca, Davide; Ferrario, Silvia; Parravicini, Chiara; Capra, Valérie; Gelosa, Paolo; Guerrini, Uliano; Belcredito, Silvia; Cimino, Mauro; Sironi, Luigi; Tremoli, Elena; Rovati, G Enrico; Martini, Claudia; Abbracchio, Maria P

    2006-10-04

    Nucleotides and cysteinyl-leukotrienes (CysLTs) are unrelated signaling molecules inducing multiple effects through separate G-protein-coupled receptors: the P2Y and the CysLT receptors. Here we show that GPR17, a Gi-coupled orphan receptor at intermediate phylogenetic position between P2Y and CysLT receptors, is specifically activated by both families of endogenous ligands, leading to both adenylyl cyclase inhibition and intracellular calcium increases. Agonist-response profile, as determined by [(35)S]GTPgammaS binding, was different from that of already known CysLT and P2Y receptors, with EC(50) values in the nanomolar and micromolar range, for CysLTs and uracil nucleotides, respectively. Both rat and human receptors are highly expressed in the organs typically undergoing ischemic damage, that is, brain, heart and kidney. In vivo inhibition of GPR17 by either CysLT/P2Y receptor antagonists or antisense technology dramatically reduced ischemic damage in a rat focal ischemia model, suggesting GPR17 as the common molecular target mediating brain damage by nucleotides and CysLTs. In conclusion, the deorphanization of GPR17 revealed a dualistic receptor for two endogenous unrelated ligand families. These findings may lead to dualistic drugs of previously unexplored therapeutic potential.

  4. PGE2 Modulates GABAA Receptors via an EP1 Receptor-Mediated Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Guang Yang

    2015-07-01

    Full Text Available Aims: PGE2 is one of the most abundant prostanoids in mammalian tissues, but its effect on neuronal receptors has not been well investigated. This study examines the effect of PGE2 on GABAA receptor currents in rat cerebellar granule neurons. Methods: GABAA currents were recorded using a patch-clamp technique. Cell surface and total protein of GABAA β1/2/3 subunits was carried out by Western blot analysis. Results: Upon incubation of neurons with PGE2 (1 µM for 60 minutes, GABAA currents were significantly potentiated. This PGE2-driven effect could be blocked by PKC or CaMKII inhibitors as well as EP1 receptor antagonist, and mimicked by PMA or EP1 receptor agonist. Furthermore, Western blot data showed that PGE2 did not increase the total expression level of GABAA receptors, but significantly increased surface levels of GABAA β1/2/3 subunits after 1 h of treatment. Consistently, both PKC and CaMKII inhibitors were able to reduce PGE2-induced increases in cell surface expression of GABAA receptors. Conclusion: Activation of either the PKC or CaMKII pathways by EP1 receptors mediates the PGE2-induced increase in GABAA currents. This suggests that upregulation of postsynaptic GABAA receptors by PGE2 may have profound effects on cerebellar functioning under physiological and pathological conditions.

  5. Has the sun set on κ3-opioid receptors?

    Science.gov (United States)

    Connor, Mark; Kitchen, Ian

    2006-01-01

    μ-Opioid receptor agonists are a mainstay of clinical analgesia, despite the significant unwanted effects and dependence liability associated with drugs like morphine. The quest for opioids that produce analgesia with fewer undesirable effects has lead to the putative identification of multiple opioid receptor subtypes, despite the identification of only four opioid-related receptor genes. One such putative receptor subtype is the κ3 receptor, activation of which supposedly produces analgesia in animals. In the present issue of this Journal, Olianas and co-workers have demonstrated that the prototypic κ3 agonist naloxone benzoylhydrazone is actually a partial agonist at the cloned μ, δ, and κ opioid receptors and an antagonist at opioid-like NOP receptors. Together with a recent study that showed that high-affinity naloxone benzoylhydrazone binding is abolished in triple μ/δ/κ receptor knockout mice, the present study provides strong evidence that in vivo effects attributed to κ3 receptor activation probably just reflect the combined actions of a particularly nonselective opioid drug. Indeed, molecular identification of any of the proposed subtypes of μ, δ, and κ opioid receptors has proven elusive, suggesting that it is perhaps time to retire the notion of opioid receptor subtypes until definitive evidence for their existence is provided. PMID:16402044

  6. Has the sun set on kappa3-opioid receptors?

    Science.gov (United States)

    Connor, Mark; Kitchen, Ian

    2006-02-01

    Mu-opioid receptor agonists are a mainstay of clinical analgesia, despite the significant unwanted effects and dependence liability associated with drugs like morphine. The quest for opioids that produce analgesia with fewer undesirable effects has lead to the putative identification of multiple opioid receptor subtypes, despite the identification of only four opioid-related receptor genes. One such putative receptor subtype is the kappa3 receptor, activation of which supposedly produces analgesia in animals. In the present issue of this Journal, Olianas and co-workers have demonstrated that the prototypic kappa3 agonist naloxone benzoylhydrazone is actually a partial agonist at the cloned mu, delta, and kappa opioid receptors and an antagonist at opioid-like NOP receptors. Together with a recent study that showed that high-affinity naloxone benzoylhydrazone binding is abolished in triple mu/delta/kappa receptor knockout mice, the present study provides strong evidence that in vivo effects attributed to kappa3 receptor activation probably just reflect the combined actions of a particularly nonselective opioid drug. Indeed, molecular identification of any of the proposed subtypes of mu, delta, and kappa opioid receptors has proven elusive, suggesting that it is perhaps time to retire the notion of opioid receptor subtypes until definitive evidence for their existence is provided.

  7. Neuropeptide FF receptors as novel targets for limbic seizure attenuation.

    Science.gov (United States)

    Portelli, Jeanelle; Meurs, Alfred; Bihel, Frederic; Hammoud, Hassan; Schmitt, Martine; De Kock, Joery; Utard, Valerie; Humbert, Jean-Paul; Bertin, Isabelle; Buffel, Ine; Coppens, Jessica; Tourwe, Dirk; Maes, Veronique; De Prins, An; Vanhaecke, Tamara; Massie, Ann; Balasubramaniam, Ambikaipakan; Boon, Paul; Bourguignon, Jean-Jacques; Simonin, Frederic; Smolders, Ilse

    2015-08-01

    Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neuropeptide. In this study, the controversial role of NPY1 receptors in epilepsy was reassessed by testing two highly selective NPY1 receptor ligands and a mixed NPY1/NPFF receptor antagonist BIBP3226 in a rat model for limbic seizures. While BIBP3226 significantly attenuated the pilocarpine-induced seizures, neither of the highly selective NPY1 receptor ligands altered the seizure severity. Administration of the NPFF1/NPFF2 receptor antagonist RF9 also significantly attenuated limbic seizure activity. To further prove the involvement of NPFF receptors in these seizure-modulating effects, low and high affinity antagonists for the NPFF receptors were tested. We observed that the low affinity ligand failed to exhibit anticonvulsant properties while the two high affinity ligands significantly attenuated the seizures. Continuous NPFF1 receptor agonist administration also inhibited limbic seizures whereas bolus administration of the NPFF1 receptor agonist was without effect. This suggests that continuous agonist perfusion could result in NPFF1 receptor desensitization and mimic NPFF1 receptor antagonist administration. Our data unveil for the first time the involvement of the NPFF system in the management of limbic seizures. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Suggestibility and signal detection performance in hallucination-prone students.

    Science.gov (United States)

    Alganami, Fatimah; Varese, Filippo; Wagstaff, Graham F; Bentall, Richard P

    2017-03-01

    Auditory hallucinations are associated with signal detection biases. We examine the extent to which suggestions influence performance on a signal detection task (SDT) in highly hallucination-prone and low hallucination-prone students. We also explore the relationship between trait suggestibility, dissociation and hallucination proneness. In two experiments, students completed on-line measures of hallucination proneness (the revised Launay-Slade Hallucination Scale; LSHS-R), trait suggestibility (Inventory of Suggestibility) and dissociation (Dissociative Experiences Scale-II). Students in the upper and lower tertiles of the LSHS-R performed an auditory SDT. Prior to the task, suggestions were made pertaining to the number of expected targets (Experiment 1, N = 60: high vs. low suggestions; Experiment 2, N = 62, no suggestion vs. high suggestion vs. no voice suggestion). Correlational and regression analyses indicated that trait suggestibility and dissociation predicted hallucination proneness. Highly hallucination-prone students showed a higher SDT bias in both studies. In Experiment 1, both bias scores were significantly affected by suggestions to the same degree. In Experiment 2, highly hallucination-prone students were more reactive to the high suggestion condition than the controls. Suggestions may affect source-monitoring judgments, and this effect may be greater in those who have a predisposition towards hallucinatory experiences.

  9. AMPA receptor ligands

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Mellor, Ian

    2004-01-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...

  10. Angiotensin type 2 receptors

    DEFF Research Database (Denmark)

    Sumners, Colin; de Kloet, Annette D; Krause, Eric G

    2015-01-01

    In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral...

  11. Identification of Human P2X1 Receptor-interacting Proteins Reveals a Role of the Cytoskeleton in Receptor Regulation*

    Science.gov (United States)

    Lalo, Ulyana; Roberts, Jonathan A.; Evans, Richard J.

    2011-01-01

    P2X1 receptors are ATP-gated ion channels expressed by smooth muscle and blood cells. Carboxyl-terminally His-FLAG-tagged human P2X1 receptors were stably expressed in HEK293 cells and co-purified with cytoskeletal proteins including actin. Disruption of the actin cytoskeleton with cytochalasin D inhibited P2X1 receptor currents with no effect on the time course of the response or surface expression of the receptor. Stabilization of the cytoskeleton with jasplakinolide had no effect on P2X1 receptor currents but decreased receptor mobility. P2X2 receptor currents were unaffected by cytochalasin, and P2X1/2 receptor chimeras were used to identify the molecular basis of actin sensitivity. These studies showed that the intracellular amino terminus accounts for the inhibitory effects of cytoskeletal disruption similar to that shown for lipid raft/cholesterol sensitivity. Stabilization of the cytoskeleton with jasplakinolide abolished the inhibitory effects of cholesterol depletion on P2X1 receptor currents, suggesting that lipid rafts may regulate the receptor through stabilization of the cytoskeleton. These studies show that the cytoskeleton plays an important role in P2X1 receptor regulation. PMID:21757694

  12. 32 CFR 1901.04 - Suggestions and complaints.

    Science.gov (United States)

    2010-07-01

    ... suggestions or complaints with regard to its administration of the Privacy Act. Many requesters will receive pre-paid, customer satisfaction survey cards. Letters of suggestion or complaint should identify the...

  13. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  14. Detection of Possible AI-2-mediated Quorum Sensing System in Commensal Intestinal Bacteria

    Czech Academy of Sciences Publication Activity Database

    Lukáš, Filip; Gorenc, G.; Kopečný, Jan

    2008-01-01

    Roč. 53, č. 3 (2008), s. 221-224 ISSN 0015-5632 R&D Projects: GA ČR GA303/06/0974 Institutional research plan: CEZ:AV0Z50450515 Keywords : quorum sensing system Subject RIV: EE - Microbiology, Virology Impact factor: 1.172, year: 2008

  15. Subcritical crack growth behavior of AI2O3-Glass dental composites

    NARCIS (Netherlands)

    Zhu, Q.; With, G. de; Dortmans, L.J.M.G.; Feenstra, F.

    2003-01-01

    The purpose of this study is to investigate the subcritical crack growth (SCG) behavior of alumina-glass dental composites. Alumina-glass composites were fabricated by infiltrating molten glass to porous alumina preforms. Rectangular bars of the composite were subject to dynamic loading in air, with

  16. Paradox in AI - AI 2.0: The Way to Machine Consciousness

    Science.gov (United States)

    Palensky, Peter; Bruckner, Dietmar; Tmej, Anna; Deutsch, Tobias

    Artificial Intelligence, the big promise of the last millennium, has apparently made its way into our daily lives. Cell phones with speech control, evolutionary computing in data mining or power grids, optimized via neural network, show its applicability in industrial environments. The original expectation of true intelligence and thinking machines lies still ahead of us. Researchers are, however, optimistic as never before. This paper tries to compare the views, challenges and approaches of several disciplines: engineering, psychology, neuroscience, philosophy. It gives a short introduction to Psychoanalysis, discusses the term consciousness, social implications of intelligent machines, related theories, and expectations and shall serve as a starting point for first attempts of combining these diverse thoughts.

  17. Spectral Variability of FSRQs Minfeng Gu1,∗ & Y. L. Ai2,3

    Indian Academy of Sciences (India)

    Osterman Meyer et al. 2008, 2009). But still not many FSRQs were found to show redder-when-brighter trends (RWB). From a sample of FSRQs selected from SDSS, we briefly show here one more FSRQ with. RWB (see Gu & Ai 2011 for details).

  18. Numerical simulation of armor capability of AI2O3 and SiC armor tiles

    Science.gov (United States)

    Rashid, T.; Aleem, M. A.; Akbar, S.; Rauf, A.; Shuaib, M.

    2016-08-01

    Alumina and Silicon Carbide armor plates have been tested numerically against 7.62x51 (mm x mm) armor piercing (AP) projectiles. A 2-D problem with axial symmetry has been designedand the simulations were carried out using commercial software ANSYS AUTODYN. Experiments were modeled for Alumina (99.5%), Alumina (99.7%) and SiC with a range of tile thicknesses (5, 10, 15 and 20 mm). The projectile was chosen as 7.62 x 51AP bullet (initial velocity 810 m/sec)with two different core materials Steel 4340 and WC, however, casing material was copper for both cores. SiC showed better defense against AP bullet as compared to Al2O3. The residual velocity and momentum of the bullet were found to decrease with increasing tile thickness. SiC tiles with thickness 15mm and 20 mm successfully sustained penetration against steel 4340 and WC core bullets, respectively. However none of the Alumina targets succeeded in stopping the bullet.

  19. Spectral Variability of FSRQs Minfeng Gu1,∗ & Y. L. Ai2,3

    Indian Academy of Sciences (India)

    (DR7; Abazajian et al. 2009) and the SN survey during 2005–2007. We use the point- spread function magnitudes. The spectral index α are calculated from ... Abdo, A. A., Ackermann, M., Ajello, M. et al. 2010, Astrophys. J., 715, 429. Abazajian, K. N. et al. 2009, Astrophys. J. Suppl., 182, 543. Ai, Y. L., Yuan, W., Zhou, H. Y. et ...

  20. P2X receptors.

    Science.gov (United States)

    North, R Alan

    2016-08-05

    Extracellular adenosine 5'-triphosphate (ATP) activates cell surface P2X and P2Y receptors. P2X receptors are membrane ion channels preferably permeable to sodium, potassium and calcium that open within milliseconds of the binding of ATP. In molecular architecture, they form a unique structural family. The receptor is a trimer, the binding of ATP between subunits causes them to flex together within the ectodomain and separate in the membrane-spanning region so as to open a central channel. P2X receptors have a widespread tissue distribution. On some smooth muscle cells, P2X receptors mediate the fast excitatory junction potential that leads to depolarization and contraction. In the central nervous system, activation of P2X receptors allows calcium to enter neurons and this can evoke slower neuromodulatory responses such as the trafficking of receptors for the neurotransmitter glutamate. In primary afferent nerves, P2X receptors are critical for the initiation of action potentials when they respond to ATP released from sensory cells such as taste buds, chemoreceptors or urothelium. In immune cells, activation of P2X receptors triggers the release of pro-inflammatory cytokines such as interleukin 1β. The development of selective blockers of different P2X receptors has led to clinical trials of their effectiveness in the management of cough, pain, inflammation and certain neurodegenerative diseases.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'. © 2016 The Author(s).

  1. Lymphocyte receptors for pertussis toxin

    Energy Technology Data Exchange (ETDEWEB)

    Clark, C.G.; Armstrong, G.D. (Univ. of Alberta, Edmonton (Canada))

    1990-12-01

    We have investigated human T-lymphocyte receptors for pertussis toxin by affinity isolation and photoaffinity labeling procedures. T lymphocytes were obtained from peripheral human blood, surface iodinated, and solubilized in Triton X-100. The iodinated mixture was then passed through pertussis toxin-agarose, and the fractions were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Autoradiography of the fixed, dried gels revealed several bands in the pertussis toxin-bound fraction that were not observed in fractions obtained from histone or fetuin-agarose. Further investigations employed a photoaffinity labeling reagent, sulfosuccinimidyl 2-(p-azido-salicylamido)-1,3'-dithiopropionate, to identify pertussis toxin receptors in freshly isolated peripheral blood monocytic cells, T lymphocytes, and Jurkat cells. In all three cell systems, the pertussis toxin affinity probe specifically labeled a single protein species with an apparent molecular weight of 70,000 that was not observed when the procedure was performed in the presence of excess unmodified pertussis toxin. A protein comparable in molecular weight to the one detected by the photoaffinity labeling technique was also observed among the species that bound to pertussis toxin-agarose. The results suggest that pertussis toxin may bind to a 70,000-Da receptor in human T lymphocytes.

  2. Entropic Control of Receptor Recycling Using Engineered Ligands.

    Science.gov (United States)

    DeGroot, Andre C M; Busch, David J; Hayden, Carl C; Mihelic, Samuel A; Alpar, Aaron T; Behar, Marcelo; Stachowiak, Jeanne C

    2018-03-27

    Receptor internalization by endocytosis regulates diverse cellular processes, from the rate of nutrient uptake to the timescale of essential signaling events. The established view is that internalization is tightly controlled by specific protein-binding interactions. However, recent work suggests that physical aspects of receptors influence the process in ways that cannot be explained by biochemistry alone. Specifically, work from several groups suggests that increasing the steric bulk of receptors may inhibit their uptake by multiple types of trafficking vesicles. How do biochemical and biophysical factors work together to control internalization? Here, we show that receptor uptake is well described by a thermodynamic trade-off between receptor-vesicle binding energy and the entropic cost of confining receptors within endocytic vesicles. Specifically, using large ligands to acutely increase the size of engineered variants of the transferrin receptor, we demonstrate that an increase in the steric bulk of a receptor dramatically decreases its probability of uptake by clathrin-coated structures. Further, in agreement with a simple thermodynamic analysis, all data collapse onto a single trend relating fractional occupancy of the endocytic structure to fractional occupancy of the surrounding plasma membrane, independent of receptor size. This fundamental scaling law provides a simple tool for predicting the impact of receptor expression level, steric bulk, and the size of endocytic structures on receptor uptake. More broadly, this work suggests that bulky ligands could be used to drive the accumulation of specific receptors at the plasma membrane surface, providing a biophysical tool for targeted modulation of signaling and metabolism from outside the cell. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  3. Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Kjaergard, L L; Gluud, C

    2001-01-01

    The pathogenesis of hepatic encephalopathy is unknown. It has been suggested that liver failure leads to the accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition which may progress to coma. Several trials have assessed benzodiazepine receptor...

  4. Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors

    International Nuclear Information System (INIS)

    Jäntti, Maria H.; Mandrika, Ilona; Kukkonen, Jyrki P.

    2014-01-01

    Highlights: • OX 1 and OX 2 orexin and CB 1 cannabinoid receptor dimerization was investigated. • Bioluminescence resonance energy transfer method was used. • All receptors readily formed constitutive homo- and heteromeric complexes. - Abstract: Human OX 1 orexin receptors have been shown to homodimerize and they have also been suggested to heterodimerize with CB 1 cannabinoid receptors. The latter has been suggested to be important for orexin receptor responses and trafficking. In this study, we wanted to assess the ability of the other combinations of receptors to also form similar complexes. Vectors for expression of human OX 1 , OX 2 and CB 1 receptors, C-terminally fused with either Renilla luciferase or GFP 2 green fluorescent protein variant, were generated. The constructs were transiently expressed in Chinese hamster ovary cells, and constitutive dimerization between the receptors was assessed by bioluminescence energy transfer (BRET). Orexin receptor subtypes readily formed homo- and hetero(di)mers, as suggested by significant BRET signals. CB 1 receptors formed homodimers, and they also heterodimerized with both orexin receptors. Interestingly, BRET efficiency was higher for homodimers than for almost all heterodimers. This is likely to be due to the geometry of the interaction; the putatively symmetric dimers may place the C-termini in a more suitable orientation in homomers. Fusion of luciferase to an orexin receptor and GFP 2 to CB 1 produced more effective BRET than the opposite fusions, also suggesting differences in geometry. Similar was seen for the OX 1 –OX 2 interaction. In conclusion, orexin receptors have a significant propensity to make homo- and heterodi-/oligomeric complexes. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB 1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations

  5. In human granulosa cells from small antral follicles, androgen receptor mRNA and androgen levels in follicular fluid correlate with FSH receptor mRNA

    DEFF Research Database (Denmark)

    Nielsen, M. E.; Rasmussen, I. A.; Kristensen, Stine Gry

    2011-01-01

    RNA analysis (24 women). Expression of Androgen Receptor (AR) mRNA levels in granulosa cells, and of androstenedione and testosterone in FF, were correlated to the expression of FSH receptor (FSHR), LH receptor (LHR), CYP19 and anti-Müllerian Hormone-receptor2 (AMHR2) mRNA in the granulosa cells and to the FF....... This suggests that follicular sensitivity towards FSH stimulation may be augmented by stimulation of androgens via the AR....

  6. An effective suggestion method for keyword search of databases

    KAUST Repository

    Huang, Hai

    2016-09-09

    This paper solves the problem of providing high-quality suggestions for user keyword queries over databases. With the assumption that the returned suggestions are independent, existing query suggestion methods over databases score candidate suggestions individually and return the top-k best of them. However, the top-k suggestions have high redundancy with respect to the topics. To provide informative suggestions, the returned k suggestions are expected to be diverse, i.e., maximizing the relevance to the user query and the diversity with respect to topics that the user might be interested in simultaneously. In this paper, an objective function considering both factors is defined for evaluating a suggestion set. We show that maximizing the objective function is a submodular function maximization problem subject to n matroid constraints, which is an NP-hard problem. An greedy approximate algorithm with an approximation ratio O((Formula presented.)) is also proposed. Experimental results show that our suggestion outperforms other methods on providing relevant and diverse suggestions. © 2016 Springer Science+Business Media New York

  7. Muscarinic receptor oligomerization.

    Science.gov (United States)

    Marsango, Sara; Ward, Richard J; Alvarez-Curto, Elisa; Milligan, Graeme

    2017-11-14

    G protein-coupled receptors (GPCRs) have been classically described as monomeric entities that function by binding in a 1:1 stoichiometric ratio to both ligand and downstream signalling proteins. However, in recent years, a growing number of studies has supported the hypothesis that these receptors can interact to form dimers and higher order oligomers although the molecular basis for these interactions, the overall quaternary arrangements and the functional importance of GPCR oligomerization remain topics of intense speculation. Muscarinic acetylcholine receptors belong to class A of the GPCR family. Each muscarinic receptor subtype has its own particular distribution throughout the central and peripheral nervous systems. In the central nervous system, muscarinic receptors regulate several sensory, cognitive, and motor functions while, in the peripheral nervous system, they are involved in the regulation of heart rate, stimulation of glandular secretion and smooth muscle contraction. Muscarinic acetylcholine receptors have long been used as a model for the study of GPCR structure and function and to address aspects of GPCR dimerization using a broad range of approaches. In this review, the prevailing knowledge regarding the quaternary arrangement for the various muscarinic acetylcholine receptors has been summarized by discussing work ranging from initial results obtained using more traditional biochemical approaches to those generated with more modern biophysical techniques. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Vitamin D Receptor and Calcium Sensing Receptor Polymorphisms and the Risk of Colorectal Cancer in European Populations

    NARCIS (Netherlands)

    Jenab, Mazda; McKay, James; Bueno-de-Mesquita, Hendrik B.; van Duijnhoven, Franzel J. B.; Ferrari, Pietro; Slimani, Nadia; Jansen, Eugene H. J. M.; Pischon, Tobias; Rinaldi, Sabina; Tjonneland, Anne; Olsen, Anja; Overvad, Kim; Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Francoise; Engel, Pierre; Kaaks, Rudolf; Linseisen, Jakob; Boeing, Heiner; Fisher, Eva; Trichopoulou, Antonia; Dilis, Vardis; Oustoglou, Erifili; Berrino, Franco; Vineis, Paolo; Mattiello, Amalia; Masala, Giovanna; Tumino, Rosario; Vrieling, Alina; van Gils, Carla H.; Peeters, Petra H.; Brustad, Magritt; Lund, Eiliv; Chirlaque, Maria-Dolores; Barricarte, Aurelio; Rodriguez Suarez, Laudina; Molina, Esther; Dorronsoro, Miren; Sala, Nuria; Hallmans, Goran; Palmqvist, Richard; Roddam, Andrew; Key, Timothy J.; Khaw, Kay-Tee; Bingham, Sheila; Boffetta, Paolo; Autier, Philippe; Byrnes, Graham; Norat, Teresa; Riboli, Elio

    Increased levels of vitamin D and calcium may play a protective role in colorectal cancer (CRC) risk. It has been suggested that these effects may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR). However, current epidemiologic evidence from

  9. Moth sex pheromone receptors and deceitful parapheromones.

    Directory of Open Access Journals (Sweden)

    Pingxi Xu

    Full Text Available The insect's olfactory system is so selective that male moths, for example, can discriminate female-produced sex pheromones from compounds with minimal structural modifications. Yet, there is an exception for this "lock-and-key" tight selectivity. Formate analogs can be used as replacement for less chemically stable, long-chain aldehyde pheromones, because male moths respond physiologically and behaviorally to these parapheromones. However, it remained hitherto unknown how formate analogs interact with aldehyde-sensitive odorant receptors (ORs. Neuronal responses to semiochemicals were investigated with single sensillum recordings. Odorant receptors (ORs were cloned using degenerate primers, and tested with the Xenopus oocyte expression system. Quality, relative quantity, and purity of samples were evaluated by gas chromatography and gas chromatography-mass spectrometry. We identified olfactory receptor neurons (ORNs housed in trichoid sensilla on the antennae of male navel orangeworm that responded equally to the main constituent of the sex pheromone, (11Z,13Z-hexadecadienal (Z11Z13-16Ald, and its formate analog, (9Z,11Z-tetradecen-1-yl formate (Z9Z11-14OFor. We cloned an odorant receptor co-receptor (Orco and aldehyde-sensitive ORs from the navel orangeworm, one of which (AtraOR1 was expressed specifically in male antennae. AtraOR1•AtraOrco-expressing oocytes responded mainly to Z11Z13-16Ald, with moderate sensitivity to another component of the sex pheromone, (11Z,13Z-hexadecadien-1-ol. Surprisingly, this receptor was more sensitive to the related formate than to the natural sex pheromone. A pheromone receptor from Heliothis virescens, HR13 ( = HvirOR13 showed a similar profile, with stronger responses elicited by a formate analog than to the natural sex pheromone, (11Z-hexadecenal thus suggesting this might be a common feature of moth pheromone receptors.

  10. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  11. P2X receptors

    OpenAIRE

    North, R. Alan

    2016-01-01

    Extracellular adenosine 5′-triphosphate (ATP) activates cell surface P2X and P2Y receptors. P2X receptors are membrane ion channels preferably permeable to sodium, potassium and calcium that open within milliseconds of the binding of ATP. In molecular architecture, they form a unique structural family. The receptor is a trimer, the binding of ATP between subunits causes them to flex together within the ectodomain and separate in the membrane-spanning region so as to open a central channel. P2...

  12. Serotonin Receptors in Hippocampus

    Science.gov (United States)

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

  13. Placebo-Suggestion Modulates Conflict Resolution in the Stroop Task

    Science.gov (United States)

    Caspar, Emilie A.; Gevers, Wim; Cleeremans, Axel

    2013-01-01

    Here, we ask whether placebo-suggestion (without any form of hypnotic induction) can modulate the resolution of cognitive conflict. Naïve participants performed a Stroop Task while wearing an EEG cap described as a “brain wave” machine. In Experiment 1, participants were made to believe that the EEG cap would either enhance or decrease their color perception and performance on the Stroop task. In Experiment 2, participants were explicitly asked to imagine that their color perception and performance would be enhanced or decreased (non-hypnotic imaginative suggestion). We observed effects of placebo-suggestion on Stroop interference on accuracy: interference was decreased with positive suggestion and increased with negative suggestion compared to baseline. Intra-individual variability was also increased under negative suggestion compared to baseline. Compliance with the instruction to imagine a modulation of performance, on the other hand, did not influence accuracy and only had a negative impact on response latencies and on intra-individual variability, especially in the congruent condition of the Stroop Task. Taken together, these results demonstrate that expectations induced by a placebo-suggestion can modulate our ability to resolve cognitive conflict, either facilitating or impairing response accuracy depending on the suggestion’s contents. Our results also demonstrate a dissociation between placebo-suggestion and non-hypnotic imaginative suggestion. PMID:24130735

  14. AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons

    DEFF Research Database (Denmark)

    Rathje, Mette; Fang, Huaqiang; Bachman, Julia L

    2013-01-01

    NMDA receptor activation promotes endocytosis of AMPA receptors, which is an important mechanism underlying long-term synaptic depression. The pH-sensitive GFP variant pHluorin fused to the N terminus of GluA2 (pH-GluA2) has been used to assay NMDA-mediated AMPA receptor endocytosis and recycling...... recovery was eliminated in the presence of the NHE1 inhibitor zoniporide. Our results indicate that the pH-GluA2 recycling assay is an unreliable assay for studying AMPA receptor trafficking and also suggest a role for PICK1 in regulating intracellular pH via modulation of NHE activity....

  15. Histamine H4 receptor antagonists: the new antihistamines?

    Science.gov (United States)

    Fung-Leung, Wai-Ping; Thurmond, Robin L; Ling, Ping; Karlsson, Lars

    2004-11-01

    Antihistamines (histamine H1 receptor antagonists) are a mainstay treatment for atopic allergy, yet they are only partially effective in relieving the symptoms of the disease. They also have very limited value for the treatment of asthma, despite the well-characterized bronchoconstrictory effects of histamine. The recent discovery of a fourth histamine receptor (H4), and the realization that it is exclusively expressed on hematopoietic cell types that are most implicated in the development and symptomatology of allergy and asthma, suggests that pharmacological targeting of the H4 receptor, either alone or in combination with H1 receptor antagonists, may prove useful for treating both allergy and asthma. Here we review the known biology associated with the H4 receptor, as well the effects of a highly selective H1 receptor antagonist.

  16. The Antibodies against the Computationally Designed Mimic of the Glycoprotein Hormone Receptor Transmembrane Domain Provide Insights into Receptor Activation and Suppress the Constitutively Activated Receptor Mutants*

    Science.gov (United States)

    Majumdar, Ritankar; Railkar, Reema; Dighe, Rajan R.

    2012-01-01

    The exoloops of glycoprotein hormone receptors (GpHRs) transduce the signal generated by the ligand-ectodomain interactions to the transmembrane helices either through direct hormonal contact and/or by modulating the interdomain interactions between the hinge region (HinR) and the transmembrane domain (TMD). The ligand-induced conformational alterations in the HinRs and the interhelical loops of luteinizing hormone receptor/follicle stimulating hormone receptor/thyroid stimulating hormone receptor were mapped using exoloop-specific antibodies generated against a mini-TMD protein designed to mimic the native exoloop conformations that were created by joining the thyroid stimulating hormone receptor exoloops constrained through helical tethers and library-derived linkers. The antibody against the mini-TMD specifically recognized all three GpHRs and inhibited the basal and hormone-stimulated cAMP production without affecting hormone binding. Interestingly, binding of the antibody to all three receptors was abolished by prior incubation of the receptors with the respective hormones, suggesting that the exoloops are buried in the hormone-receptor complexes. The antibody also suppressed the high basal activities of gain-of-function mutations in the HinRs, exoloops, and TMDs such as those involved in precocious puberty and thyroid toxic adenomas. Using the antibody and point/deletion/chimeric receptor mutants, we demonstrate that changes in the HinR-exoloop interactions play an important role in receptor activation. Computational analysis suggests that the mini-TMD antibodies act by conformationally locking the transmembrane helices by means of restraining the exoloops and the juxta-membrane regions. Using GpHRs as a model, we describe a novel computational approach of generating soluble TMD mimics that can be used to explain the role of exoloops during receptor activation and their interplay with TMDs. PMID:22904318

  17. Therapeutic suggestion has no effect on postoperative morphine requirements

    NARCIS (Netherlands)

    W.H. van der Laan (W.); B.L. van Leeuwen (B.); P.S. Sebel (P.); E. Winograd (E.); P. Baumann (P.); B. Bonke (Benno)

    1996-01-01

    textabstractThis study was designed to confirm the effect of therapeutic intraoperative auditory suggestion on recovery from anesthesia, to establish the effect of preoperative suggestion, and to assess implicit memory for intraoperative information using an indirect memory task. Sixty consenting

  18. Theory-of-Mind Development Influences Suggestibility and Source Monitoring

    Science.gov (United States)

    Bright-Paul, Alexandra; Jarrold, Christopher; Wright, Daniel B.

    2008-01-01

    According to the mental-state reasoning model of suggestibility, 2 components of theory of mind mediate reductions in suggestibility across the preschool years. The authors examined whether theory-of-mind performance may be legitimately separated into 2 components and explored the memory processes underlying the associations between theory of mind…

  19. Simple suggestions for including vertical physics in oil spill models

    International Nuclear Information System (INIS)

    D'Asaro, Eric; University of Washington, Seatle, WA

    2001-01-01

    Current models of oil spills include no vertical physics. They neglect the effect of vertical water motions on the transport and concentration of floating oil. Some simple ways to introduce vertical physics are suggested here. The major suggestion is to routinely measure the density stratification of the upper ocean during oil spills in order to develop a database on the effect of stratification. (Author)

  20. Critical Success Factors of Suggestions Systems. | Marx | IFE ...

    African Journals Online (AJOL)

    A literature study approach is followed to establish which factors contribute to the success and failure of various suggestion systems. It was found ... The value of the paper firstly, shows the importance of creativity and innovation within the organisation's own culture and the framework of a formal suggestion system. Secondly ...

  1. User Simulations for Interactive Search : Evaluating Personalized Query Suggestion

    NARCIS (Netherlands)

    Verberne, S.; Sappelli, M.; Järvelin, K.; Kraaij, W.

    2015-01-01

    In this paper, we address the question “what is the influence of user search behaviour on the effectiveness of personalized query suggestion?”. We implemented a method for query suggestion that generates candidate follow-up queries from the documents clicked by the user. This is a potentially

  2. Students' Suggestions for Eliminating Bullying at a University

    Science.gov (United States)

    Meriläinen, Matti; Puhakka, Helena; Sinkkonen, Hanna-Maija

    2015-01-01

    Students' suggestions for how to eliminate bullying at universities were gathered as part of an e-questionnaire sent to each university student (N = 10,551) at a Finnish university. The suggestions (n = 2804) regarding how to address bullying at universities were divided into the following four classes: support (944), punishment (78), support and…

  3. Exploration of Opinion-aware Approach to Contextual Suggestion

    Science.gov (United States)

    2014-11-01

    are selected since they cover 1 http://www.yelp.com Report Documentation Page Form ApprovedOMB No. 0704-0188 Public reporting burden for the collection...suggestion are crawled. Approximately 60,442 candidate sug- gestions are crawled for all contexts, resulting in average 1208 candidate suggestions per

  4. Enhancing business intelligence by means of suggestive reviews.

    Science.gov (United States)

    Qazi, Atika; Raj, Ram Gopal; Tahir, Muhammad; Cambria, Erik; Syed, Karim Bux Shah

    2014-01-01

    Appropriate identification and classification of online reviews to satisfy the needs of current and potential users pose a critical challenge for the business environment. This paper focuses on a specific kind of reviews: the suggestive type. Suggestions have a significant influence on both consumers' choices and designers' understanding and, hence, they are key for tasks such as brand positioning and social media marketing. The proposed approach consists of three main steps: (1) classify comparative and suggestive sentences; (2) categorize suggestive sentences into different types, either explicit or implicit locutions; (3) perform sentiment analysis on the classified reviews. A range of supervised machine learning approaches and feature sets are evaluated to tackle the problem of suggestive opinion mining. Experimental results for all three tasks are obtained on a dataset of mobile phone reviews and demonstrate that extending a bag-of-words representation with suggestive and comparative patterns is ideal for distinguishing suggestive sentences. In particular, it is observed that classifying suggestive sentences into implicit and explicit locutions works best when using a mixed sequential rule feature representation. Sentiment analysis achieves maximum performance when employing additional preprocessing in the form of negation handling and target masking, combined with sentiment lexicons.

  5. Suggestibility, intelligence, memory recall and personality: an experimental study.

    Science.gov (United States)

    Gudjonsson, G H

    1983-01-01

    A new suggestibility test, potentially useful in the context of police interrogation, was administered to 45 subjects who also completed the Wechsler Adult Intelligence Scale and the Eysenck Personality Questionnaire. Suggestibility was significantly related to low intelligence, poor memory recall, neuroticism and social desirability.

  6. Hypnotic suggestibility predicts the magnitude of the imaginative word blindness suggestion effect in a non-hypnotic context.

    Science.gov (United States)

    Parris, Benjamin A; Dienes, Zoltan

    2013-09-01

    The present study investigated how the magnitude the word blindness suggestion effect on Stroop interference depended on hypnotic suggestibility when given as an imaginative suggestion (i.e. not post-hypnotic suggestion) and under conditions in which hypnosis was not mentioned. Hypnotic suggestibility is shown to be a significant predictor of the magnitude of the imaginative word blindness suggestion effect under these conditions. This is therefore the first study to show a linear relationship between the imaginative word blindness suggestion effect and hypnotic suggestibility across the whole hypnotizability spectrum. The results replicate previous findings showing that highs respond to the word blindness suggestion to a greater extent than lows but extend previous work by showing that the advantage for those higher on the hypnotizability spectrum occurs even in a non-hypnotic context. Negative attitudes about hypnosis may not explain the failure to observe similar effects of the word blindness suggestion in less hypnotizable individuals. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Cellular prion protein and NMDA receptor modulation: protecting against excitotoxicity

    Directory of Open Access Journals (Sweden)

    Stefanie A.G. Black

    2014-08-01

    Full Text Available Although it is well established that misfolding of the cellular prion protein (PrPC into the beta-sheet-rich, aggregated scrapie conformation (PrPSc causes a variety of transmissible spongiform encephalopathies (TSEs, the physiological roles of PrPC are still incompletely understood. There is accumulating evidence describing the roles of PrPC in neurodegeneration and neuroinflammation. Recently, we identified a functional regulation of NMDA receptors by PrPC that involves formation of a physical protein complex between these proteins. Excessive NMDA receptor activity during conditions such as ischemia mediates enhanced Ca2+ entry into cells and contributes to excitotoxic neuronal death. In addition, NMDA receptors and/or PrPC play critical roles in neuroinflammation and glial cell toxicity. Inhibition of NMDA receptor activity protects against PrPSc-induced neuronal death. Moreover, in mice lacking PrPC, infarct size is increased after focal cerebral ischemia, and absence of PrPC increases susceptibility of neurons to NMDA receptor-dependent death. Recently, PrPC was found to be a receptor for oligomeric beta-amyloid (Abeta peptides, suggesting a role for PrPC in Alzheimer’s disease. Our recent findings suggest that Abeta peptides enhance NMDA receptor current by perturbing the normal copper- and PrPC-dependent regulation of these receptors. Here, we review evidence highlighting a role for PrPC in preventing NMDA receptor-mediated excitotoxicity and inflammation. There is a need for more detailed molecular characterization of PrPC-mediated regulation of NMDA receptors, such as determining which NMDA receptor subunits mediate pathogenic effects upon loss of PrPC-mediated regulation and identifying PrPC binding site(s on the receptor. This knowledge will allow development of novel therapeutic interventions for not only TSEs, but also for Alzheimer’s disease and other neurodegenerative disorders involving dysfunction of PrPC.

  8. Somatostatin receptor skintigrafi

    DEFF Research Database (Denmark)

    Rasmussen, Karin; Nielsen, Jørn Theil; Rehling, Michael

    2005-01-01

    Somatostatin receptor scintigraphy (SRS) is a very valuable imaging technique for visualisation of a diversity of neuroendocrine tumours. The sensitivity for localisation of carcinoid tumours is high, but somewhat lower for other neuroendocrine tumours. The methodology, multiple clinical aspects ...

  9. The impact of hypnotic suggestibility in clinical care settings

    Science.gov (United States)

    Montgomery, Guy H.; Schnur, Julie B.; David, Daniel

    2013-01-01

    Hypnotic suggestibility has been described as a powerful predictor of outcomes associated with hypnotic interventions. However, there have been no systematic approaches to quantifying this effect across the literature. The present meta-analysis evaluates the magnitude of the effect of hypnotic suggestibility on hypnotic outcomes in clinical settings. PsycINFO and PubMed were searched from their inception through July 2009. Thirty-four effects from ten studies and 283 participants are reported. Results revealed a statistically significant overall effect size in the small to medium range (r = 0.24; 95% Confidence Interval = −0.28 to 0.75), indicating that greater hypnotic suggestibility led to greater effects of hypnosis interventions. Hypnotic suggestibility accounted for 6% of the variance in outcomes. Smaller sample size studies, use of the SHCS, and pediatric samples tended to result in larger effect sizes. Results question the usefulness of assessing hypnotic suggestibility in clinical contexts. PMID:21644122

  10. Using suggestion to model different types of automatic writing.

    Science.gov (United States)

    Walsh, E; Mehta, M A; Oakley, D A; Guilmette, D N; Gabay, A; Halligan, P W; Deeley, Q

    2014-05-01

    Our sense of self includes awareness of our thoughts and movements, and our control over them. This feeling can be altered or lost in neuropsychiatric disorders as well as in phenomena such as "automatic writing" whereby writing is attributed to an external source. Here, we employed suggestion in highly hypnotically suggestible participants to model various experiences of automatic writing during a sentence completion task. Results showed that the induction of hypnosis, without additional suggestion, was associated with a small but significant reduction of control, ownership, and awareness for writing. Targeted suggestions produced a double dissociation between thought and movement components of writing, for both feelings of control and ownership, and additionally, reduced awareness of writing. Overall, suggestion produced selective alterations in the control, ownership, and awareness of thought and motor components of writing, thus enabling key aspects of automatic writing, observed across different clinical and cultural settings, to be modelled. Copyright © 2014. Published by Elsevier Inc.

  11. Muscarinic receptor oligomerization

    OpenAIRE

    Marsango, Sara; Ward, Richard J.; Alvarez-Curto, Elisa; Milligan, Graeme

    2017-01-01

    G protein-coupled receptors (GPCRs) have been classically described as monomeric entities that function by binding in a 1:1 stoichiometric ratio to both ligand and downstream signalling proteins. However, in recent years, a growing number of studies has supported the hypothesis that these receptors can interact to form dimers and higher order oligomers although the molecular basis for these interactions, the overall quaternary arrangements and the functional importance of GPCR oligomerization...

  12. Cannabinoid Receptors: A Novel Target for Treating Prostate Cancer

    National Research Council Canada - National Science Library

    Mukhtar, Hasan; Afaq, Farrukh; Sarfaraz, Sami

    2006-01-01

    .... Based on these data we suggested that WlN-55,212-2 or other non-habit forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer (Sarfaraz et al., 2005...

  13. Early events triggering delayed vasoconstrictor receptor upregulation and cerebral ischemia after subarachnoid hemorrhage

    DEFF Research Database (Denmark)

    Povlsen, Gro Klitgaard; Johansson, Sara Ellinor; Larsen, Carl Christian

    2013-01-01

    Upregulation of vasoconstrictor receptors in cerebral arteries, including endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors, has been suggested to contribute to delayed cerebral ischemia, a feared complication after subarachnoid hemorrhage (SAH). This receptor upregulation has been...

  14. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis.

    Science.gov (United States)

    Janero, David R; Makriyannis, Alexandros

    2009-03-01

    The endogenous cannabinoid (CB) (endocannabinoid) signaling system is involved in a variety of (patho)physiological processes, primarily by virtue of natural, arachidonic acid-derived lipids (endocannabinoids) that activate G protein-coupled CB1 and CB2 receptors. A hyperactive endocannabinoid system appears to contribute to the etiology of several disease states that constitute significant global threats to human health. Consequently, mounting interest surrounds the design and profiling of receptor-targeted CB antagonists as pharmacotherapeutics that attenuate endocannabinoid transmission for salutary gain. Experimental and clinical evidence supports the therapeutic potential of CB1 receptor antagonists to treat overweight/obesity, obesity-related cardiometabolic disorders, and substance abuse. Laboratory data suggest that CB2 receptor antagonists might be effective immunomodulatory and, perhaps, anti-inflammatory drugs. One CB1 receptor antagonist/inverse agonist, rimonabant, has emerged as the first-in-class drug approved outside the United States for weight control. Select follow-on agents (taranabant, otenabant, surinabant, rosonabant, SLV-319, AVE1625, V24343) have also been studied in the clinic. However, rimonabant's market withdrawal in the European Union and suspension of rimonabant's, taranabant's, and otenabant's ongoing development programs have highlighted some adverse clinical side effects (especially nausea and psychiatric disturbances) of CB1 receptor antagonists/inverse agonists. Novel CB1 receptor ligands that are peripherally directed and/or exhibit neutral antagonism (the latter not affecting constitutive CB1 receptor signaling) may optimize the benefits of CB1 receptor antagonists while minimizing any risk. Indeed, CB1 receptor-neutral antagonists appear from preclinical data to offer efficacy comparable to or better than that of prototype CB1 receptor antagonists/inverse agonists, with less propensity to induce nausea. Continued

  15. Anaesthetic Impairment of Immune Function Is Mediated via GABAA Receptors

    Science.gov (United States)

    Wheeler, Daniel W.; Thompson, Andrew J.; Corletto, Federico; Reckless, Jill; Loke, Justin C. T.; Lapaque, Nicolas; Grant, Andrew J.; Mastroeni, Pietro; Grainger, David J.; Padgett, Claire L.; O'Brien, John A.; Miller, Nigel G. A.; Trowsdale, John

    2011-01-01

    Background GABAA receptors are members of the Cys-loop family of neurotransmitter receptors, proteins which are responsible for fast synaptic transmission, and are the site of action of wide range of drugs [1]. Recent work has shown that Cys-loop receptors are present on immune cells, but their physiological roles and the effects of drugs that modify their function in the innate immune system are currently unclear [2]. We are interested in how and why anaesthetics increase infections in intensive care patients; a serious problem as more than 50% of patients with severe sepsis will die [3]–[6]. As many anaesthetics act via GABAA receptors [7], the aim of this study was to determine if these receptors are present on immune cells, and could play a role in immunocompromising patients. Principal Findings We demonstrate, using RT-PCR, that monocytes express GABAA receptors constructed of α1, α4, β2, γ1 and/or δ subunits. Whole cell patch clamp electrophysiological studies show that GABA can activate these receptors, resulting in the opening of a chloride-selective channel; activation is inhibited by the GABAA receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABAA receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin. Significance Our results show that functional GABAA receptors are present on monocytes with properties similar to CNS GABAA receptors. The functional data provide a possible explanation as to why chronic propofol and thiopental administration can increase the risk of infection in critically ill patients: their action on GABAA receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABAA receptors are insensitive to diazepam, thus the use of benzodiazepines as an alternative anesthetising agent may be

  16. Adenosine receptor neurobiology: overview.

    Science.gov (United States)

    Chen, Jiang-Fan; Lee, Chien-fei; Chern, Yijuang

    2014-01-01

    Adenosine is a naturally occurring nucleoside that is distributed ubiquitously throughout the body as a metabolic intermediary. In the brain, adenosine functions as an important upstream neuromodulator of a broad spectrum of neurotransmitters, receptors, and signaling pathways. By acting through four G-protein-coupled receptors, adenosine contributes critically to homeostasis and neuromodulatory control of a variety of normal and abnormal brain functions, ranging from synaptic plasticity, to cognition, to sleep, to motor activity to neuroinflammation, and cell death. This review begun with an overview of the gene and genome structure and the expression pattern of adenosine receptors (ARs). We feature several new developments over the past decade in our understanding of AR functions in the brain, with special focus on the identification and characterization of canonical and noncanonical signaling pathways of ARs. We provide an update on functional insights from complementary genetic-knockout and pharmacological studies on the AR control of various brain functions. We also highlight several novel and recent developments of AR neurobiology, including (i) recent breakthrough in high resolution of three-dimension structure of adenosine A2A receptors (A2ARs) in several functional status, (ii) receptor-receptor heterodimerization, (iii) AR function in glial cells, and (iv) the druggability of AR. We concluded the review with the contention that these new developments extend and strengthen the support for A1 and A2ARs in brain as therapeutic targets for neurologic and psychiatric diseases. © 2014 Elsevier Inc. All rights reserved.

  17. Genetics of taste receptors.

    Science.gov (United States)

    Bachmanov, Alexander A; Bosak, Natalia P; Lin, Cailu; Matsumoto, Ichiro; Ohmoto, Makoto; Reed, Danielle R; Nelson, Theodore M

    2014-01-01

    Taste receptors function as one of the interfaces between internal and external milieus. Taste receptors for sweet and umami (T1R [taste receptor, type 1]), bitter (T2R [taste receptor, type 2]), and salty (ENaC [epithelial sodium channel]) have been discovered in the recent years, but transduction mechanisms of sour taste and ENaC-independent salt taste are still poorly understood. In addition to these five main taste qualities, the taste system detects such noncanonical "tastes" as water, fat, and complex carbohydrates, but their reception mechanisms require further research. Variations in taste receptor genes between and within vertebrate species contribute to individual and species differences in taste-related behaviors. These variations are shaped by evolutionary forces and reflect species adaptations to their chemical environments and feeding ecology. Principles of drug discovery can be applied to taste receptors as targets in order to develop novel taste compounds to satisfy demand in better artificial sweeteners, enhancers of sugar and sodium taste, and blockers of bitterness of food ingredients and oral medications.

  18. Mechanisms of eyewitness suggestibility: tests of the explanatory role hypothesis.

    Science.gov (United States)

    Rindal, Eric J; Chrobak, Quin M; Zaragoza, Maria S; Weihing, Caitlin A

    2017-10-01

    In a recent paper, Chrobak and Zaragoza (Journal of Experimental Psychology: General, 142(3), 827-844, 2013) proposed the explanatory role hypothesis, which posits that the likelihood of developing false memories for post-event suggestions is a function of the explanatory function the suggestion serves. In support of this hypothesis, they provided evidence that participant-witnesses were especially likely to develop false memories for their forced fabrications when their fabrications helped to explain outcomes they had witnessed. In three experiments, we test the generality of the explanatory role hypothesis as a mechanism of eyewitness suggestibility by assessing whether this hypothesis can predict suggestibility errors in (a) situations where the post-event suggestions are provided by the experimenter (as opposed to fabricated by the participant), and (b) across a variety of memory measures and measures of recollective experience. In support of the explanatory role hypothesis, participants were more likely to subsequently freely report (E1) and recollect the suggestions as part of the witnessed event (E2, source test) when the post-event suggestion helped to provide a causal explanation for a witnessed outcome than when it did not serve this explanatory role. Participants were also less likely to recollect the suggestions as part of the witnessed event (on measures of subjective experience) when their explanatory strength had been reduced by the presence of an alternative explanation that could explain the same outcome (E3, source test + warning). Collectively, the results provide strong evidence that the search for explanatory coherence influences people's tendency to misremember witnessing events that were only suggested to them.

  19. FGF receptor genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Agarwal, D; Pineda, S; Michailidou, K

    2014-01-01

    Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying...... was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.Conclusion:Our results suggest...

  20. Orchestrated regulation of Nogo receptors, LOTUS, AMPA receptors and BDNF in an ECT model suggests opening and closure of a window of synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Max Nordgren

    Full Text Available Electroconvulsive therapy (ECT is an efficient and relatively fast acting treatment for depression. However, one severe side effect of the treatment is retrograde amnesia, which in certain cases can be long-term. The mechanisms behind the antidepressant effect and the amnesia are not well understood. We hypothesized that ECT causes transient downregulation of key molecules needed to stabilize synaptic structure and to prevent Ca2+ influx, and a simultaneous increase in neurotrophic factors, thus providing a short time window of increased structural synaptic plasticity. Here we followed regulation of NgR1, NgR3, LOTUS, BDNF, and AMPA subunits GluR1 and GluR2 flip and flop mRNA levels in hippocampus at 2, 4, 12, 24, and 72 hours after a single episode of induced electroconvulsive seizures (ECS in rats. NgR1 and LOTUS mRNA levels were transiently downregulated in the dentate gyrus 2, 4, 12 and 4, 12, 24 h after ECS treatment, respectively. GluR2 flip, flop and GluR1 flop were downregulated at 4 h. GluR2 flip remained downregulated at 12 h. In contrast, BDNF, NgR3 and GluR1 flip mRNA levels were upregulated. Thus, ECS treatment induces a transient regulation of factors important for neuronal plasticity. Our data provide correlations between ECS treatment and molecular events compatible with the hypothesis that both effects and side effects of ECT may be caused by structural synaptic rearrangements.

  1. Orchestrated Regulation of Nogo Receptors, Lotus, AMPA Receptors and BDNF in an ECT Model Suggests Opening and Closure of a Window of Synaptic Plasticity

    OpenAIRE

    Nordgren, Max; Karlsson, Tobias; Svensson, Maria; Koczy, Josefin; Josephson, Anna; Olson, Lars; Tingstroem, Anders; Brene, Stefan

    2013-01-01

    Electroconvulsive therapy (ECT) is an efficient and relatively fast acting treatment for depression. However, one severe side effect of the treatment is retrograde amnesia, which in certain cases can be long-term. The mechanisms behind the antidepressant effect and the amnesia are not well understood. We hypothesized that ECT causes transient downregulation of key molecules needed to stabilize synaptic structure and to prevent Ca2+ influx, and a simultaneous increase in neurotrophic factors, ...

  2. Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS.

    Science.gov (United States)

    Leonhardt, Julia; Villela, Daniel C; Teichmann, Anke; Münter, Lisa-Marie; Mayer, Magnus C; Mardahl, Maibritt; Kirsch, Sebastian; Namsolleck, Pawel; Lucht, Kristin; Benz, Verena; Alenina, Natalia; Daniell, Nicholas; Horiuchi, Masatsugu; Iwai, Masaru; Multhaup, Gerhard; Schülein, Ralf; Bader, Michael; Santos, Robson A; Unger, Thomas; Steckelings, Ulrike Muscha

    2017-06-01

    The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may indicate heterodimerization of these receptors. Therefore, this study investigated the molecular and functional interplay between MAS and the AT2R. Molecular interactions were assessed by fluorescence resonance energy transfer and by cross correlation spectroscopy in human embryonic kidney-293 cells transfected with vectors encoding fluorophore-tagged MAS or AT2R. Functional interaction of AT2R and MAS was studied in astrocytes with CX3C chemokine receptor-1 messenger RNA expression as readout. Coexpression of fluorophore-tagged AT2R and MAS resulted in a fluorescence resonance energy transfer efficiency of 10.8 ± 0.8%, indicating that AT2R and MAS are capable to form heterodimers. Heterodimerization was verified by competition experiments using untagged AT2R and MAS. Specificity of dimerization of AT2R and MAS was supported by lack of dimerization with the transient receptor potential cation channel, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked by an AT2R antagonist (PD123319) and also by a MAS antagonist (A-779). Knockout of a single of these receptors made astrocytes unresponsive for both agonists. Our results suggest that MAS and the AT2R form heterodimers and that-at least in astrocytes-both receptors functionally depend on each other. © 2017 American Heart Association, Inc.

  3. Cell-Surface Receptors Transactivation Mediated by G Protein-Coupled Receptors

    Science.gov (United States)

    Cattaneo, Fabio; Guerra, Germano; Parisi, Melania; De Marinis, Marta; Tafuri, Domenico; Cinelli, Mariapia; Ammendola, Rosario

    2014-01-01

    G protein-coupled receptors (GPCRs) are seven transmembrane-spanning proteins belonging to a large family of cell-surface receptors involved in many intracellular signaling cascades. Despite GPCRs lack intrinsic tyrosine kinase activity, tyrosine phosphorylation of a tyrosine kinase receptor (RTK) occurs in response to binding of specific agonists of several such receptors, triggering intracellular mitogenic cascades. This suggests that the notion that GPCRs are associated with the regulation of post-mitotic cell functions is no longer believable. Crosstalk between GPCR and RTK may occur by different molecular mechanism such as the activation of metalloproteases, which can induce the metalloprotease-dependent release of RTK ligands, or in a ligand-independent manner involving membrane associated non-receptor tyrosine kinases, such as c-Src. Reactive oxygen species (ROS) are also implicated as signaling intermediates in RTKs transactivation. Intracellular concentration of ROS increases transiently in cells stimulated with GPCR agonists and their deliberated and regulated generation is mainly catalyzed by enzymes that belong to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family. Oxidation and/or reduction of cysteine sulfhydryl groups of phosphatases tightly controls the activity of RTKs and ROS-mediated inhibition of cellular phosphatases results in an equilibrium shift from the non-phosphorylated to the phosphorylated state of RTKs. Many GPCR agonists activate phospholipase C, which catalyze the hydrolysis of phosphatidylinositol 4,5-bis-phosphate to produce inositol 1,4,5-triphosphate and diacylglicerol. The consequent mobilization of Ca2+ from endoplasmic reticulum leads to the activation of protein kinase C (PKC) isoforms. PKCα mediates feedback inhibition of RTK transactivation during GPCR stimulation. Recent data have expanded the coverage of transactivation to include Serine/Threonine kinase receptors and Toll-like receptors. Herein, we

  4. 32 CFR 1900.04 - Suggestions and complaints.

    Science.gov (United States)

    2010-07-01

    ... complaints. The Agency welcomes suggestions or complaints with regard to its administration of the Freedom of Information Act. Many requesters will receive pre-paid, customer satisfaction survey cards. Letters of...

  5. Sexual Harrassment: Suggested Policy and Procedures for Handling Complaints.

    Science.gov (United States)

    Academe, 1983

    1983-01-01

    AAUP guidelines on establishing institutional policy and procedures for handling sexual harassment complaints are outlined. Sexual harassment is defined and procedures for both bringing and resolving a complaint are suggested. (MSE)

  6. Using Neurolinguistic Programming: Some Suggestions for the Remedial Teacher.

    Science.gov (United States)

    Burton, Grace M.

    1986-01-01

    The use of neurolinguistic programming techniques is suggested as a means of enhancing rapport with students. Mirroring, digital mirroring, analog mirroring, metaphors, knowing persons, and how these aid in presenting content are each discussed. (MNS)

  7. Regulating professional behavior: codes of ethics or law? Suggested criteria.

    Science.gov (United States)

    Libman, Liron A

    2013-09-01

    This paper suggests considering a few parameters when making policy decisions as to the proper "tool" to regulate professional behavior: law or professional ethics. This is done on the background of understanding the place of codes of professional ethics between "pure" ethics and law. Suggested criteria are then illustrated using a few examples. Further discourse may reveal additional factors to support a more rational process of decision-making in this field.

  8. Molecular piracy of chemokine receptors by herpesviruses.

    Science.gov (United States)

    Murphy, P M

    1994-01-01

    To succeed as a biological entity, viruses must exploit normal cellular functions and elude the host immune system; they often do so by molecular mimicry. One way that mimicry may occur is when viruses copy and modify host genes. The best studied examples of this are the oncogenes of RNA retroviruses, but a growing number of examples are also known for DNA viruses. So far they all come from just two groups of DNA viruses, the herpesviruses and poxviruses, and the majority of examples are for genes whose products regulate immune responses, such as cytokines, cytokine receptors, and complement control proteins. This review will focus on human and herpesvirus receptors for chemokines, a family of leukocyte chemoattractant and activating factors that are thought to be important mediators of inflammation. Although the biological roles of the viral chemokine receptor homologues are currently unknown, their connection to specific sets of chemokines has suggested a number of possible functions.

  9. Humanin and the receptors for humanin.

    Science.gov (United States)

    Matsuoka, Masaaki; Hashimoto, Yuichi

    2010-02-01

    Alzheimer's disease (AD) is a prevalent dementia-causing neurodegenerative disease. Neuronal death is closely linked to the progression of AD-associated dementia. Accumulating evidence has established that a 24-amino-acid bioactive peptide, Humanin, protects neurons from AD-related neuronal death. A series of studies using various murine AD models including familial AD gene-expressing transgenic mice have shown that Humanin is effective against AD-related neuronal dysfunction in vivo. Most recently, it has been shown that Humanin inhibits neuronal cell death and dysfunction by binding to a novel IL-6-receptor-related receptor(s) on the cell surface involving CNTFRalpha, WSX-1, and gp130. These findings suggest that endogenous Humanin [or a Humanin-like substance(s)] may suppress the onset of AD-related dementia by inhibiting both AD-related neuronal cell death and dysfunction.

  10. NMDA receptor activity in neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Shaheen E Lakhan

    2013-06-01

    Full Text Available N-Methyl-D-aspartate (NMDA receptors play a variety of physiologic roles and their proper signaling is essential for cellular homeostasis. Any disruption in this pathway, leading to either enhanced or decreased activity, may result in the manifestation of neuropsychiatric pathologies such as schizophrenia, mood disorders, substance induced psychosis, Huntington's disease, Alzheimer's disease, and neuropsychiatric systemic lupus erythematosus. Here, we explore the notion that the overlap in activity of at least one biochemical pathway, the NMDA receptor pathway, may be the link to understanding the overlap in psychotic symptoms between diseases. This review intends to present a broad overview of those neuropsychiatric disorders for which alternations in NMDA receptor activity is prominent thus suggesting that continued direction of pharmaceutical intervention to this pathway may present a viable option for managing symptoms.

  11. Pharmacology and function of melatonin receptors

    International Nuclear Information System (INIS)

    Dubocovich, M.L.

    1988-01-01

    The hormone melatonin is secreted primarily from the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone, through an action in the brain, appears to be involved in the regulation of various neural and endocrine processes that are cued by the daily change in photoperiod. This article reviews the pharmacological characteristics and function of melatonin receptors in the central nervous system, and the role of melatonin in mediating physiological functions in mammals. Melatonin and melatonin agonists, at picomolar concentrations, inhibit the release of dopamine from retina through activation of a site that is pharmacologically different from a serotonin receptor. These inhibitory effects are antagonized by the novel melatonin receptor antagonist luzindole (N-0774), which suggests that melatonin activates a presynaptic melatonin receptor. In chicken and rabbit retina, the pharmacological characteristics of the presynaptic melatonin receptor and the site labeled by 2-[125I]iodomelatonin are identical. It is proposed that 2-[125I]iodomelatonin binding sites (e.g., chicken brain) that possess the pharmacological characteristics of the retinal melatonin receptor site (order of affinities: 2-iodomelatonin greater than 6-chloromelatonin greater than or equal to melatonin greater than or equal to 6,7-di-chloro-2-methylmelatonin greater than 6-hydroxymelatonin greater than or equal to 6-methoxymelatonin greater than N-acetyltryptamine greater than or equal to luzindole greater than N-acetyl-5-hydroxytryptamine greater than 5-methoxytryptamine much greater than 5-hydroxytryptamine) be classified as ML-1 (melatonin 1). The 2-[125I]iodomelatonin binding site of hamster brain membranes possesses different binding and pharmacological characteristics from the retinal melatonin receptor site and should be classified as ML-2. 64 references

  12. Analysis of the hormone-binding domain of steroid receptors using chimeras generated by homologous recombination

    International Nuclear Information System (INIS)

    Martinez, Elisabeth D.; Pattabiraman, Nagarajan; Danielsen, Mark

    2005-01-01

    The glucocorticoid receptor and the mineralocorticoid receptor are members of the steroid receptor family that exhibit ligand cross-reactivity. Specificity of steroid receptor action is investigated in the present work by the construction and characterization of chimeras between the glucocorticoid receptor and the mineralocorticoid receptor. We used an innovative approach to make novel steroid receptor proteins in vivo that in general, contrary to our expectations, show increased ligand specificity compared to the parental receptors. We describe a receptor that is specific for the potent synthetic glucocorticoid triamcinolone acetonide and does not bind aldosterone. A further set of chimeras has an increased ability to discriminate between ligands, responding potently to mineralocorticoids and only very weakly to synthetic glucocorticoids. A chimera with the fusion site in the hinge highlights the importance of the region between the DNA-binding and the hormone-binding domains since, unlike both the glucocorticoid and mineralocorticoid receptors, it only responds to mineralocorticoids. One chimera has reduced specificity in that it acts as a general corticoid receptor, responding to glucocorticoids and mineralocorticoids with similar potency and efficacy. Our data suggest that regions of the glucocorticoid and mineralocorticoid receptor hormone-binding domains are functionally non-reciprocal. We present transcriptional, hormone-binding, and structure-modeling evidence that suggests that receptor-specific interactions within and across domains mediate aspects of specificity in transcriptional responses to steroids

  13. Placebo Effects of Open-label Verbal Suggestions on Itch

    Directory of Open Access Journals (Sweden)

    Stefanie H. Meeuwis

    2017-11-01

    Full Text Available Placebo effects are positive outcomes that are not due to active treatment components, which may be elicited even when patients are aware of receiving an inert substance (open-label. This proof-of-principle study investigated for the first time whether open-label placebo effects on itch can be induced by verbal suggestions alone. Ninety-two healthy volunteers were randomized to experimental (open-label suggestions or control (no suggestions groups. Self-reported itch evoked by histamine iontophoresis was the primary study outcome. In addition, itch expectations, skin condition and affect were assessed. The experimental group expected lower itch than the control group, which was, in turn, related to less experienced itch in this group only, although no significantly different itch levels were reported between groups. The results illustrate a potential role for open-label placebo effects in itch, and suggest that further study of verbal suggestions through an extensive explanation of placebo effects might be promising for clinical practice.

  14. Evaluation of the improvement suggestion system in a nuclear facility

    Energy Technology Data Exchange (ETDEWEB)

    Carnaval, Joao Paulo Rodrigues; Moraes, Geice Almeida, E-mail: joaocarnaval@inb.gov.br, E-mail: geice@inb.gov.br [Industrias Nucleares do Brasil S.A (INB), Resende, RJ (Brazil)

    2017-11-01

    This work evaluated methods for processing improvement suggestions of a nuclear factory, with the intention to verify those which best fits to the company purposes. Two methods for processing improvement suggestions were applied in the studied organization. The first one was guided to the processing suggestions by specific independent sectors of the company and the second one was conducted to the processing of suggestions by a multidisciplinary team. It has been concluded that a multidisciplinary team focused on research and development would be the best option to the implementation of improvement suggestions and technological innovation on this facility, instead of multi sector processing which revealed to be excessive bureaucratic before the expected goals. This study can be used by nuclear facilities to optimize an existing system of improvements analysis or even guide them for the implantation of a new one. It is more significant for the companies certified on ISO and OHSAS standards for the quality management, environmental and safety and occupational health systems which requires that the continuous improvement must exist and to be demonstrated. But it is also relevant for nuclear plants aiming to implement an Integrated Management System certified on ISO Standards. (author)

  15. Hypnosis, hypnotic suggestibility, memory, and involvement in films.

    Science.gov (United States)

    Maxwell, Reed; Lynn, Steven Jay; Condon, Liam

    2015-05-01

    Our research extends studies that have examined the relation between hypnotic suggestibility and experiential involvement and the role of an hypnotic induction in enhancing experiential involvement (e.g., absorption) in engaging tasks. Researchers have reported increased involvement in reading (Baum & Lynn, 1981) and music-listening (Snodgrass & Lynn, 1989) tasks during hypnosis. We predicted a similar effect for film viewing: greater experiential involvement in an emotional (The Champ) versus a non-emotional (Scenes of Toronto) film. We tested 121 participants who completed measures of absorption and trait dissociation and the Harvard Group Scale of Hypnotic Susceptibility and then viewed the two films after either an hypnotic induction or a non-hypnotic task (i.e., anagrams). Experiential involvement varied as a function of hypnotic suggestibility and film clip. Highly suggestible participants reported more state depersonalization than less suggestible participants, and depersonalization was associated with negative affect; however, we observed no significant correlation between hypnotic suggestibility and trait dissociation. Although hypnosis had no effect on memory commission or omission errors, contrary to the hypothesis that hypnosis facilitates absorption in emotionally engaging tasks, the emotional film was associated with more commission and omission errors compared with the non-emotional film. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Suggestions on Writing for Publication in Language Learning Journals

    Directory of Open Access Journals (Sweden)

    George M. Jacobs

    1999-01-01

    Full Text Available This article provides suggestions on writing for journals in the field of language learning. These suggestions are presented in three sections. The first section discusses how to begin. Suggestions in this section are that we appreciate the benefits of writing for publication, develop good ideas, work efficiently, ponder options as to what type of writing to do, choose a good topic, consider replication of other's research, and cooperate with others. The second section presents suggestions on doing the actual writing. Here, it is suggested that we connect ideas, delve deeply into the ideas we present, strive to write the reader friendly manner, use visuals, and improve our writing by noticing how other journal authors write. The third section concerns relations with editors. The advice given is that we choose carefully the journal to which we submit our work, follow that journal's directions to contributors, include a cover letter, be prepared to wait patiently, welcome critical feedback from editors and reviewers, and view editors as colleagues.

  17. Evaluation of the improvement suggestion system in a nuclear facility

    International Nuclear Information System (INIS)

    Carnaval, Joao Paulo Rodrigues; Moraes, Geice Almeida

    2017-01-01

    This work evaluated methods for processing improvement suggestions of a nuclear factory, with the intention to verify those which best fits to the company purposes. Two methods for processing improvement suggestions were applied in the studied organization. The first one was guided to the processing suggestions by specific independent sectors of the company and the second one was conducted to the processing of suggestions by a multidisciplinary team. It has been concluded that a multidisciplinary team focused on research and development would be the best option to the implementation of improvement suggestions and technological innovation on this facility, instead of multi sector processing which revealed to be excessive bureaucratic before the expected goals. This study can be used by nuclear facilities to optimize an existing system of improvements analysis or even guide them for the implantation of a new one. It is more significant for the companies certified on ISO and OHSAS standards for the quality management, environmental and safety and occupational health systems which requires that the continuous improvement must exist and to be demonstrated. But it is also relevant for nuclear plants aiming to implement an Integrated Management System certified on ISO Standards. (author)

  18. Seasonal variation in glucocorticoid receptor binding characteristics in human mononuclear leucocytes.

    Science.gov (United States)

    Blackhurst, G; McElroy, P K; Fraser, R; Swan, R L; Connell, J M

    2001-11-01

    Glucocorticoid sensitivity varies between individuals and between tissues in the same individual. Although some of this variation is explained by the activity of the 11 beta-hydroxysteroid dehydrogenase enzymes, the possibility that glucocorticoid receptor sensitivity is modulated remains unexplored. This study examined glucocorticoid receptor binding in leucocytes and assessed the effects of seasonal hormonal variation on receptor binding. Two populations were studied. In the first, 318 healthy subjects were studied over 2 years with a single measurement of receptor binding made on each. In the second study nine healthy male subjects each had receptor binding measurements made at 3-week intervals over 1 year. In both populations there was significant seasonal variation in receptor binding. In the first population Kd for dexamethasone was highest in November and lowest in July (8.37 +/- 0.5 nmol/l vs. 1.58 +/- 0.7, mean +/- SEM P vs. 4969 +/- 302, P melatonin raised Kd without affecting receptor number. Co-incubation with forskolin lowered Kd suggesting that melatonin might act through the ML1 receptor class by inhibiting adenylyl cyclase. No correlations were found with 0900 h plasma cortisol. The results suggest that the glucocorticoid receptor might be modulated by season. Melatonin might mediate part of these effects. The lack of correlation with cortisol suggests that it is not an important determinant of receptor binding and that leucocyte receptors are regulated differently from central receptors.

  19. Nature and regulation of the insulin receptor: structure and function

    International Nuclear Information System (INIS)

    Czech, M.P.

    1985-01-01

    Native, cell-surface insulin receptor consists of two glycoprotein subunit types with apparent masses of about 125,000 daltons (alpha subunit) and 90,000 daltons (beta subunit). The alpha and beta insulin-receptor subunits seem to have distinct functions such that alpha appears to bind hormone whereas beta appears to possess intrinsic tyrosine kinase activity. In detergent extracts, insulin activates receptor autophosphorylation of tyrosine residues on its beta subunit, whereas in the presence of reductant, the alpha subunit is also phosphorylated. In intact cells, insulin activates serine/threonine phosphorylation of insulin receptor beta subunit as well as tyrosine phosphorylation. The biological role of the receptor-associated tyrosine kinase is not known. The insulin receptor kinase is regulated by beta-adrenergic agonists and other agents that elevate cAMP in adipocytes, presumably via the cAMP-dependent protein kinase. Such agents decrease receptor affinity for insulin and partially uncouple receptor tyrosine kinase activity from activation by insulin. These effects appear to contribute to the biological antagonism between insulin and beta-agonists. These data suggest the hypothesis that a complex network of tyrosine and serine/threonine phosphorylations on the insulin receptor modulate its binding and kinase activities in an antagonistic manner

  20. Steroid receptors and their ligands: Effects on male gamete functions

    Energy Technology Data Exchange (ETDEWEB)

    Aquila, Saveria; De Amicis, Francesca, E-mail: francesca.deamicis@unical.it

    2014-11-01

    In recent years a new picture of human sperm biology is emerging. It is now widely recognized that sperm contain nuclear encoded mRNA, mitochondrial encoded RNA and different transcription factors including steroid receptors, while in the past sperm were considered incapable of transcription and translation. One of the main targets of steroid hormones and their receptors is reproductive function. Expression studies on Progesterone Receptor, estrogen receptor, androgen receptor and their specific ligands, demonstrate the presence of these systems in mature spermatozoa as surface but also as nuclear conventional receptors, suggesting that both systemic and local steroid hormones, through sperm receptors, may influence male reproduction. However, the relationship between the signaling events modulated by steroid hormones and sperm fertilization potential as well as the possible involvement of the specific receptors are still controversial issues. The main line of this review highlights the current research in human sperm biology examining new molecular systems of response to the hormones as well as specific regulatory pathways controlling sperm cell fate and biological functions. Most significant studies regarding the identification of steroid receptors are reported and the mechanistic insights relative to signaling pathways, together with the change in sperm metabolism energy influenced by steroid hormones are discussed.The reviewed evidences suggest important effects of Progesterone, Estrogen and Testosterone and their receptors on spermatozoa and implicate the involvement of both systemic and local steroid action in the regulation of male fertility potential. - Highlights: • One of the main targets of steroid hormones and their receptors is reproductive function. • Pg/PR co-work to stimulate enzymatic activities to sustain a capacitation process. • E2/ERs regulate sperm motility, capacitation and acrosome reaction and act as survival factors. • Androgens

  1. Steroid receptors and their ligands: Effects on male gamete functions

    International Nuclear Information System (INIS)

    Aquila, Saveria; De Amicis, Francesca

    2014-01-01

    In recent years a new picture of human sperm biology is emerging. It is now widely recognized that sperm contain nuclear encoded mRNA, mitochondrial encoded RNA and different transcription factors including steroid receptors, while in the past sperm were considered incapable of transcription and translation. One of the main targets of steroid hormones and their receptors is reproductive function. Expression studies on Progesterone Receptor, estrogen receptor, androgen receptor and their specific ligands, demonstrate the presence of these systems in mature spermatozoa as surface but also as nuclear conventional receptors, suggesting that both systemic and local steroid hormones, through sperm receptors, may influence male reproduction. However, the relationship between the signaling events modulated by steroid hormones and sperm fertilization potential as well as the possible involvement of the specific receptors are still controversial issues. The main line of this review highlights the current research in human sperm biology examining new molecular systems of response to the hormones as well as specific regulatory pathways controlling sperm cell fate and biological functions. Most significant studies regarding the identification of steroid receptors are reported and the mechanistic insights relative to signaling pathways, together with the change in sperm metabolism energy influenced by steroid hormones are discussed.The reviewed evidences suggest important effects of Progesterone, Estrogen and Testosterone and their receptors on spermatozoa and implicate the involvement of both systemic and local steroid action in the regulation of male fertility potential. - Highlights: • One of the main targets of steroid hormones and their receptors is reproductive function. • Pg/PR co-work to stimulate enzymatic activities to sustain a capacitation process. • E2/ERs regulate sperm motility, capacitation and acrosome reaction and act as survival factors. • Androgens

  2. Suggested Interactivity: Seeking Perceived Affordances for Information Visualization.

    Science.gov (United States)

    Boy, Jeremy; Eveillard, Louis; Detienne, Françoise; Fekete, Jean-Daniel

    2016-01-01

    In this article, we investigate methods for suggesting the interactivity of online visualizations embedded with text. We first assess the need for such methods by conducting three initial experiments on Amazon's Mechanical Turk. We then present a design space for Suggested Interactivity (i. e., visual cues used as perceived affordances-SI), based on a survey of 382 HTML5 and visualization websites. Finally, we assess the effectiveness of three SI cues we designed for suggesting the interactivity of bar charts embedded with text. Our results show that only one cue (SI3) was successful in inciting participants to interact with the visualizations, and we hypothesize this is because this particular cue provided feedforward.

  3. Hypnosis, suggestion, and placebo in the reduction of experimental pain.

    Science.gov (United States)

    Spanos, N P; Perlini, A H; Robertson, L A

    1989-08-01

    Two experiments compared placebo and hypnotic analgesia in high and low hypnotizable subjects. Experiment 1 demonstrated that hypnotic and placebo analgesia were equally ineffective in low hypnotizables, but that hypnotic analgesia was much more effective than placebo analgesia in high hypnotizables. Experiment 2 replicated these results, but also included low and high hypnotizables who were given a nonhypnotic suggestion for analgesia. Both the low and high hypnotizables in this group reported greater suggested than placebo analgesia and as much suggested analgesia as high hypnotizable hypnotic subjects. Both experiments found substantial discrepancies between the amount of pain reduction subjects expected from the various treatments and the amount of pain reduction they actually reported following exposure to those treatments. In Experiment 2, subjects in all treatments who reduced reported pain engaged in more cognitive coping and less catastrophizing than those who did not reduce pain. Theoretical implications are discussed.

  4. Therapeutic suggestion has not effect on postoperative morphine requirements.

    Science.gov (United States)

    van der Laan, W H; van Leeuwen, B L; Sebel, P S; Winograd, E; Baumann, P; Bonke, B

    1996-01-01

    This study was designed to confirm the effect of therapeutic intraoperative auditory suggestion on recovery from anesthesia, to establish the effect of preoperative suggestion, and to assess implicit memory for intraoperative information using an indirect memory task. Sixty consenting unpremedicated patients scheduled for elective gynecologic surgery were randomly divided into three equal groups: Group 1 received a tape of therapeutic suggestions preoperatively, and the story of Robinson Crusoe intraoperatively; Group 2 heard the story of Peter Pan preoperatively and therapeutic suggestions intraoperatively; Group 3 heard the Crusoe story preoperatively and the Peter Pan story intraoperatively. A standardized anesthetic technique was used with fentanyl, propofol, isoflurane, and nitrous oxide. After surgery, all patients received patient-controlled analgesia (PCA) with a standardized regimen. In the 24 h postsurgery, morphine use was recorded every 6 h and at 24 h an indirect memory test (free association) was used to test for memory of the stories. Anxiety scores were measured before surgery and at 6 and 24 h postsurgery. There were no significant differences between groups for postoperative morphine use, pain or nausea scores, anxiety scores, or days spent in hospital after surgery. Seven of 20 patients who heard the Pan story intraoperative gave a positive association with the word "Hook," whereas 2 of 20 who did not hear the story gave such an association. Indirect memory for the Pan story was established using confidence interval (CI) analysis. (The 95% CI for difference in proportion did not include zero). No indirect memory for the Crusoe story could be demonstrated. This study did not confirm previous work which suggested that positive therapeutic auditory suggestions, played intraoperatively, reduced PCA morphine requirements. In contrast, a positive implicit memory effect was found for a story presented intraoperatively.

  5. Androgen receptor in estrogen receptor positive breast cancer: Beyond expression.

    Science.gov (United States)

    Basile, Debora; Cinausero, Marika; Iacono, Donatella; Pelizzari, Giacomo; Bonotto, Marta; Vitale, Maria Grazia; Gerratana, Lorenzo; Puglisi, Fabio

    2017-12-01

    In recent years, new therapeutic approaches have reshaped the overall strategy of breast cancer (BC) treatment and have markedly improved patient survival. This is, in part, due to novel therapies for estrogen receptor (ER)-positive BC. Unfortunately, many patients present de novo resistance to these therapies or develop an acquired resistance over time. Therefore, research is now focused on discovering new molecular targets to overcome these resistances. Interestingly, preclinical and clinical studies have shown a critical role for the cross-talk between androgen receptor (AR) and ER in luminal-like BC. AR is expressed in >60% of BC and in up to 90% of ERα-positive tumors. Multiple studies suggest that AR is associated with a favorable prognosis. However, AR overexpression and, in particular, the high AR:ER ratio, seem to be involved in resistance to hormonal treatment. In this setting, a group of BCs could benefit from AR-inhibitors; nevertheless, some ER-positive BC patients do not seem to benefit from this strategy. Therefore, it is crucial to identify biomarkers that would enable the selection of patients who might benefit from combination treatment with ER and AR inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Children's suggestibility research: Things to know before interviewing a child

    Directory of Open Access Journals (Sweden)

    Amelia Courtney Hritz

    2015-01-01

    Full Text Available Children's testimony is often the only evidence of alleged abuse. Thus, the importance of conducting forensic interviews that are free from bias and misleading information is immense, as these could lead to false reports. In the current paper, we review unexpected findings in children's suggestibility that illustrate the difficulty in distinguishing between false and accurate reports. We explore situations in which a younger person's memory account may be more accurate than that of an adult, when a single suggestive interview may be as detrimental as multiple interviews, and when children can make inaccurate reports spontaneously. We conclude with recommendations for interviewers to decrease false reporting by both children and adults.

  7. G-protein coupling of cannabinoid receptors

    International Nuclear Information System (INIS)

    Glass, M.

    2001-01-01

    Full text: Since the cloning of the cannabinoid CB1 and CB2 receptors in the early 1990's extensive research has focused on understanding their signal transduction pathways. While it has been known for sometime that both receptors can couple to intracellular signalling via pertussis toxin sensitive G-proteins (Gi/Go), the specificity and kinetics of these interactions have only recently been elucidated. We have developed an in situ reconstitution approach to investigating receptor-G-protein interactions. This approach involves chaotropic extraction of receptor containing membranes in order to inactivate or remove endogenous G-proteins. Recombinant or isolated brain G-proteins can then be added back to the receptors, and their activation monitored through the binding of [ 35 S]-GTPγS. This technique has been utilised for an extensive study of cannabinoid receptor mediated activation of G-proteins. In these studies we have established that CB1 couples with high affinity to both Gi and Go type G-proteins. In contrast, CB2 couples strongly to Gi, but has a very low affinity for Go. This finding correlated well with the previous findings that while CB1 and CB2 both couple to the inhibition of adenylate cyclase, CB1 but not CB2 could also inhibit calcium channels. We then examined the ability of a range of cannabinoid agonists to activate the Gi and Go via CB1. Conventional receptor theory suggests that a receptor is either active or inactive with regard to a G-protein and that the active receptor activates all relevant G-proteins equally. However, in this study we found that agonists could produce different degrees of activation, depending on which G-protein was present. Further studies have compared the ability of the two endocannabinoids to drive the activation of Gi or Go. These studies show that agonists can induce multiple forms of activated receptor that differ in their ability to catalyse the activation of Gi or Go. The ability of an agonist to drive a receptor

  8. CANNABINOID RECEPTOR AGONISTS UPREGULATE AND ENHANCE SEROTONIN 2A (5-HT2A) RECEPTOR ACTIVITY VIA ERK1/2 SIGNALING

    Science.gov (United States)

    Franklin, Jade M.; Carrasco, Gonzalo A.

    2012-01-01

    Recent behavioral studies suggest that non-selective agonists of cannabinoid receptors may regulate serotonin 2A (5-HT2A) receptor neurotransmission. Two cannabinoids receptors are found in brain, CB1 and CB2 receptors, but the molecular mechanism by which cannabinoid receptors would regulate 5-HT2A receptor neurotransmission remains unknown. Interestingly, we have recently found that certain cannabinoid receptor agonists can specifically upregulate 5-HT2A receptors. Here, we present experimental evidence that rats treated with a non-selective cannabinoid receptor agonist (CP 55,940, 50μg/kg, 7 days) showed increases in 5-HT2A receptor protein levels, 5-HT2A receptor mRNA levels, and 5-HT2A receptor-mediated phospholipase C Beta (PLCβ) activity in prefrontal cortex (PFCx). Similar effects were found in neuronal cultured cells treated with CP 55,940 but these effects were prevented by selective CB2, but not selective CB1, receptor antagonists. CB2 receptors couple to the extracellular kinase (ERK) signaling pathway by Gαi/o class of G-proteins. Noteworthy, GP 1a (selective CB2 receptor agonist) produced a strong upregulation of 5-HT2A receptor mRNA and protein, an effect that was prevented by selective CB2 receptor antagonists and by an ERK1/2 inhibitor, PD 198306. In summary, our results identified a strong cannabinoid-induced upregulation of 5-HT2A receptor signaling in rat PFCx. Our cultured cell studies suggest that selective CB2 receptor agonists upregulate 5-HT2A receptor signaling by activation of the ERK1/2 signaling pathway. Activity of cortical 5-HT2A receptors has been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety & depression and schizophrenia. Therefore, these results might provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to the pathophysiology of some cognitive and mood disorders in humans. PMID:23151877

  9. Teaching Culture Through Language: Suggestions for the Italian Language Class.

    Science.gov (United States)

    Ciccarelli, Andrea

    1996-01-01

    Examines the conflict between students' focus on learning the grammar and vocabulary of a foreign language instead of considering the culture that lies beneath the target language, in this case, Italian. Suggestions are made for overcoming the practical difficulty of imposing a language as a cultural entity upon the students. (25 references) (CK)

  10. A suggestion for planning cover crop mixtures: zones of occupancy

    Science.gov (United States)

    Producers may be able to improve the competitiveness of cover crop mixtures by selecting species to occupy zones in the cover crop canopy. This suggestion is based on a study where we compared four cover crop treatments, 1, 3, 6, and 9 species mixtures, for biomass production. Treatments were est...

  11. Disorganized Cortical Patches Suggest Prenatal Origin of Autism

    Science.gov (United States)

    ... the National Institutes of Health. Published in the New England Journal of Medicine on March 27, 2014, this study suggests that brain irregularities in children with autism can be traced back to ... of NIMH. “If this new report of disorganized architecture in the brains of ...

  12. A Suggested Journalism Curriculum for California Junior Colleges.

    Science.gov (United States)

    Margosian, Arthur

    The purpose of this study was to develop a suggested journalism curriculum for California junior colleges, based upon the functions and content of journalism programs as they should be, as perceived by a representative group of junior college instructrs and editors of daily and weekly newspapers in California. Data were collected from…

  13. Suggestions for the Classical Shelves of a School Library.

    Science.gov (United States)

    Colebourn, R., Comp.; Cleeve, Marigold, Comp.

    This bibliography is suggested for use by students and teachers of Latin, Greek and ancient civilizations. Entries are compiled under the headings of: (1) bibliographies and journals including booklists, periodicals, and books for teachers; (2) reference works in literature, mythology, history and antiquities, and language; (3) texts and…

  14. Asthma control - Practical suggestions for practicing doctors in family ...

    African Journals Online (AJOL)

    Abstract. Many surveys of asthma care suggest that only 5% of asthmatics are meeting the 'Goals of asthma management' as set out in the. Global Initiative for Asthma (GINA) guidelines. Despite the availability of useful asthma therapies and treatment strategies, the morbidity from asthma has remained significant.

  15. A Privacy-by-Design Contextual Suggestion System for Tourism

    NARCIS (Netherlands)

    Efraimidis, Pavlos; Drosatos, George; Arampatzis, Avi; Stamatelatos, Giorgos; Athanasiadis, Ioannis

    2016-01-01

    We focus on personal data generated by the sensors and through the everyday usage of smart devices and take advantage of these data to build a non-invasive contextual suggestion system for tourism. The system, which we call Pythia, exploits the computational capabilities of modern smart devices to

  16. Suggested guidelines for gas emission monitoring at danish landfills

    DEFF Research Database (Denmark)

    Kjeldsen, Peter; Scheutz, Charlotte

    2015-01-01

    Landfill gas is produced on waste disposal sites receiving organic waste resulting in emission of methane. Regulation requires that the landfill gas is managed in order to reduce emissions, but very few suggestions exist to how the landfill gas management activities are monitored, what requiremen...

  17. Should Authors be Requested to Suggest Peer Reviewers?

    Science.gov (United States)

    Teixeira da Silva, Jaime A; Al-Khatib, Aceil

    2018-02-01

    As part of a continuous process to explore the factors that might weaken or corrupt traditional peer review, in this paper, we query the ethics, fairness and validity of the request, by editors, of authors to suggest peer reviewers during the submission process. One of the reasons for the current crisis in science pertains to a loss in trust as a result of a flawed peer review which is by nature biased unless it is open peer review. As we indicate, the fact that some editors and journals rely on authors' suggestions in terms of who should peer review their paper already instills a potential way to abuse the trust of the submission and publishing system. An author-suggested peer reviewer choice might also tempt authors to seek reviewers who might be more receptive or sympathetic to the authors' message or results, and thus favor the outcome of that paper. Authors should thus not be placed in such a potentially ethically compromising situation, especially as a mandatory condition for submission. However, the fact that they do not have an opt-out choice during the submission process-especially when using an online submission system that makes such a suggestion compulsory-may constitute a violation of authors' rights.

  18. Where to Look First for Suggestibility in Young Children.

    Science.gov (United States)

    Newcombe, Peter A.; Siegal, Michael

    1996-01-01

    Investigated preschool children's suggestibility following exposure to biased information. Children heard a story followed the next day by either biased, unbiased, or no information. Found that children were able to identify the original story details six days later when the questions were phrased in an explicit manner that referred to the time of…

  19. Studies and Suggestions on English Vocabulary Teaching and Learning

    Science.gov (United States)

    Zheng, Shigao

    2012-01-01

    To improve vocabulary learning and teaching in ELT settings, two questionnaires are designed and directed to more than 100 students and teachers in one of China's key universities. The findings suggest that an enhanced awareness of cultural difference, metaphorical competence, and learners' autonomy in vocabulary acquisition will effectively…

  20. Halloween Costumes May Suggest Influence of Violent Models on Children.

    Science.gov (United States)

    Owen, John W.; Sterling, Bruce S.

    Halloween costumes may be used to examine the influence violent models have on children. On Halloween evening observers recorded the frequency of violent and nonviolent costumes worn by children. When all of the data are inspected they suggest that children confronted with several aggressive models may be more likely to identify with the…

  1. Suggestions for Improving Ugandan Higher Education to Produce ...

    African Journals Online (AJOL)

    Every country invests in formal education to develop and empower its citizens with the capacity needed to practically work and transform their surrounding environmental resources into productive employment after graduation. The high and growing rate of graduate unemployment in Uganda suggests however, that most of ...

  2. The Family Life Cycle: Some Suggestions for Recycling

    Science.gov (United States)

    Feldman, Harold; Feldman, Margaret

    1975-01-01

    The lifetime family, the family of ego, is distinguished from the lineage family which is the family lasting through time over generations. Use of the term lifetime family career and lineage family cycle is suggested. The family career is used to describe the participation of a person in the family. (Author)

  3. False Memories for Suggestions: The Impact of Conceptual Elaboration

    Science.gov (United States)

    Zaragoza, Maria S.; Mitchell, Karen J.; Payment, Kristie; Drivdahl, Sarah

    2011-01-01

    Relatively little attention has been paid to the potential role that reflecting on the meaning and implications of suggested events (i.e., conceptual elaboration) might play in promoting the creation of false memories. Two experiments assessed whether encouraging repeated conceptual elaboration, would, like perceptual elaboration, increase false…

  4. Barriers to Policy Change and a Suggested Path for Change

    Science.gov (United States)

    Jing, Yijia

    2013-01-01

    China's one-child policy has been an unprecedented policy experiment in human history. Despite its significant achievements, the policy has induced equally significant potential problems. As problems of the one-child policy have been widely noticed and suggestions for adjustments are available, the leadership transition of China in 2012 and 2013…

  5. Suggested physical therapy protocol for reduction of lipomatosis ...

    African Journals Online (AJOL)

    The purpose of this study was to investigate the efficacy of suggested physical therapy protocol in lipomatosis dolorosa of the legs. Twenty female patients with stage I lipomatosis dolorosa of the legs ranged in age from 30 to 45 years. They received a complete decongestive physical therapy program and diet regimen.

  6. Hotel Employees' Japanese Language Experiences: Implications and Suggestions.

    Science.gov (United States)

    Makita-Discekici, Yasuko

    1998-01-01

    Analyzes the Japanese language learning experiences of 13 hotel employees in Guam. Results of the study present implications and suggestions for a Japanese language program for the hotel industry. The project began as a result of hotel employees frustrations when they were unable to communicate effectively with their Japanese guests. (Auth/JL)

  7. Tuck in Your Shirt, You Squid: Suggestions in ESL.

    Science.gov (United States)

    Banerjee, Janet; Carrell, Patricia L.

    1988-01-01

    An English discourse completion questionnaire consisting of 60 situations designed to elicit suggestions in English was administered to 28 native speakers of Chinese or Malay and to 12 native speakers of American English. Non-native speakers of English were more direct in their responses. Native and non-native speakers significantly differed in…

  8. Animal Rights: Selected Resources and Suggestions for Further Study.

    Science.gov (United States)

    Davidoff, Donald J.

    1989-01-01

    Presents an annotated list of selected resources intended to serve as a guide to the growing amount of material on animal rights. Suggestions to aid in additional research include subject headings used to find books, indexes used to locate periodical articles, sources for locating organizations, and a selected list of animal rights organizations.…

  9. Male-limited evolution suggests no extant intralocus sexual conflict ...

    Indian Academy of Sciences (India)

    2011-12-02

    Dec 2, 2011 ... estimates of sexually antagonistic selection will be important to fully resolve these alternatives. [Bedhomme S., Chippindale A. K., Prasad N. G., Delcourt M., Abbott J. K., Mallet M. A. and Rundle H. D. 2011 Male-limited evolution suggests no extant intralocus sexual conflict over the sexually dimorphic ...

  10. The Classroom as a Service Encounter: Suggestions for Value Creation.

    Science.gov (United States)

    Chung, Ed; McLarney, Carolan

    2000-01-01

    Conceives of the classroom as a service encounter between marketer (instructor) and stakeholders (students), making stakeholder satisfaction the key to meeting learning goals. Suggests ways to create value in the classroom: understanding what stakeholders need and want, efficiently delivering services, and demonstrating product leadership. (SK)

  11. History of Mathematics and Problem Solving: A Teaching Suggestion

    Science.gov (United States)

    Meavilla, V.; Flores, A.

    2007-01-01

    This note presents a teaching suggestion, using the history of mathematics, to give students from middle school and high school the possibility of facing problems found in old mathematics books and comparing their solutions with those given in those books. (Contains 3 figures and 1 table.)

  12. A SUGGESTED CHECKLIST FOR ASSESSING A SCIENCE PROGRAM.

    Science.gov (United States)

    Office of Education (DHEW), Washington, DC.

    SUGGESTIONS AND A CHECKLIST FOR THE EVALUATION OF ELEMENTARY AND SECONDARY SCHOOL SCIENCE PROGRAMS ARE CONTAINED IN THIS UNITED STATES OFFICE OF EDUCATION BULLETIN. AN INTRODUCTORY SECTION DEALS WITH THE IMPORTANCE OF (1) BROAD FACULTY PARTICIPATION, AND (2) UP-TO-DATE CONTENT AND METHODS IN PROGRAM EVALUATION. EXPLANATIONS FOR THE CONSTRUCTION…

  13. Asthma control - Practical suggestions for practicing doctors in family ...

    African Journals Online (AJOL)

    ... the 'Goals of asthma management' as set out in the Global Initiative for Asthma (GINA) guidelines. Despite the availability of useful asthma therapies and treatment strategies, the morbidity from asthma has remained significant. This review includes practical suggestions on optimal asthma control for the family practitioner.

  14. DNA-energetics-based analyses suggest additional genes in ...

    Indian Academy of Sciences (India)

    2012-06-25

    Jun 25, 2012 ... [Khandelwal G, Gupta J and Jayaram B 2012 DNA-energetics-based analyses suggest additional genes in prokaryotes. J. Biosci. 37 433–444] DOI ..... illustration for detecting potential new genes in 12 different genomes with varied GC ..... maps and genetic map of DNA double strand. J. Phys. Soc. Jpn.

  15. Learning through doing: Suggesting a deliberative approach to ...

    African Journals Online (AJOL)

    ... democracy as a more substantive approach to political participation, and by some consideration of how this relates to the rights and capabilities of children as political actors. The paper concludes with some tentative suggestions about how institutions in South Africa could be utilized to realize a more flexible and nuanced ...

  16. An Instructional Method Suggestion: Conveying Stories through Origami (Storigami)

    Science.gov (United States)

    Oguz, Aysegul

    2016-01-01

    The purpose of this study was to elucidate how to convey stories through origami and suggest its use in education with the help of pre-service elementary teachers' opinions. The participants of the study were 103 elementary teacher candidates from a state university in the 2014-2015 academic year. In this qualitative study, the data were collected…

  17. The association of metabotropic glutamate receptor type 5 with the neuronal Ca2+-binding protein 2 modulates receptor function.

    Science.gov (United States)

    Canela, Laia; Fernández-Dueñas, Víctor; Albergaria, Catarina; Watanabe, Masahiko; Lluís, Carme; Mallol, Josefa; Canela, Enric I; Franco, Rafael; Luján, Rafael; Ciruela, Francisco

    2009-10-01

    Metabotropic glutamate (mGlu) receptors mediate in part the CNS effects of glutamate. These receptors interact with a large array of intracellular proteins in which the final role is to regulate receptor function. Here, using co-immunoprecipitation and pull-down experiments we showed a close and specific interaction between mGlu(5) receptor and NECAB2 in both transfected human embryonic kidney cells and rat hippocampus. Interestingly, in pull-down experiments increasing concentrations of calcium drastically reduced the ability of these two proteins to interact, suggesting that NECAB2 binds to mGlu(5) receptor in a calcium-regulated manner. Immunoelectron microscopy detection of NECAB2 and mGlu(5) receptor in the rat hippocampal formation indicated that both proteins are codistributed in the same subcellular compartment of pyramidal cells. In addition, the NECAB2/mGlu(5) receptor interaction regulated mGlu(5b)-mediated activation of both inositol phosphate accumulation and the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. Overall, these findings indicate that NECAB2 by its physical interaction with mGlu(5b) receptor modulates receptor function.

  18. [Tones and being tuned. Suggestions for the common origins of music therapy and hypnotherapy].

    Science.gov (United States)

    Vas, József Pál

    2013-01-01

    Sound vibrations are viewed to play an important role in embryonic development. Before the cochlea evolves, the haptic and mechanic skin-receptors detect the amniotic fluid's pressure-waves produced by sounds in uterus. Touching and hearing are seen as primordial and the most relevant stimuli both of mother-fetus attunement and development of fetal nervous system. Man is attuned to environmental stimuli, mainly to human speaking since the embryonic period. Attunement is secured by energy zones (chakras) circling around body. It is considered to be base of our music capacity. Origin of hypnotic susceptibility is viewed as being in embryonic period as well. Movements, experiences supposed, bonding and communication patterns of both of fetus and hypnotized person are suggested to show similarities. Prenatal audio-somatosensory stimulating program facilitates newborn babies' cognitive, emotional and bonding capacities. As a matter of fact, by virtue of regressive fetus-like experiences, hypnotherapy contributes to the restart of personality development halted by trauma.

  19. Communicating about nuclear events: Some suggestions to improve INES

    International Nuclear Information System (INIS)

    Kermisch, Céline; Labeau, Pierre-Etienne

    2013-01-01

    This paper provides a critical analysis of the International Nuclear and Radiological Event Scale (INES) and its use, both from an epistemic and an ethical perspective. As very few papers have been dedicated to this subject, our critical analysis is mainly based on the INES 2009 User's Manual and on technical information issued by different nuclear agencies. Our critical analysis leads to suggest several elements, which could contribute to the improvement of the INES scale and thereby to a better communication about nuclear events. First, we show that multiple criteria are used to assign an INES rating, which could lead to an insufficient differentiation between events. In order to avoid this issue, we suggest to clarify the criteria that are used to assess the level of the event. Then, we show that level 7 of the INES scale is ill-defined as it does not allow to properly take differences in severity between disasters into account. In this regard, we recommend to use an open scale instead. Moreover, we highlight the fact that INES is able to take into account neither events with long-term evolution nor events involving multiple initiators. In this respect, we suggest providing additional guidelines and reflecting about the data on which to rely, in order to assess an INES level. Furthermore, we reflect on who should be rating a nuclear event and we recommend that, for severe events, an independent and plural agency should be in charge. Finally, we show why INES appears to be insufficient for a global communication, and we suggest to complement the INES rating with additional information in parallel. -- Highlights: •We provide a critical analysis of the INES scale and suggestions to improve it. •The rating criteria should be clarified to allow differentiation between events. •An open scale should be used to differentiate between level-7 accidents. •Additional guidelines should be provided for complex and evolving events. •We provide suggestions to satisfy

  20. DIPNECH: when to suggest this diagnosis on CT

    International Nuclear Information System (INIS)

    Chassagnon, G.; Favelle, O.; Marchand-Adam, S.; De Muret, A.; Revel, M.P.

    2015-01-01

    Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is an under-recognized disease characterized by proliferation of neuroendocrine cells in the bronchial wall. It is considered a pre-invasive lesion for lung carcinoid tumours and is found in 5.4% of patients undergoing surgical resection for lung carcinoid tumours. Other manifestations of DIPNECH include bronchial obstruction and formation of tumorlets. DIPNECH preferentially affects middle-aged women. Patients are either asymptomatic or present with long-standing dyspnoea due to obstructive syndrome that can be mistaken for asthma. At CT, mosaic attenuation with multiple small nodules is very suggestive of DIPNECH. The aim of this review is to describe DIPNECH-related CT features and correlate them with histology, in order to help radiologists suggest this diagnosis and distinguish DIPNECH from other causes of mosaic perfusion

  1. Suggestions for the Improvement of Environmental Radiation Monitoring in Kenya

    International Nuclear Information System (INIS)

    Shadrack, A. K.

    2012-01-01

    Environmental radiation monitoring in Kenya was started in 1990 following the 1979 Three Mile Island and the 1986 Chernobyl nuclear power plants accidents. The main purpose was to measure the radioactivity of foodstuffs imported from oversees and to carry out environmental radiation monitoring of soil, rock, water and air sample to check for contamination. Through environmental radiation monitoring, the Food and Environmental Monitoring Section (FEM) of the Kenya Radiation Protection Board (RPB) works to protect the public and environment from hazards associated with ionizing radiation. The purpose of this paper was to highlight suggestions for the improvement of environmental radiation monitoring in Kenya with respect to protecting the public and the environment against undue radiation risk by ensuring that potential exposures are kept As Low As Reasonably Achievable (ALARA). The suggestions for improvement will serve as a guideline for the strengthening of environmental radiation monitoring program in Kenya

  2. Ten suggestions to strengthen the science of ecology

    Science.gov (United States)

    Belovsky, G.E.; Botkin, Daniel B.; Crowl, T.A.; Cummins, K.W.; Franklin, J.F.; Hunter, M.L.; Joern, A.; Lindenmayer, D.B.; MacMahon, J.A.; Margules, C.R.; Scott, J.M.

    2004-01-01

    There are few well-documented, general ecological principles that can be applied to pressing environmental issues. When they discuss them at all, ecologists often disagree about the relative importance of different aspects of the science's original and still important issues. It may be that the sum of ecological science is not open to universal statements because of the wide range of organizational, spatial, and temporal phenomena, as well as the sheer number of possible interactions. We believe, however, that the search for general principles has been inadequate to establish the extent to which generalities are possible. We suggest that ecologists may need to reconsider how we view our science. This article lists 10 suggestions for ecology, recognizing the many impediments to finding generalizations in this field, imposed in part by the complexity of the subject and in part by limits to funding for the study of ecology.

  3. Collider shot setup for Run 2 observations and suggestions

    International Nuclear Information System (INIS)

    Annala, J.; Joshel, B.

    1996-01-01

    This note is intended to provoke discussion on Collider Run II shot setup. We hope this is a start of activities that will converge on a functional description of what is needed for shot setups in Collider Run II. We will draw on observations of the present shot setup to raise questions and make suggestions for the next Collider run. It is assumed that the reader has some familiarity with the Collider operational issues. Shot setup is defined to be the time between the end of a store and the time the Main Control Room declares colliding beams. This is the time between Tevatron clock events SCE and SCB. This definition does not consider the time experiments use to turn on their detectors. This analysis was suggested by David Finley. The operational scenarios for Run II will require higher levels of reliability and speed for shot setup. See Appendix I and II. For example, we estimate that a loss of 3 pb -1 /week (with 8 hour stores) will occur if shot setups take 90 minutes instead of 30 minutes. In other words: If you do 12 shots for one week and accept an added delay of one minute in each shot, you will loose more than 60 nb -1 for that week alone (based on a normal shot setup of 30 minutes). These demands should lead us to be much more pedantic about all the factors that affect shot setups. Shot setup will be viewed as a distinct process that is composed of several inter- dependent 'components': procedures, hardware, controls, and sociology. These components don't directly align with the different Accelerator Division departments, but are topical groupings of the needed accelerator functions. Defining these components, and categorizing our suggestions within them, are part of the goal of this document. Of course, some suggestions span several of these components

  4. Analysis of existing risk assessments, and list of suggestions

    CERN Document Server

    Heimsch, Laura

    2016-01-01

    The scope of this project was to analyse risk assessments made at CERN and extracting some crucial information about the different methodologies used, profiles of people who make the risk assessments, and gathering information of whether the risk matrix was used and if the acceptable level of risk was defined. Second step of the project was to trigger discussion inside HSE about risk assessment by suggesting a risk matrix and a risk assessment template.

  5. Oncologic prevention and suggested working standards in primary health care

    Directory of Open Access Journals (Sweden)

    Konstantinović Dejan

    2016-01-01

    Full Text Available On the ground of the available data, this paper presents the problem of malignant diseases in Central Serbia, and most common carcinogens. Division of carcinogens, cancerogenesis and natural history of disease, early detection of cancer and palliative management are explained. The role and capacities of primary health care doctors in treatment of patients with suspect malignant disease are presented. Authors are suggesting standards for medical tasks and contemporary principles in approach to patients with malignant diseases in everyday practice.

  6. Genetic theory – a suggested cupping therapy mechanism of action

    OpenAIRE

    Shaban , Tamer; Ravalia , Munir

    2017-01-01

    The Cupping Therapy mechanism of action is not clear. Cupping may increase local blood circulation, and may have an immunomodulation effect. Local and systemic effects of Cupping Therapy were reported. Genetic expression is a physiological process that regulates body functions. Genetic modulation is a reported acupuncture effect. In this article, the authors suggest genetic modulation theory as one of the possible mechanisms of action of cupping therapy.

  7. Epistemological Suggestions in „Entropy Low and Economic Process”

    Directory of Open Access Journals (Sweden)

    Emil Dinga

    2006-06-01

    Full Text Available The paper is aimed to derive, on criticism basis (following, especially, the critic rationalism, as method, epistemological suggestions from the crucial work of Nicholas Georgescu-Roegen, “The Entropy Law and the Economic Process”, in order to these suggestions or challenges constitute going points for further logical assessments or polemical debates. By this way, four basic epistemological suggestions are identified: a inconsistency between the analytical description of the economic process and its evolutionist nature (that implies qualitative changes; b logical and epistemological bases for the possibility of a theoretical economic science (i.e. of a theory of the economic science; c impact of the qualitative changes of the economic process on the non-linearity of the economic models for prognosis; d logics, based on the entropy law, to pass off the rationality of optimality and to enter the rationality of sustainability. Each of these suggestions (explicit or implicit mentioned in the evocated work plays as rational, for the authors, to formulate epistemological assessments, critics or proposals for solutions aimed at to pass over the arisen epistemological or methodological problems. The authors believe that the entropic paradigm proposed by Nicholas Georgescu-Roegen for the economic epistemology and methodology is one of the most interesting, from the philosophic and logic points of view, having abundant resources to open a re-conceptualization of the logical bases of the economic science, to rethink the theoreticity of the sciences that study fields where evolutive processes are going, and to think, with more maturity, to the way in which the human rationality could answer the challenges the entropy law arises.

  8. Early sonographic findings suggestive of the human fetal tail.

    Science.gov (United States)

    Zimmer, E Z; Bronshtein, M

    1996-04-01

    The prenatal diagnosis of a human tail was suggested in six fetuses with ultrasound findings of an echogenic protrusion in the lumbo-sacral region. All fetuses were at 14-16 weeks' gestation. The ultrasound findings disappeared in all cases at 22-23 weeks. Dermal abnormalities such as pilonidal sinus, deep dimples, and scarred tissue were found in all six newborns. It is possible that the late regression of the embryonic human tail was the cause of these dermal findings.

  9. Overview of the TREC 2013 Contextual Suggestion Track

    Science.gov (United States)

    2013-11-01

    once if in the area! I really enjoyed it. URL http://www.elfrethsalley.org • ID 65 Title Red Mango Description Red Mango is committed to providing the...venue categorization, for example “landmark” or “amusement park”, then the system creates a language model for each category. The category-specific... language models are used to perform the retrieval for each individual category mentioned in a user’s profile. Suggestions are personalized by making

  10. Marketing Suggestions for Home Original Chicken, Hefei China

    OpenAIRE

    Cheng, Ran

    2014-01-01

    The research “Marketing Suggestions for Home Original Chicken, Hefei China” was commissioned by Home Original Chicken Co. Ltd, which is the biggest Chinese fast-food restaurant chain in Anhui Province. The theory needed in the research was marketing mix strategies. Marketing mix consists of product, price, place and promotion. The marketing strategies contain product decisions (including individual products decisions, product line decisions, product mix decisions), price decisions (contai...

  11. A Privacy-by-Design Contextual Suggestion System for Tourism

    OpenAIRE

    Efraimidis, Pavlos; Drosatos, George; Arampatzis, Avi; Stamatelatos, Giorgos; Athanasiadis, Ioannis

    2016-01-01

    We focus on personal data generated by the sensors and through the everyday usage of smart devices and take advantage of these data to build a non-invasive contextual suggestion system for tourism. The system, which we call Pythia, exploits the computational capabilities of modern smart devices to offer high quality personalized POI (point of interest) recommendations. To protect user privacy, we apply a privacy by design approach within all of the steps of creating Pythia. The outcome is a s...

  12. Suggested instructions for the completion of delivery commitment schedules

    International Nuclear Information System (INIS)

    Vance, S.A.

    1992-01-01

    This presentation discusses the Delivery Commitment Schedule form contained in Appendix C of the Standard Contract for Disposal of Spent Nuclear Fuel and/or High-Level Radioactive Waste (the Standard Contract). In particular, the presentation describes some preliminary suggested instructions for completing the form in a manner that may aid the US Department of Energy (DOE) in the development of the Federal Waste Management System (FWMS)

  13. Women's Suggestions for Improving Midwifery Care in The Netherlands.

    Science.gov (United States)

    Baas, Carien I; Erwich, Jan Jaap H M; Wiegers, Therese A; de Cock, T Paul; Hutton, Eileen K

    2015-12-01

    The experience of the care a woman receives during pregnancy and childbirth has an immediate and long-lasting effect on her well being. The involvement of patients and clients in health care has increased over the last decades. The Dutch maternity care system offers an excellent opportunity to explore and involve women's suggestions for the improvement of midwifery care in the current maternity care model. This qualitative study is part of the "DELIVER" study. Clients were recruited from 20 midwifery practices. Purposive sampling was used to select the practices. The clients received up to three questionnaires, in which they could respond to the question; "Do you have any suggestions on how your midwife could improve his/her provision of care?" The answers were analyzed with a qualitative thematic content analysis, using the software program MAXQDA. Altogether, 3,499 answers were provided. One overarching concept emerged: clients' desire for individualized care. Within this concept, suggestions could be clustered around 1) provider characteristics: interpersonal skills, communication, and competence, and 2) service characteristics: content and quantity of care, guidance and support, continuity of care provider, continuity of care, information, and coordination of care. Informed by the suggestions of women, care to women and their families could be improved by the following: 1) more continuity of the care provider during the prenatal, natal, and postnatal periods, 2) more information and information specifically tailored for the person, 3) client-centered communication, and 4) a personal approach with 5) enough time spent per client. © 2015 Wiley Periodicals, Inc.

  14. CHINESE EFL UNDERGRADUATES’ ACADEMIC WRITING: RHETORICAL DIFFICULTIES AND SUGGESTIONS

    Directory of Open Access Journals (Sweden)

    Xiaoyun Bian

    2016-07-01

    Full Text Available Difficulties encountered by students in L2 academic writing has been a subject of research for several decades. However, to date, there still remains a lack of detailed and in-depth investigation into this area of interest. This qualitative study thoroughly investigated the rhetorical difficulties faced by Chinese EFL undergraduate academic writers, and collected suggestions on how to address these rhetorical issues. To be sufficiently detailed and thorough, this study divided students' difficulties into process- and product-related difficulties, and used triangulated data from supervisors' perspectives, students' perspectives, and supervisors' comments to address research questions. Although there were no strong generalizations derived from data from different perspectives and sources, the findings of this study showed supervisor perceptions of the rhetorical difficulties the students experienced were almost identical. In nature these rhetorical difficulties were culturallyembedded and genre-related issues; and the degree of difficulty experienced by each student varied. In this study, supervisors and students both suggested that, to solve rhetorical difficulties, teacher student communication should be improved. This study provided empirical evidence to contrastive rhetoric theory and socio-cultural theory. It also offered suggestions on how to strengthen future research in this area of inquiry, and how to improve academic writing teaching in L2 educational contexts.

  15. Perinatal pathology: practice suggestions for limited-resource settings.

    Science.gov (United States)

    Roberts, Drucilla J

    2013-06-01

    The practice of perinatal pathology in much of the world suffers, as do all subspecialties of anatomic pathology, from inadequate resources (equipment, consumables, and both professional and technical personnel), from lack of education (not only of the pathologist but also of the clinicians responsible for sending the specimens, and the technicians processing the specimens), and from lack of appropriate government sector support. Perinatal pathology has significant public health-related utility and should be championing its service by providing maternal and fetal/infant mortality and morbidity data to governmental health ministries. It is with this pathologic data that informed decisions can be made on health-related courses of action and allocation of resources. These perinatal pathology data are needed to develop appropriate public health initiatives, specifically toward achieving the Millennium Developmental Goals as the best way to effectively decrease infant and maternal deaths and to determine causes of perinatal mortality and morbidity. The following overview will focus on the utility of perinatal pathology specifically as related to its public health function and will suggest methods to improve its service in resource-poor settings. This article is offered not as a critique of the current practice that most pathologists find themselves working in globally, but to provide suggestions for improving perinatal pathology services, which could be implemented with the limited available resources and manpower most pathology departments currently have. In addition, we offer suggestions for graded improvements ("ramping up") over time.

  16. Public opinion and organ donation suggestions for overcoming barriers.

    Science.gov (United States)

    Cantarovich, Félix

    2005-01-01

    Getting organs for transplantation depends on people's decision; thus, public opinion is essential to finding a solution to this problem. Efforts to improve organ shortage focus on: 1) Living, unrelated donation, 2) increasing marginal donors and 3) proposing economic support for donors. Paradoxically, no initiative has been suggested to modify public opinion towards cadaver donors. Several reasons explain the resistance to donating cadaver organs: Lack of awareness, religious uncertainties, distrust of medicine, hostility to new ideas, and misinformation. Education should be used to reshape public opinion about the use of organs for transplantation. Society should accept that "using" body parts is moral and offers a source of health for everybody. The concept that using cadaver organs implies sharing a source of health might be a social agreement between all members of Society. Suggestions for improving organ shortage include: 1) Society should understand that during one's life one may be just as easily a potential organ receiver as one is an organ donor. 2) Cadaver organs are an irreplaceable source of health. 3) As self-interest is one obstacle to donating cadaver organs, the "concept that allowing the use of our organs after death represents a chance of sharing health for everybody" may be useful for a change of attitude. Even though a poll among transplant professionals supported this suggestion, an international public survey should be carried out to evaluate people's reaction to this message.

  17. A Privacy-by-Design Contextual Suggestion System for Tourism

    Directory of Open Access Journals (Sweden)

    Pavlos S. Efraimidis

    2016-05-01

    Full Text Available We focus on personal data generated by the sensors and through the everyday usage of smart devices and take advantage of these data to build a non-invasive contextual suggestion system for tourism. The system, which we call Pythia, exploits the computational capabilities of modern smart devices to offer high quality personalized POI (point of interest recommendations. To protect user privacy, we apply a privacy by design approach within all of the steps of creating Pythia. The outcome is a system that comprises important architectural and operational innovations. The system is designed to process sensitive personal data, such as location traces, browsing history and web searches (query logs, to automatically infer user preferences and build corresponding POI-based user profiles. These profiles are then used by a contextual suggestion engine to anticipate user choices and make POI recommendations for tourists. Privacy leaks are minimized by implementing an important part of the system functionality at the user side, either as a mobile app or as a client-side web application, and by taking additional precautions, like data generalization, wherever necessary. As a proof of concept, we present a prototype that implements the aforementioned mechanisms on the Android platform accompanied with certain web applications. Even though the current prototype focuses only on location data, the results from the evaluation of the contextual suggestion algorithms and the user experience feedback from volunteers who used the prototype are very positive.

  18. Pedunculated Pulmonary Artery Sarcoma Suggested by Transthoracic Echocardiography.

    Science.gov (United States)

    Wang, Xiaobing; Ren, Weidong; Yang, Jun

    2016-04-01

    Pulmonary artery sarcoma (PAS) is an extremely rare malignancy. It is usually found after it grows large enough to occupy almost the entire lumen of the pulmonary artery and causes serious clinical symptoms. Thus, it is usually difficult to distinguish PAS from pulmonary thromboembolism based on imaging examinations. Few case reports had shown the attachment of PAS to pulmonary artery, a key characteristic for diagnosis, and differential diagnosis of PAS. In this case, we found a PAS, which did not cause local obstruction and some tumor emboli, which obstructed the branches of the pulmonary arteries and caused pulmonary hypertension and clinical symptoms. Transthoracic echocardiography (TTE) revealed a part of the tumor attached to the intima of the main pulmonary artery with a peduncle and had obvious mobility, which was suggestive of PAS and differentiated it from the pulmonary thromboembolism. To our knowledge, this is the first case report of a pedunculated PAS suggested by TTE. Combined with pulmonary artery computed tomography angiography, the diagnosis of PAS is strongly suggested before the operation. This case indicates that TTE could reveal the attachment and mobility of PAS in the main pulmonary and may provide useful information for the diagnosis and differential diagnosis of PAS, especially a pedunculated PAS. © 2015, Wiley Periodicals, Inc.

  19. 5-Hydroxytryptamine 4 Receptor in the Endothelial Cells

    DEFF Research Database (Denmark)

    Profirovic, Jasmina; Vardya, Irina; Voyno-Yasenetskaya, Tatyana

    2006-01-01

    gap formation in HUVECs. We are currently investigating the mechanism underlying 5-HT4 receptor-induced actin cytoskeleton changes in the endothelial cells. These data suggest that by activating 5-HT4 receptor, serotonin could be involved in regulation of actin cytoskeleton dynamics in the endothelial......39 5-HYDROXYTRYPTAMINE 4 RECEPTOR IN THE ENDOTHELIAL CELLS. J. Profirovic, I. Vardya, T. Voyno-Yasenetskaya, Department of Pharmacology, University of Illinois at Chicago, Chicago, IL. Serotonin (5-hydroxytryptamine [5-HT]) is an important neurotransmitter that regulates multiple events...... in the central nervous system (CNS). We have recently demonstrated that 5-HT4 receptor couples to G13 protein to induce RhoA-dependent gene transcription, neurite retraction, and neuronal cell rounding (Ponimaskin et al, 2002). Although multiple studies were focused on the function of the 5-HT4 receptor...

  20. Identification of the receptor scavenging hemopexin-heme complexes

    DEFF Research Database (Denmark)

    Hvidberg, Vibeke; Maniecki, Maciej Bogdan; Jacobsen, Christian

    2005-01-01

    and is suggested to facilitate cellular heme metabolism. Using a ligand-affinity approach, we purified the human hemopexin-heme receptor and identified it as the low-density lipoprotein receptor-related protein (LRP)/CD91, a receptor expressed in several cell types including macrophages, hepatocytes, neurons......-heme complexes are removed by a receptor-mediated pathway showing striking similarities to the CD163-mediated haptoglobin-hemoglobin clearance in macrophages. Furthermore, the data indicate a hitherto unknown role of LRP/CD91 in inflammation......., and syncytiotrophoblasts. Binding experiments, including Biacore analysis, showed that hemopexin-heme complex formation elicits the high receptor affinity. Uptake studies of radio-labeled hemopexin-heme complex in LRP/CD91-expressing COS cells and confocal microscopy of the cellular processing of fluorescent hemopexin...

  1. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    Directory of Open Access Journals (Sweden)

    Akinori Hirashima

    2003-04-01

    Full Text Available The compounds 1-(2,6-diethylphenylimidazolidine-2-thione and 2-(2,6-diethylphenylimidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor.

  2. GRK mythology: G-protein receptor kinases in cardiovascular disease.

    Science.gov (United States)

    Dorn, Gerald W

    2009-05-01

    G-protein receptor kinases (GRKs) are indispensable for terminating signaling of G-protein coupled receptors (GPCR) through receptor desensitization and downregulation. Increased neurohormone levels in heart failure and the adverse consequences of constant neurohormonal stimulation suggest an important protective role for mechanisms that desensitize neurohormone receptor responses. For that reason, GRK2, the first GRK identified in the heart, has been extensively studied in heart failure, cardiac hypertrophy, and myocardial infarction. However, our understanding of the roles of GRKs in general, and the differential effects of cardiac receptor phosphorylation by individual cardiac-expressed GRKs, have evolved considerably in the last few years. Here, recent developments are reviewed, with an emphasis on novel GRK functions and signaling pathways.

  3. Interaction among Saccharomyces cerevisiae pheromone receptors during endocytosis

    Directory of Open Access Journals (Sweden)

    Chien-I Chang

    2014-03-01

    Full Text Available This study investigates endocytosis of Saccharomyces cerevisiae α-factor receptor and the role that receptor oligomerization plays in this process. α-factor receptor contains signal sequences in the cytoplasmic C-terminal domain that are essential for ligand-mediated endocytosis. In an endocytosis complementation assay, we found that oligomeric complexes of the receptor undergo ligand-mediated endocytosis when the α-factor binding site and the endocytosis signal sequences are located in different receptors. Both in vitro and in vivo assays suggested that ligand-induced conformational changes in one Ste2 subunit do not affect neighboring subunits. Therefore, recognition of the endocytosis signal sequence and recognition of the ligand-induced conformational change are likely to be two independent events.

  4. The ligand specificities of the insulin receptor and the insulin-like growth factor I receptor reside in different regions of a common binding site

    Energy Technology Data Exchange (ETDEWEB)

    Kjeldsen, T.; Andersen, A.S.; Wiberg, F.C.; Rasmussen, J.S.; Schaeffer, L.; Balschmidt, P.; Moller, K.B.; Moller, N.P.H. (Novo Nordisk, Bagsvaerd (Denmark))

    1991-05-15

    To identify the region(s) of the insulin receptor and the insulin-like growth factor I (IGF-I) receptor responsible for ligand specificity (high-affinity binding), expression vectors encoding soluble chimeric insulin/IGF-I receptors were prepared. The chimeric receptors were expressed in mammalian cells and partially purified. Binding studies revealed that a construct comprising an IGF-I receptor in which the 68 N-terminal amino acids of the insulin receptor {alpha}-subunit had replaced the equivalent IGF-I receptor segment displayed a markedly increased affinity for insulin. In contrast, the corresponding IGF-I receptor sequence is not critical for high-affinity IGF-I binding. It is shown that part of the cysteine-rich domain determines IGF-I specificity. The authors have previously shown that exchanging exons 1, 2, and 3 of the insulin receptor with the corresponding IGF-I receptor sequence results in loss of high affinity for insulin and gain of high affinity for IGF-I. Consequently, it is suggested that the ligand specificities of the two receptors (i.e., the sequences that discriminate between insulin and IGF-I) reside in different regions of a binding site with common features present in both receptors.

  5. adrenergic receptor with preeclampsia

    African Journals Online (AJOL)

    User

    2011-05-09

    May 9, 2011 ... expenditure and lipolysis. The mechanisms underlying lipolytic resistance to catecholamines in obesity are not clear and may include desensitization of ADRB2 function. (Yamada et al., 1999). Many studies have reported on the relationship between obesity and genetic variants in β-2 adrenergic receptors ...

  6. Ginkgolides and glycine receptors

    DEFF Research Database (Denmark)

    Jaracz, Stanislav; Nakanishi, Koji; Jensen, Anders A.

    2004-01-01

    Ginkgolides from the Ginkgo biloba tree are diterpenes with a cage structure consisting of six five-membered rings and a unique tBu group. They exert a variety of biological properties. In addition to being antagonists of the platelet activating factor receptor (PAFR), it has recently been shown ...

  7. Meeting report: nuclear receptors

    DEFF Research Database (Denmark)

    Tuckermann, Jan; Bourguet, William; Mandrup, Susanne

    2010-01-01

    The biannual European Molecular Biology Organization (EMBO) conference on nuclear receptors was organized by Beatrice Desvergne and Laszlo Nagy and took place in Cavtat near Dubrovnik on the Adriatic coast of Croatia September 25-29, 2009. The meeting brought together researchers from all over...

  8. Metformin and insulin receptors

    International Nuclear Information System (INIS)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    1984-01-01

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125 I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125 I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded

  9. Receptors, adenylate cyclase, depression, and lithium.

    Science.gov (United States)

    Belmaker, R H

    1981-04-01

    Although numerous studies have suggested that depression may be associated with a reduction in synaptic noradrenaline in the brain, direct beta-adrenergic receptor agonists have not been tested in the treatment of depression until recently. Moreover, newer theories of antidepressant action suggest that a reduction in beta-adrenergic receptor sensitivity is a better correlate of antidepressant treatment than noradrenaline turnover changes. It is possible to evaluate the beta-adrenergic receptor-adenylate cyclase complex in the human periphery by measuring the plasma cyclic AMP rise after adrenergic agonists. A clinical trial of the beta-2 adrenergic agonist salbutamol in depression provided an opportunity to test whether adrenergic receptor subsensitivity does occur during clinical antidepressant treatment. Plasma cyclic AMP before treatment with salbutamol rose 26% in response to salbutamol 0.25 mg iv. After 1 and 3 weeks of oral salbutamol treatment, depression scores declined significantly in 11 depressed patients, while the plasma cyclic AMP response to iv salbutamol declined over 60%. The beta-adrenergic adenylate cyclase remained subsensitive 4 days after cessation of salbutamol therapy. The results support the concept that receptor sensitivity changes occur during human antidepressant therapy. Data are presented that Li, too, markedly reduces activity of beta-adrenergic adenylate cyclase in humans. The effect was evaluated by studying the effect of Li at therapeutic serum concentrations on the plasma cyclic AMP response to subcutaneous epinephrine. The Li effect is specific, since the plasma cyclic AMP response to glucagon is not inhibited. The plasma cyclic GMP response to subcutaneous epinephrine, suggested as a model for presynaptic alpha-noradrenergic mechanisms, is also partially inhibited by Li therapy. Since cyclic AMP and cyclic GMP may be viewed as balancing substances, their interaction may provide a mechanism for Li's dual clinical effects in mania

  10. [Suggested low vision care for visually impaired children in Slovakia].

    Science.gov (United States)

    Gajdosová, E; Kukurová, E; Gerinec, A

    2011-02-01

    There is currently no system of registration for visually impaired children in Slovakia and the current prevalence of visual impairment (VI), low vision and blindness is unknown for this population. We propose a template for a process of registration of visually impaired children in Slovakia as well as a system for the Low Vision Health Core for this population. Based on a literature search, we report our data of the estimated prevalence of VI in children in Slovakia and the number of registered students with VI. We have created a registration form and suggested a template of registration for VI children as well as the Health Care System for this population. In industrialized countries, the prevalence of VI, including blindness is 10 -22/10,000 in children aged less than 16 years. Extrapolating these figures to the Slovak population, we estimate that there will be between 1500 to 3200 VI children under the age of 19 years. Only 752 students with VI of this age were recorded in Slovakia in 2009/2010. We suggest that three Low Vision Centres for VI children should be adequate to cater for the VI population, each of which should provide all levels of care and that ophthalmologists should register patients with VI by filling the proposed registration form. The number of VI children in Slovakia appears to be very low. The only way of accurately assessing the prevalence is to introduce a VI registration system into the country, to be carried out by the ophthalmologists. We suggest that the Low vision service provided by the health authority needs to be divided into primary, secondary and tertiary care (including visual rehabilitation by low vision aids). Only if the Health Insurance will adequately remunerate the Ophthalmologists for the individual procedures will they be motivated enough to provide this level of health care to VI patients.

  11. Suggestions for a consistent terminology for seismic anisotropy

    Energy Technology Data Exchange (ETDEWEB)

    Crampin, S. (British Geological Survey, Edinburgh (UK))

    1989-10-01

    Seismic anisotropy is an unfamiliar concept to many geophysicists and the use of misleading and ambiguous terminology has made it more difficult to understand. The author suggests here a consistent terminology in which simple expressions have specific meanings similar to their colloquial meanings. It is hoped that the use of such language will help to make the increasing number of papers reporting seismic anisotropy more readily comprehensible to the non-specialist. This is a list of terms which may make anisotropy easier to understand for those familiar with wave propagation in isotropic solids.

  12. Analysis and suggestions on standard system for general nuclear instruments

    International Nuclear Information System (INIS)

    Xiong Zhenglong

    1999-08-01

    The standard system has been analyzed and researched for the general nuclear instruments and propounded following suggestions against the problems in standard's system: seriously adopting the international standards and recommending Chinese standards toward the world; appropriately regularizing the system's frame and the standard's configurations to make it more scientific, perfect and applicable; enhancing the construction of technical and basic standards, promoting the standardization of entire nuclear instruments; replenishing the standards of the testing methods and straightening out the standard's level, further completing the standard's system. In short, all of them are to enhance quality, readability and maneuverability of standards, to exert sufficiently the effects of standards

  13. Making academic research more relevant: A few suggestions

    Directory of Open Access Journals (Sweden)

    Abinash Panda

    2014-09-01

    Full Text Available Academic research in the domain of management scholarship, though steeped in scientific and methodological rigour, is generally found to be of little relevance to practice. The authors of this paper have revisited the rigour-relevance debate in light of recent developments and with special reference to the management research scenario in India. The central thesis of the argument is that the gulf between rigour and relevance needs to be bridged to make academic research more relevant to business organizations and practitioners. They have offered some suggestions to enhance the relevance of academic research to practice.

  14. Partnership-Based Health Care: Suggestions for Effective Application

    Directory of Open Access Journals (Sweden)

    Teddie M Potter

    2015-06-01

    Full Text Available Societal transformation often starts with one visionary and a compelling idea. However, if there are no followers, the idea quickly becomes marginalized. It “takes a village” to build a movement, and the more system layers that can be addressed, the more likely the transformation will take hold. This article describes the framework for creating the necessary changes for partnership-based health care. It also makes suggestions for ensuring successful application of partnership-based systems change. This article is for all readers seeking to apply partnership principles in their own fields of influence.

  15. A new dynamic system suggested for earth expansion

    International Nuclear Information System (INIS)

    Fitzpatrick, J.

    1972-01-01

    It is here suggested that there may have been much more radioactive materials in the deep interior of the earth than bitherto supposed. Trapped heat being generated in the interior would provide a mechanism for earth expansion. An assumption of heat generation in the deep interior of the earth of the order of 0,5 X 10-13 calories per second, per cubic centimeter, would provide sufficient thermal expansion to account for approximately 0.1 mm. change in the radius of the earth per year

  16. A suggestion for multidisciplinarity: the fluorescence phenomenon observation

    Directory of Open Access Journals (Sweden)

    Jorge Roberto Pimentel

    2014-05-01

    Full Text Available Multidisciplinary approaches involving daily phenomena are valuable teaching tools to stimulate reflections in order to comprehend that scientific knowledge is developed in a collective process, as well as to understand the importance that scientific research cannot be done in a unique area of knowledge for the full understanding of any phenomenon. We suggest the fluorescence phenomenon observation in some materials, objects and living organisms so that students realize the interaction between Physics, Chemistry and Biology, generally regarded as not correlated disciplines.

  17. Solid-State Lighting 2017 Suggested Research Topics

    Energy Technology Data Exchange (ETDEWEB)

    None, None

    2017-09-29

    A 2017 update to the Solid-State Lighting R&D Plan that is divided into two documents. The first document describes a list of suggested SSL priority research topics and the second document provides context and background, including information drawn from technical, market, and economic studies. Widely referenced by industry and government both here and abroad, these documents reflect SSL stakeholder inputs on key R&D topics that will improve efficacy, reduce cost, remove barriers to adoption, and add value for LED and OLED lighting solutions over the next three to five years, and discuss those applications that drive and prioritize the specific R&D.

  18. Six Suggestions for Research on Games in Cognitive Science.

    Science.gov (United States)

    Chabris, Christopher F

    2017-04-01

    Games are more varied and occupy more of daily life than ever before. At the same time, the tools available to study game play and players are more powerful than ever, especially massive data sets from online platforms and computational engines that can accurately evaluate human decisions. This essay offers six suggestions for future cognitive science research on games: (1) Don't forget about chess, (2) Look beyond action games and chess, (3) Use (near)-optimal play to understand human play and players, (4) Investigate social phenomena, (5) Raise the standards for studies of games as treatments, (6) Talk to real experts. Copyright © 2017 Cognitive Science Society, Inc.

  19. Persistent Web References – Best Practices and New Suggestions

    DEFF Research Database (Denmark)

    Zierau, Eld; Nyvang, Caroline; Kromann, Thomas Hvid

    for various research fields, since an increasing number of references point to resources that only exist on the web. However, present practices using URL and date reference cannot be regarded as persistent due to the volatile nature of the Internet, - and present practices for references to web archives only...... refer to archive URLs which depends on the web archives access implementations. A major part of the suggested adjustments is a new web reference standard for archived web references (called wPID), which is a supplement to the current practices. The purpose of the standard is to support general, global...

  20. Credit risk identification and suggestions of electricity market

    Science.gov (United States)

    He, Chuan; Wang, Haichao; Chen, Zhongyuan; Hao, Yuxing; Jiang, Hailong; Qian, Hanhan; Wang, Meibao

    2018-03-01

    The power industry has a long history of credit problems, and the power industry has credit problems such as power users defaulting on electricity bills before the new electricity reform. With the reform of the power system, the credit problems in the power industry will be more complicated. How to effectively avoid the risk factors existing in the course of market operation and how to safeguard the fairness and standardization of market operation is an urgent problem to be solved. This paper first describes the credit risk in power market, and analyzes the components of credit risk identification in power market, puts forward suggestions on power market risk management.

  1. S-Nitrosothiols modulate G protein-coupled receptor signaling in a reversible and highly receptor-specific manner

    Directory of Open Access Journals (Sweden)

    Mönkkönen Kati S

    2005-04-01

    show for the first time in a broader general context that RSNOs are capable of modulating GPCR signaling in a reversible and highly receptor-specific manner. Given that the enzymatic machinery responsible for endogenous NO production is located in close proximity with the GPCR signaling complex, especially with that for several receptors whose signaling is shown here to be modulated by exogenous RSNOs, our data suggest that GPCR signaling in vivo is likely to be subject to substantial, and highly receptor-specific modulation by NO-derived RSNOs.

  2. Impaired water maze learning performance in mu-opioid receptor knockout mice.

    Science.gov (United States)

    Jang, Choon-Gon; Lee, Seok-Yong; Yoo, Ji-Hoon; Yan, Ji-Jing; Song, Dong-Keun; Loh, Horace H; Ho, Ing K

    2003-09-10

    Previous study has demonstrated that the lack of mu-opioid receptor decreased LTP in the dentate gyrus of the hippocampus, suggesting the possibility that the lack of mu-opioid receptor may accompany a change in learning and memory. However, no behavioral study has been undertaken to correlate LTP deficits with spatial memory impairment in mu-opioid receptor knockout mice. Therefore, the present study investigated the hypothesis that mu-opioid receptors contribute to learning and memory by using the Morris water maze, and comparing responses in wild type and mu-opioid receptor gene knockout mice. Our results indicated that mu-opioid receptor knockout mice showed a significant spatial memory impairment compared to wild type in the Morris water maze. This result suggests that the expression of mu-opioid receptor plays an important role in spatial learning and memory examined by Morris water maze.

  3. THE NATURE OF ACETYLCHOLINE RECEPTOR

    Directory of Open Access Journals (Sweden)

    M.E. TASHAYOD

    1983-05-01

    Full Text Available The present work with consideratlon to the autoradiographic pictures, suggests that cholinergic receptors are located at the gate of a channel originating from synaptic cleft coming to lie within the muscle fibre. AChE molecules stand at the gate of this channel,controlling the entrance of different cholinergic agents. It was report- ••• ed previously that dtc molecules s t.abD ;:.2e the AChE rnolecules and will obstruct the gate. This blocks the acess of ionic flux within the channel thus producing a non-depolarizing neuromuscular paralysis.The presented experiments imply that depolarizing agent will bring a considerable change in conformation of AChE mole cule and this causes the opening of the gate allowing ioni flux and depolarization .In case of ACh this process is repeated in a fraction of milli second, due to rapid regeneration of AChE while in case of suxamethonium and neostigmine(given in high dose, the regeneration of AChE takes much longer time thus will produce a depolarizing blockade. In this hypothepis the main responsa~ility of AChE"nis confined to identification of cholinergic agents and Cooperation in their function so,it can be accepted as Cholinergic receptor. In regard to clinic, this work suggests that only the use of minimum effective dose of neostigmine is advisable, in reversing curarisation. In contrast to general belief , the dose of neostigmine should be s elec t ed in relation to r eceptor dtc occupation and not depending on pati ent 's weight . As it was demonstrated , the early use"nof high dose o f neostigmine may a lso potent i a te curar i s a tion

  4. Modulation of nicotinic acetylcholine receptors by strychnine

    Science.gov (United States)

    García-Colunga, Jesús; Miledi, Ricardo

    1999-01-01

    Strychnine, a potent and selective antagonist at glycine receptors, was found to inhibit muscle (α1β1γδ, α1β1γ, and α1β1δ) and neuronal (α2β2 and α2β4) nicotinic acetylcholine receptors (AcChoRs) expressed in Xenopus oocytes. Strychnine alone (up to 500 μM) did not elicit membrane currents in oocytes expressing AcChoRs, but, when applied before, concomitantly, or during superfusion of acetylcholine (AcCho), it rapidly and reversibly inhibited the current elicited by AcCho (AcCho-current). Although in the three cases the AcCho-current was reduced to the same level, its recovery was slower when the oocytes were preincubated with strychnine. The amount of AcCho-current inhibition depended on the receptor subtype, and the order of blocking potency by strychnine was α1β1γδ > α2β4 > α2β2. With the three forms of drug application, the Hill coefficient was close to one, suggesting a single site for the receptor interaction with strychnine, and this interaction appears to be noncompetitive. The inhibitory effects on muscle AcChoRs were voltage-independent, and the apparent dissociation constant for AcCho was not appreciably changed by strychnine. In contrast, the inhibitory effects on neuronal AcChoRs were voltage-dependent, with an electrical distance of ≈0.35. We conclude that strychnine regulates reversibly and noncompetitively the embryonic type of muscle AcChoR and some forms of neuronal AcChoRs. In the former case, strychnine presumably inhibits allosterically the receptor by binding at an external domain whereas, in the latter case, it blocks the open receptor-channel complex. PMID:10097172

  5. Computer Modeling of Human Delta Opioid Receptor

    Directory of Open Access Journals (Sweden)

    Tatyana Dzimbova

    2013-04-01

    Full Text Available The development of selective agonists of δ-opioid receptor as well as the model of interaction of ligands with this receptor is the subjects of increased interest. In the absence of crystal structures of opioid receptors, 3D homology models with different templates have been reported in the literature. The problem is that these models are not available for widespread use. The aims of our study are: (1 to choose within recently published crystallographic structures templates for homology modeling of the human δ-opioid receptor (DOR; (2 to evaluate the models with different computational tools; and (3 to precise the most reliable model basing on correlation between docking data and in vitro bioassay results. The enkephalin analogues, as ligands used in this study, were previously synthesized by our group and their biological activity was evaluated. Several models of DOR were generated using different templates. All these models were evaluated by PROCHECK and MolProbity and relationship between docking data and in vitro results was determined. The best correlations received for the tested models of DOR were found between efficacy (erel of the compounds, calculated from in vitro experiments and Fitness scoring function from docking studies. New model of DOR was generated and evaluated by different approaches. This model has good GA341 value (0.99 from MODELLER, good values from PROCHECK (92.6% of most favored regions and MolProbity (99.5% of favored regions. Scoring function correlates (Pearson r = -0.7368, p-value = 0.0097 with erel of a series of enkephalin analogues, calculated from in vitro experiments. So, this investigation allows suggesting a reliable model of DOR. Newly generated model of DOR receptor could be used further for in silico experiments and it will give possibility for faster and more correct design of selective and effective ligands for δ-opioid receptor.

  6. Tachykinins and tachykinin receptors in the gut, with special reference to NK2 receptors in human.

    Science.gov (United States)

    Lecci, Alessandro; Capriati, Angela; Altamura, Maria; Maggi, Carlo Alberto

    2006-06-30

    Tachykinins (TKs), substance P (SP), neurokinin A (NKA) and B (NKB) are important peptide modulators of intestinal motility in animal species studied so far, including humans. Modulation of motility by TKs can occur at various levels, since these peptides are expressed in cholinergic excitatory motor neurons projecting to both circular and longitudinal muscle, interneurons, and intramural and extramural sensory neurons. The effects of SP, NKA and NKB are preferentially mediated through the stimulation of NK1, NK2 and NK3 receptors, respectively; however, the selectivity of natural TKs for their preferred receptors is relative. In addition, SP and NKA are expressed in similar quantities in the human intestine and adequate stimuli can release similar amount of these TKs from enteric nerves. Furthermore, a single anatomical substrate can express more than one TK receptor type, so that the blockade of a single receptor type may not reveal functional effects in integrated models of motility. In isolated human small intestine and colon circular muscle strips, both NK1 and NK2 receptors mediate contractile effects. Indeed, in the human small intestine, smooth muscle electrical and motor events induced by electrical field stimulation (EFS) can involve either or both NK1 and NK2 receptors or these latter receptors predominantly, depending on the experimental conditions. In contrast, in the human colonic smooth muscle, only the NK2 receptor-mediated component of the response to EFS is prominent and some evidence would suggest that this component is the main excitatory motor mechanism at this level. Furthermore, a NK2 receptor-mediated secretory component in the human colonic mucosa has been recently demonstrated. Thus, it could be speculated that the blockade of both NK1 and NK2 receptors will be necessary to antagonise motor effects induced by exogenous administration or endogenous release of TKs in the small intestine, whereas the blockade of the NK2 receptors would be

  7. Angiotensin type 2 receptor (AT2R) and receptor Mas

    DEFF Research Database (Denmark)

    Villela, Daniel; Leonhardt, Julia; Patel, Neal

    2015-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking...... the phenomenon of blockade of angiotensin-(1-7) [Ang-(1-7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1...

  8. Five suggestions for future medical education in Korea.

    Science.gov (United States)

    Yang, Eunbae B; Meng, Kwang Ho

    2014-09-01

    This study is to investigate the historical characteristics of medical education and healthcare environment in Korea and to suggest the desirable direction for future medical education. We draw a consensus through the literature analysis and several debates from the eight experts of medical education. There are several historical characteristics of medical education: medical education as vocational education and training, as a higher education, rapid growth of new medical schools, change to the medical education system, curriculum development, reinforcement of medical humanities, improvement of teaching and evaluation methods, validation of the national health personnel licensing examination, accreditation system for quality assurance, and establishment of specialized medical education division. The changes of health care environment in medical education are development of medical technologies, changes in the structures of the population and diseases, growth of information and communication technology, consumer-centered society, and increased intervention by the third party stakeholder. We propose five suggestions to be made to improve future medical education. They are plan for outcome and competency-based medical education, connection between the undergraduate and graduate medical education, reinforcement of continuous quality improvement of medical education, reorganization of the medical education system and construction of leadership of "academic medicine."

  9. Children Undergoing Radiotherapy: Swedish Parents’ Experiences and Suggestions for Improvement

    Science.gov (United States)

    Mullaney, Tara; Nilsson, Kristina; Wickart-Johansson, Gun; Svärd, Anna-Maja; Nyholm, Tufve; Lindh, Jack; Lindh, Viveca

    2015-01-01

    Approximately 300 children, from 0 to 18 years old, are diagnosed with cancer in Sweden every year. Of these children, 80–90 of them undergo radiotherapy treatment for their cancer. Although radiotherapy is an encounter with advanced technology, few studies have investigated the child’s and the parent’s view of the procedure. As part of an ongoing multicenter study aimed to improve patient preparation and the care environment in pediatric radiotherapy, this article reports the findings from interviews with parents at baseline. The aim of the present study was twofold: to describe parents’ experience when their child undergoes radiotherapy treatment, and to report parents’ suggestions for improvements during radiotherapy for their children. Sixteen mothers and sixteen fathers of children between 2–16 years old with various cancer diagnoses were interviewed. Data were analyzed using content analysis. The findings showed that cancer and treatment turns people’s lives upside down, affecting the entire family. Further, the parents experience the child’s suffering and must cope with intense feelings. Radiotherapy treatment includes preparation by skilled and empathetic staff. The parents gradually find that they can deal with the process; and lastly, parents have suggestions for improvements during the radiotherapy treatment. An overarching theme emerged: that despair gradually turns to a sense of security, with a sustained focus on and close interaction with the child. In conclusion, an extreme burden was experienced around the start of radiotherapy, though parents gradually coped with the process. PMID:26509449

  10. Current and Suggested focus on Sustainability in Pyrometallurgy

    Science.gov (United States)

    See, J. B.; Robertson, D. G. C.; Mackey, P. J.

    The production of iron and steel and non-ferrous metals by pyrometallurgical processes will remain a critical element in meeting the demand for materials in both developed and developing nations. Given the important need to reduce and minimise greenhouse gas emissions the technological focus of future pyrometallurgical R&D by universities and industry alike must concentrate on sustainability issues such as improved energy efficiency, recycling and waste minimization. Continued efforts are also needed on process optimization and new process development with a view to reducing capital and operating costs of the new large "mega" plants. Using the academic and industrial backgrounds of the authors, the present paper reviews the current status of R&D in pyrometallurgy in university departments with a particular emphasis on sustainability issues. The role of industry and government laboratories is also reviewed although primarily for developed countries. The paper also includes comments and suggestions on the future requirements for education and R&D in pyrometallurgy in developed countries to maximise sustainability. It is also suggested that future R&D in pyrometallurgy will be even more concentrated in developing countries — most notably China.

  11. Eyewitness recall and suggestibility in individuals with Down syndrome.

    Science.gov (United States)

    Collins, D; Henry, L

    2016-12-01

    Many criminal justice professionals perceive the eyewitness skills of individuals with intellectual disabilities to be weaker than those of typically developing (TD) individuals. Down syndrome (DS) is one of the most common genetic causes of intellectual disabilities, yet there is no research addressing eyewitness skills in this population. This study examined the eyewitness recall and suggestibility of young people with DS. Young people with DS and mental age-matched TD children viewed a video of a non-violent petty crime and were subsequently asked to freely recall the event before being asked general and specific questions incorporating both misleading and non-leading prompts. Compared with mental age-matched TD individuals, young people with DS produced as much information, were just as accurate and were no more suggestible. The eyewitness memory skills of young people with DS are comparable to those of mental age-matched TD children. The implications of these findings for the forensic context and eyewitness memory are discussed. © 2016 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

  12. CGRP Receptor Family and Accessory Protein Localization: Implications for Predicted Function

    Directory of Open Access Journals (Sweden)

    K.R. Oliver

    2001-01-01

    Full Text Available Calcitonin gene-related peptide (CGRP, adrenomedullin, amylin, and calcitonin are functionally related neuropeptides. Certain of these peptides mediate their action through receptors which have common components, such as the receptor activity modifying proteins (RAMPs and CGRP-receptor component protein, as well as possibly through other distinct receptors. Specifically, the molecular pharmacology of CGRP and adrenomedullin is determined by coexpression of one of three receptor activity-modifying proteins (RAMPs with calcitonin receptor-like receptor (CRLR. Additionally, through formation of another hetero-oligomer, RAMPs also govern the pharmacology of the calcitonin receptor, which in association with RAMP1 or RAMP3, binds amylin with high affinity. We have used multiple approaches to discern the regional and cellular expression of these various receptor components and binding sites for the above neuropeptides in multiple species and in different tissues. Techniques applied include in situ hybridization, immunohistochemistry and radioligand autoradiography. These data allow further understanding of both the complexity of receptor-receptor component and receptor-ligand interactions in vivo. Interestingly, these localization data suggest that RAMPs may interact with receptors additional to those already identified for the CGRP family and may be involved in binding innate neuropeptides or other neurotransmitters which are not members of the calcitonin gene-related peptide fam

  13. Prostanoid Receptors Involved in Regulation of the Beating Rate of Neonatal Rat Cardiomyocytes

    Science.gov (United States)

    Mechiche, Hakima; Grassin-Delyle, Stanislas; Robinet, Arnaud; Nazeyrollas, Pierre; Devillier, Philippe

    2012-01-01

    Although prostanoids are known to be involved in regulation of the spontaneous beating rate of cultured neonatal rat cardiomyocytes, the various subtypes of prostanoid receptors have not been investigated in detail. In our experiments, prostaglandin (PG)F2α and prostanoid FP receptor agonists (fluprostenol, latanoprost and cloprostenol) produced a decrease in the beating rate. Two prostanoid IP receptor agonists (iloprost and beraprost) induced first a marked drop in the beating rate and then definitive abrogation of beating. In contrast, the prostanoid DP receptor agonists (PGD2 and BW245C) and TP receptor agonists (U-46619) produced increases in the beating rate. Sulprostone (a prostanoid EP1 and EP3 receptor agonist) induced marked increases in the beating rate, which were suppressed by SC-19220 (a selective prostanoid EP1 antagonist). Butaprost (a selective prostanoid EP2 receptor agonist), misoprostol (a prostanoid EP2 and EP3 receptor agonist), 11-deoxy-PGE1 (a prostanoid EP2, EP3 and EP4 receptor agonist) did not alter the beating rate. Our results strongly suggest that prostanoid EP1 receptors are involved in positive regulation of the beating rate. Prostanoid EP1 receptor expression was confirmed by western blotting with a selective antibody. Hence, neonatal rat cardiomyocytes express both prostanoid IP and FP receptors (which negatively regulate the spontaneous beating rate) and prostanoid TP, DP1 and EP1 receptors (which positively regulate the spontaneous beating rate). PMID:22984630

  14. Tyrosine phosphorylation of the insulin receptor is not required for receptor internalization: studies in 2,4-dinitrophenol-treated cells

    International Nuclear Information System (INIS)

    Backer, J.M.; Kahn, C.R.; White, M.F.

    1989-01-01

    The relation between insulin-stimulated autophosphorylation of the insulin receptor and internalization of the receptor was studied in Fao rat hepatoma cells. Treatment of Fao cells with 2,4-dinitrophenol for 45 min depleted cellular ATP by 80% and equally inhibited insulin-stimulated receptor autophosphorylation, as determined by immunoprecipitation of surface-iodinated or [ 32 P]phosphate-labeled cells with anti-phosphotyrosine antibody. In contrast, internalization of the insulin receptor and internalization and degradation of 125 I-labeled insulin by 2,4-dinitrophenol-treated cells were normal. These data show that autophosphorylation of the insulin receptor is not required for the receptor-mediated internalization of insulin in Fao cells and suggest that insulin receptor recycling is independent of autophosphorylation

  15. Tachykinins and tachykinin receptors: structure and activity relationships.

    Science.gov (United States)

    Almeida, T A; Rojo, J; Nieto, P M; Pinto, F M; Hernandez, M; Martín, J D; Candenas, M L

    2004-08-01

    In addition to the classical neurotransmitters, acetylcholine and noradrenaline, a wide number of peptides with neurotransmitter activity have been identified in the past few years. Among them, the tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) appear to act as mediators of nonadrenergic, noncholinergic (NANC) excitatory neurotransmission. Tachykinins interact with specific membrane proteins, belonging to the family of G protein-coupling cell membrane receptors. Until now, three tachykinin receptors termed NK1 (NK1R), NK2 (NK2R) and NK3 (NK3R) have been cloned in different species. A large amount of reports suggests that these peptides are involved in nociception and neuroimmunomodulation, and in the development of different diseases such as bronchial asthma, inflammatory bowel syndrome and psychiatric disorders. Tachykinin receptor antagonists are therefore promising, therapeutically relevant agents. However, and in spite of extensive research, the obtention of selective antagonists of tachykinin receptors have revealed very difficult. An understanding of how ligands interact with their receptors is essential to permit a rational design of compounds acting selectively at the tachykinin receptor level. The major aim of the present article is to review the structure-activity data that exist for tachykinins and their receptors, with the purpose of getting insight into basic structural requirements that determine ligand/receptor interaction. Copyright 2004 Bentham Science Publishers Ltd.

  16. Protease-activated receptor 2, a receptor involved in melanosome transfer, is upregulated in human skin by ultraviolet irradiation.

    Science.gov (United States)

    Scott, G; Deng, A; Rodriguez-Burford, C; Seiberg, M; Han, R; Babiarz, L; Grizzle, W; Bell, W; Pentland, A

    2001-12-01

    Previous studies have shown that the protease-activated receptor 2 is involved in skin pigmentation through increased phagocytosis of melanosomes by keratinocytes. Ultraviolet irradiation is a potent stimulus for melanosome transfer. We show that protease-activated receptor 2 expression in human skin is upregulated by ultraviolet irradiation. Subjects with skin type I, II, or III were exposed to two or three minimal erythema doses of irradiation from a solar simulator. Biopsies were taken from nonexposed and irradiated skin 24 and 96 h after irradiation and protease-activated receptor 2 expression was detected using immunohistochemical staining. In nonirradiated skin, protease-activated receptor 2 expression was confined to keratinocytes in the lower one-third of the epidermis. After ultraviolet irradiation protease-activated receptor 2 expression was observed in keratinocytes in the upper two-thirds of the epidermis or the entire epidermis at both time points studied. Subjects with skin type I showed delayed upregulation of protease-activated receptor 2 expression, however, compared with subjects with skin types II and III. Irradiated cultured human keratinocytes showed upregulation in protease-activated receptor 2 expression as determined by immunofluorescence microscopy and Western blotting. Cell culture supernatants from irradiated keratinocytes also exhibited a dose-dependent increase in protease-activated receptor-2 cleavage activity. These results suggest an important role for protease-activated receptor-2 in pigmentation in vivo. Differences in protease-activated receptor 2 regulation in type I skin compared with skin types II and III suggest a potential mechanism for differences in tanning in subjects with different skin types.

  17. Genomic organization, annotation, and ligand-receptor inferences of chicken chemokines and chemokine receptor genes based on comparative genomics

    Directory of Open Access Journals (Sweden)

    Sze Sing-Hoi

    2005-03-01

    Full Text Available Abstract Background Chemokines and their receptors play important roles in host defense, organogenesis, hematopoiesis, and neuronal communication. Forty-two chemokines and 19 cognate receptors have been found in the human genome. Prior to this report, only 11 chicken chemokines and 7 receptors had been reported. The objectives of this study were to systematically identify chicken chemokines and their cognate receptor genes in the chicken genome and to annotate these genes and ligand-receptor binding by a comparative genomics approach. Results Twenty-three chemokine and 14 chemokine receptor genes were identified in the chicken genome. All of the chicken chemokines contained a conserved CC, CXC, CX3C, or XC motif, whereas all the chemokine receptors had seven conserved transmembrane helices, four extracellular domains with a conserved cysteine, and a conserved DRYLAIV sequence in the second intracellular domain. The number of coding exons in these genes and the syntenies are highly conserved between human, mouse, and chicken although the amino acid sequence homologies are generally low between mammalian and chicken chemokines. Chicken genes were named with the systematic nomenclature used in humans and mice based on phylogeny, synteny, and sequence homology. Conclusion The independent nomenclature of chicken chemokines and chemokine receptors suggests that the chicken may have ligand-receptor pairings similar to mammals. All identified chicken chemokines and their cognate receptors were identified in the chicken genome except CCR9, whose ligand was not identified in this study. The organization of these genes suggests that there were a substantial number of these genes present before divergence between aves and mammals and more gene duplications of CC, CXC, CCR, and CXCR subfamilies in mammals than in aves after the divergence.

  18. Autoinducer 2 Signaling via the Phosphotransferase FruA Drives Galactose Utilization by Streptococcus pneumoniae, Resulting in Hypervirulence

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    Claudia Trappetti

    2017-01-01

    Full Text Available Communication between bacterial cells is crucial for the coordination of diverse cellular processes that facilitate environmental adaptation and, in the case of pathogenic species, virulence. This is achieved by the secretion and detection of small signaling molecules called autoinducers, a process termed quorum sensing. To date, the only signaling molecule recognized by both Gram-positive and Gram-negative bacteria is autoinducer 2 (AI-2, synthesized by the metabolic enzyme LuxS (S-ribosylhomocysteine lyase as a by-product of the activated methyl cycle. Homologues of LuxS are ubiquitous in bacteria, suggesting a key role in interspecies, as well as intraspecies, communication. Gram-negative bacteria sense and respond to AI-2 via the Lsr ABC transporter system or by the LuxP/LuxQ phosphorelay system. However, homologues of these systems are absent from Gram-positive bacteria and the AI-2 receptor is unknown. Here we show that in the major human pathogen Streptococcus pneumoniae, sensing of exogenous AI-2 is dependent on FruA, a fructose-specific phosphoenolpyruvate-phosphotransferase system that is highly conserved in Gram-positive pathogens. Importantly, AI-2 signaling via FruA enables the bacterium to utilize galactose as a carbon source and upregulates the Leloir pathway, thereby leading to increased production of capsular polysaccharide and a hypervirulent phenotype.

  19. Personal receptor repertoires: olfaction as a model

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    Olender Tsviya

    2012-08-01

    Full Text Available Abstract Background Information on nucleotide diversity along completely sequenced human genomes has increased tremendously over the last few years. This makes it possible to reassess the diversity status of distinct receptor proteins in different human individuals. To this end, we focused on the complete inventory of human olfactory receptor coding regions as a model for personal receptor repertoires. Results By performing data-mining from public and private sources we scored genetic variations in 413 intact OR loci, for which one or more individuals had an intact open reading frame. Using 1000 Genomes Project haplotypes, we identified a total of 4069 full-length polypeptide variants encoded by these OR loci, average of ~10 per locus, constituting a lower limit for the effective human OR repertoire. Each individual is found to harbor as many as 600 OR allelic variants, ~50% higher than the locus count. Because OR neuronal expression is allelically excluded, this has direct effect on smell perception diversity of the species. We further identified 244 OR segregating pseudogenes (SPGs, loci showing both intact and pseudogene forms in the population, twenty-six of which are annotatively “resurrected” from a pseudogene status in the reference genome. Using a custom SNP microarray we validated 150 SPGs in a cohort of 468 individuals, with every individual genome averaging 36 disrupted sequence variations, 15 in homozygote form. Finally, we generated a multi-source compendium of 63 OR loci harboring deletion Copy Number Variations (CNVs. Our combined data suggest that 271 of the 413 intact OR loci (66% are affected by nonfunctional SNPs/indels and/or CNVs. Conclusions These results portray a case of unusually high genetic diversity, and suggest that individual humans have a highly personalized inventory of functional olfactory receptors, a conclusion that might apply to other receptor multigene families.

  20. H1-histamine receptor affinity predicts weight gain with antidepressants.

    Science.gov (United States)

    Salvi, Virginio; Mencacci, Claudio; Barone-Adesi, Francesco

    2016-10-01

    Weight gain and metabolic abnormalities are extensively found in patients taking psychotropic medications. Although mainly antipsychotics have been implicated, also antidepressants carry the potential to induce weight gain, with tricyclics and mirtazapine being associated with the greatest weight gain. It has been suggested that this could be due to the different ability of antidepressants to block adrenergic, cholinergic, and histaminergic postsynaptic receptors. To date, however, the link between antidepressant-induced weight gain and their receptor affinity profile has not been established. We reanalysed data from a previous meta-analysis to evaluate whether weight change is associated with specific receptor affinity of antidepressants. We retrieved data from the only meta-analysis that assessed weight change with antidepressants. We searched in the Psychoactive Drug Screening Program (PDSP) Ki database data on the affinities of antidepressants to receptors hypothetically linked with weight change: H1-histamine, 5HT2c, M3-muscarinic, and α1A-adrenergic receptors. The association between weight change and receptor affinities was estimated using meta-regression. We found a significant association between the affinity of antidepressants to H1-receptor and weight gain (p value: antidepressants. These results further stress a reclassification of antidepressants according to their pharmacodynamic properties, and suggest avoiding prescribing antidepressants with an anti-histaminergic profile to patients at risk for cardio-metabolic disturbances. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  1. Leptin receptor in peripheral adipose tissues of obese subjects

    International Nuclear Information System (INIS)

    Du Tongxin; Sun Junjiang; Wang Zizheng; Wang Shukui; Fu Lei; Han Liu

    2002-01-01

    Objective: To investigate the relationship between leptin receptor and obesity by studying the leptin receptor density B max and dissociation constant K d in peripheral adipose tissue in subjects with different body weight mass (BMI). Methods: Leptin receptor density B max and K d were assayed via radioligand method in 71 cases, including 32 classified as obese, 19 over-weight and 20 normal control. Results: With the escalating of BMI, the leptin receptor density significantly decreased in obese and over-weight group compared with that in normal control (both P d values were of no differences among all three groups suggesting no correlation between the binding ability of leptin to its receptor and BMI. A negative correlation between BMI and B max (r=-0.76, P<0.01) displayed after all. Conclusion: Leptin receptor density correlates with the BMI in obese cases and it suggests that the down-regulation of leptin receptor may contribute to the occurrence of leptin resistance and obesity after-wards

  2. Hemimegalencephaly: signal changes suggesting abnormal myelination on MRI

    Energy Technology Data Exchange (ETDEWEB)

    Yagishita, A. [Dept. of Neuroradiology, Tokyo Metropolitan Neurological Hospital (Japan); Arai, N. [Dept. of Clinical Neuropathology, Tokyo Metropolitan Inst. for Neuroscience, Tokyo (Japan); Tamagawa, K. [Dept. of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo (Japan); Oda, M. [Dept. of Neuropathology, Tokyo Metropolitan Neurological Hospital, Tokyo (Japan)

    1998-11-01

    We reviewed the MRI of 17 patients with hemimegalencephaly to investigate abnormal myelination in this condition. On images of seven patients aged 18 months or less, the white matter on the affected side suggested advanced myelination for the age. On T1-weighted images of three patients aged 1 month, the anterior limb of the internal capsule in the affected hemisphere was myelinated, and T1 shortening was not clearly seen in the pre- and postcentral gyri. The cortical grey matter and subcortical white matter was isointense in two patients. Images of two patients aged 4 to 5 months and of five patients aged 8-18 months showed myelination that extended more peripherally in the white matter of the affected hemisphere. (orig.) With 3 figs., 1 tab., 8 refs.

  3. Suggestions for teacher education from concept mapping studies

    Directory of Open Access Journals (Sweden)

    Priit Reiska

    2015-03-01

    Full Text Available In order to enhance primary and secondary education, teaching and learning methods need to be continuously developed as well as, of course, promote teaching quality dependent on teacher personality, teacher professional development, teacher self-development, etc. Teacher professional development gives the novice teacher access to a wide set of teaching methods and assessment opportunities, especially geared to flexible learning and assessment methods, which can be considered for adoption. One such flexible method is the use of concept mapping. This article describes the results of several studies, where concept mapping method was used, giving many didactical suggestions for using concept mapping for learning and especially for assessment. Additionally, considerations are introduced on using concept maps as a research instrument.

  4. A review of cyberbullying and suggestions for online psychological therapy

    Directory of Open Access Journals (Sweden)

    Mairéad Foody

    2015-09-01

    Full Text Available Investigations of cyberbullying are beginning to emerge in the scientific literature because of their implications for child and adolescent development. In particular, cyberbullying victimisation has been associated with similar negative consequences to traditional or face-to-face bullying such as lower academic achievement, anxiety, and sometimes even suicide. Research has also started to emerge investigating the impact of such incidences on the life of adults. The literature in this area has been steadily growing over the last decade and this review highlights the current situation in terms of relevant features and the psychological impact on victims. The selection process consisted of a comprehensive search that was conducted in January 2015 in the following databases: PsychInfo, ERIC, Web of Science and Medline. A total of 19 papers were included. We conclude with suggestions for online psychological treatment for victims and bullies as a means of coping with the distress caused from cyberbullying experiences.

  5. Predicting Low Back Pain Outcomes: Suggestions for Future Directions.

    Science.gov (United States)

    Boissoneault, Jeff; Mundt, Jennifer; Robinson, Michael; George, Steven Z

    2017-09-01

    Chronic low back pain (LBP) is a common and costly musculoskeletal pain condition, and effective treatment of LBP represents a significant goal of physical therapists. Establishing a targeted track of treatment for patients with LBP at high risk for chronicity that is focused on modifiable prognostic factors could have significant personal and societal benefit. Such an approach would require that clinicians accurately predict the patients who are at an elevated risk of developing chronic LBP in the early stages of the condition. In this Viewpoint, we consider the strengths and limitations of existing literature and propose suggestions that may lead to the development of parsimonious, cost-effective, and accurate predictive models of LBP chronicity. J Orthop Sports Phys Ther 2017;47(9):588-592. doi:10.2519/jospt.2017.0607.

  6. Considerations about ISO 14001, and suggestions for the next revision

    DEFF Research Database (Denmark)

    Jørgensen, Tine Herreborg

    2006-01-01

    The aim of this paper is to discuss a number of issues related to ISO 14001:2004, the international standard for environmental management systems (EMS) with the purpose of improving the next edition in order to recognize and reflect new recognitions in approaches to pollution prevention. The stan......The aim of this paper is to discuss a number of issues related to ISO 14001:2004, the international standard for environmental management systems (EMS) with the purpose of improving the next edition in order to recognize and reflect new recognitions in approaches to pollution prevention....... The standard is a process standard that leaves room for interpretation at company level as well as among lead auditors from certifying bodies. A case study is presented and shows lack of life cycle thinking in product development. The paper suggests changes of ISO 14001:2004 in order to include a clear product...

  7. Genomic analysis suggests higher susceptibility of children to air pollution

    DEFF Research Database (Denmark)

    van Leeuwen, Danitsja M; Pedersen, Marie; Hendriksen, Peter J M

    2008-01-01

    Differences in biological responses to exposure to hazardous airborne substances between children and adults have been reported, suggesting children to be more susceptible. Aim of this study was to improve our understanding of differences in susceptibility in cancer risk associated with air...... pollution by comparing genome-wide gene expression profiles in peripheral blood of children and their parents. Gene expression analysis was performed in blood from children and parents living in two different regions in the Czech Republic with different levels of air pollution. Data were analyzed by two...... in relation to air pollution exposure at the transcriptome level. The findings underline the necessity of implementing environmental health policy measures specifically for protecting children's health....

  8. Neurogenesis suggests independent evolution of opercula in serpulid polychaetes

    DEFF Research Database (Denmark)

    Brinkmann, Nora; Wanninger, Andreas

    2009-01-01

    BACKGROUND: The internal phylogenetic relationships of Annelida, one of the key lophotrochozoan lineages, are still heavily debated. Recent molecular analyses suggest that morphologically distinct groups, such as the polychaetes, are paraphyletic assemblages, thus questioning the homology...... systematics. RESULTS: By reconstructing the developmental neuroanatomy of the serpulid polychaete Spirorbis cf. spirorbis (Spirorbinae), we found striking differences in the overall neural architecture, the innervation pattern, and the ontogenetic establishment of the nervous supply of the operculum...... such as the prostomial appendages may have evolved independently in respective serpulid sublineages and therefore require reassessment before being used in phylogenetic analyses. Our findings corroborate recent molecular studies that argue for a revision of serpulid systematics. In addition, our data on Spirorbis...

  9. Yellowish lesions of the oral cavity. Suggestion for a classification.

    Science.gov (United States)

    Gómez, Iria; Varela, Pablo; Romero, Amparo; García, María José; Suárez, María Mercedes; Seoane, Juan

    2007-08-01

    The colour of a lesion is due to its nature and to its histological substratum. In order to ease diagnosis, oral cavity lesions have been classified according to their colour in: white, red, white and red, bluish and/or purple, brown, grey and/or black lesions. To the best of our knowledge, there is no such a classification for yellow lesions. So, a suggestion for a classification of yellowish lesions according to their semiology is made with the following headings: diffuse macular lesions, papular, hypertrophic, or pustular lesions, together with cysts and nodes. This interpretation of the lesions by its colour is the first step to diagnosis. It should be taken into account that, as happens with any other classification, the yellowish group of lesions includes items with different prognosis as well as possible markers of systemic disorders.

  10. Sexual health and older adults: suggestions for social science research.

    Science.gov (United States)

    Hinchliff, Sharron

    2016-11-01

    The body of evidence on older adults' sexual health is beginning to grow. However, it remains an under-researched area particularly within the social sciences. This viewpoint outlines four considerations for those who carry out social science research in this area: 1. defining the age category "older adults"; 2. being clear about the types of sex under research; 3. capturing a range of diverse voices; and 4. considering the use of qualitative research methods to explore the topic in depth. These suggestions are aimed at helping researchers to avoid some of the pitfalls of research in this area, as well as improving the evidence base in order to advance recognition of the issues and drive change in service provision. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Autolysis: a plausible finding suggestive of long ESD procedure time.

    Science.gov (United States)

    Hyun, Jong Jin; Chun, Hoon Jai; Keum, Bora; Seo, Yeon Seok; Kim, Yong Sik; Jeen, Yoon Tae; Lee, Hong Sik; Um, Soon Ho; Kim, Chang Duck; Ryu, Ho Sang; Chae, Yang-Seok

    2012-04-01

    Autolysis is the enzymatic digestion of cells by the action of its own enzymes, and it mostly occurs in dying or dead cells. It has previously been suggested that prolonged procedure time could lead to autolytic changes from the periphery of the endoscopic submucosal dissection specimens. Recently, the authors have experienced a case of autolysis; due to the presence of ulcer, fibrosis, and frequent bleeding from the cut surface, it took 6 hours to complete the resection. More than halfway through the resection; bluish purple discoloration of the part of the dissected flap where the dissection was initiated was noticed. Histologic examination of this site showed diffuse distortion of epithelial lining and cellular architectures along with loss of cell components, compatible with autolysis. Because autolysis could theoretically pose a potential problem regarding the evaluation of resection margin, endoscopists and pathologists should communicate with each other for a reliable pathologic decision.

  12. Morphology suggests noseleaf and pinnae cooperate to enhance bat echolocation.

    Science.gov (United States)

    Kuc, Roman

    2010-11-01

    A protruding noseleaf and concave pinna structures suggest that some bats may use these to enhance their echolocation capabilities. This paper considers two possible mechanisms that each exploit the combination of direct and delayed acoustic paths to achieve more complex emission or sensitivity echolocation patterns. The first is an emission mechanism, in which the protruding noseleaf vibrates to emit sound in both the forward and backward directions, and pinna structures reflect the backward emission to enhance the forward beam. The second is a reception mechanism, which has a direct echo path to the ear canal and a delayed path involving pinna structures reflecting onto the noseleaf and then into the ear canal. A model using Davis' Round-eared Bat illustrates that such direct and delayed acoustic paths provide target elevation cues. The model demonstrates the delayed pinna component can increase the on-axis emission strength, narrow the beam width, and sculpt frequency-dependent beam patterns useful for echolocation.

  13. School satisfaction and social relations: Swedish schoolchildren's improvement suggestions.

    Science.gov (United States)

    Persson, Louise; Haraldsson, Katarina; Hagquist, Curt

    2016-01-01

    The aim was to explore schoolchildren's views on how to increase school satisfaction and improve social relations among peers at school. Improvement suggestions were collected from school children aged 10-12 years with the help of a feedback model developed for the purpose. Qualitative content analysis was used. Two categories emerged from the analysis: 'psychosocial climate', which included the subcategories 'adults' roles and responsibilities' and 'classmates' norms and values'; 'influence', which included the subcategories 'changes in the physical environment' and 'flexible learning'. The categories are seen as important to increase school satisfaction and improve social relations among peers at school. Examining children's opinions is requested and promoted by the UN convention on the Rights of the Child. The findings contribute to the field by showing how school satisfaction and social relations might be improved, if the child perspective is considered in the planning of health promotion activities in school.

  14. MOOCs for Teacher Professional Development: Reflections and Suggested Actions

    Directory of Open Access Journals (Sweden)

    Pradeep Kumar Misra

    2018-02-01

    Full Text Available Teacher Professional Development (TPD has become a major policy priority within education systems worldwide. But keeping teachers professionally up-to-date and providing them professional development opportunities on continuing basis is a big challenge. Massive Open Online Courses (MOOCs can be a cost and resource effective means to complement the traditional methods of professional development of teachers. This optimism is based on the assumption that use of MOOCs will facilitate mass training of teachers as per their convenience and ease. The other assumption is that being MOOCs-based training, it will be easy to adapt it to different cultures and languages. Considering these assumptions, this concept paper which is based on reviews of different reports, documents and research papers - discusses the challenges of TPD, reflects upon promises of using MOOCs for TPD; details initiatives and experiences of using MOOCs for TPD; and suggests actions for promoting the use of MOOCs for TPD.

  15. Selective mutism: an update and suggestions for future research.

    Science.gov (United States)

    Scott, Samantha; Beidel, Deborah C

    2011-08-01

    Speculation continues regarding the accurate classification of selective mutism and potential etiologic factors. Current research has shed some light on several factors that may predispose some children to this disorder, but conclusions are difficult to draw due to reliance on subjective measures, few comparison groups, and/or limited theoretical grounding. This article provides an update on recent efforts to elucidate the etiologic pathways of selective mutism and on the current debate regarding its strong overlap with anxiety disorders, most notably social phobia. An additional attempt is made to examine findings based on a developmental perspective that accounts for multiple pathways, context, and the developmental stage of the child. Emotion regulation theory is offered as a potential factor in why some children may be more vulnerable to the etiologic factors described. Suggestions for future research are offered based on this integration of information.

  16. Ethnobiology of snappers (Lutjanidae: target species and suggestions for management

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    Clauzet Mariana

    2011-03-01

    Full Text Available Abstract In this study, we sought to investigate the biology (diet and reproduction and ethnobiology (fishers knowledge and fishing spots used to catch snappers of five species of snappers (Lutjanidae, including Lutjanus analis, Lutjanus synagris, Lutjanus vivanus, Ocyurus chrysurus, and Romboplites saliens at five sites along the northeast (Riacho Doce, Maceió in Alagoas State, and Porto do Sauípe, Entre Rios at Bahia State and the southeast (SE Brazilian coast (Paraty and Rio de Janeiro cities at Rio de Janeiro State, and Bertioga, at São Paulo State.. We collected 288 snappers and interviewed 86 fishermen. The stomach contents of each fish were examined and macroscopic gonad analysis was performed. Snappers are very important for the fisheries of NE Brazil, and our results indicated that some populations, such as mutton snapper (L. analis and lane snapper (L. synagris, are being caught when they are too young, at early juvenile stages. Local knowledge has been shown to be a powerful tool for determining appropriate policies regarding management of target species, and artisanal fishermen can be included in management processes. Other suggestions for managing the fisheries are discussed, including proposals that could provide motivation for artisanal fishermen to participate in programs to conserve resources, such as co-management approaches that utilize local knowledge, the establishment of fishing seasons, and compensation of fishermen, through 'payment for environmental services'. These suggestions may enhance the participation of local artisanal fishermen in moving to a more realistic and less top-down management approach of the fish population.

  17. An hypnotic suggestion: review of hypnosis for clinical emergency care.

    Science.gov (United States)

    Iserson, Kenneth V

    2014-04-01

    Hypnosis has been used in medicine for nearly 250 years. Yet, emergency clinicians rarely use it in emergency departments or prehospital settings. This review describes hypnosis, its historical use in medicine, several neurophysiologic studies of the procedure, its uses and potential uses in emergency care, and a simple technique for inducing hypnosis. It also discusses reasons why the technique has not been widely adopted, and suggests methods of increasing its use in emergency care, including some potential research areas. A limited number of clinical studies and case reports suggest that hypnosis may be effective in a wide variety of conditions applicable to emergency medical care. These include providing analgesia for existing pain (e.g., fractures, burns, and lacerations), providing analgesia and sedation for painful procedures (e.g., needle sticks, laceration repair, and fracture and joint reductions), reducing acute anxiety, increasing children's cooperation for procedures, facilitating the diagnosis and treatment of acute psychiatric conditions, and providing analgesia and anxiolysis for obstetric/gynecologic problems. Although it is safe, fast, and cost-effective, emergency clinicians rarely use hypnosis. This is due, in part, to the myths surrounding hypnosis and its association with alternative-complementary medicine. Genuine barriers to its increased clinical use include a lack of assured effectiveness and a lack of training and training requirements. Based on the results of further research, hypnosis could become a powerful and safe nonpharmacologic addition to the emergency clinician's armamentarium, with the potential to enhance patient care in emergency medicine, prehospital care, and remote medical settings. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Dependency plots suggest the kinetic structure of ion channels.

    Science.gov (United States)

    Magleby, K L; Song, L

    1992-08-22

    Ion channels are integral membrane proteins that regulate ionic flux through cell membranes by opening and closing (gating) their pores. The gating can be monitored by observing step changes in the current flowing through single channels, and analysis of the observed open and closed interval durations has provided a window to develop kinetic models for the gating process. One difficulty in developing such models has been to determine the connections (transition pathways) among the various kinetic states involved in the gating. To help overcome this difficulty we present a transform (dependency plot) of the single-channel data that can give immediate insight into the connections. A dependency plot is derived by calculating a contingency table from a two-dimensional (joint density) dwell-time distribution of adjacent open and closed intervals by assuming that the two classified criteria are the open and closed durations of each pair of adjacent intervals. A three-dimensional surface plot of the fractional difference between the numbers of observed interval pairs and the numbers expected if the durations of adjacent intervals are independent then gives the dependency plot. An excess of interval pairs in the dependency plot suggests that the open and closed states (or compound states) that give rise to the interval pairs in excess are directly connected. A deficit of interval pairs suggests that the open and closed states (or compound states) that give rise to the interval pairs in deficit are either not directly connected or that there are additional open-closed transition pathways arising from the directly connected states.

  19. Detection of melatonin receptor mRNA in human muscle

    International Nuclear Information System (INIS)

    Li Lei

    2004-01-01

    To verify the expression of melatonin receptor mRNA in human, muscle, muscle beside vertebrae was collected to obtain total RNA and the mRNA of melatonin receptor was detected by RT-PCR method. The electrophoretic results of RT-PCR products by mt 1 and MT 2 primer were all positive and the sequence is corresponding with human melatonin receptor cDNA. It suggests that melatonin may act on the muscle beside vertebrae directly and regulate its growth and development. (authors)

  20. Flavonoids with M1 Muscarinic Acetylcholine Receptor Binding Activity

    Directory of Open Access Journals (Sweden)

    Meyyammai Swaminathan

    2014-06-01

    Full Text Available Muscarinic acetylcholine receptor-active compounds have potential for the treatment of Alzheimer’s disease. In this study, a series of natural and synthetic flavones and flavonols was assayed in vitro for their ability to inhibit radioligand binding at human cloned M1 muscarinic receptors. Several compounds were found to possess competitive binding affinity (Ki = 40–110 µM, comparable to that of acetylcholine (Ki = 59 µM. Despite the fact that these compounds lack a positively-charged ammonium group under physiological conditions, molecular modelling studies suggested that they bind to the orthosteric site of the receptor, mainly through non-polar interactions.

  1. Differential Expression of Chemokine Receptors and their Roles in Cancer Imaging

    International Nuclear Information System (INIS)

    Nimmagadda, Sridhar

    2012-01-01

    Chemokine/chemokine receptor interactions play diverse roles in cell migration and homeostasis. Emerging evidence suggests that cancer cells co-opt chemokine networks for survival, proliferation, immune evasion, and metastasis. Most of the chemokine receptors are reported to be involved in tumor progression. Given their extensive implication in cancer progression, several chemokine receptor/ligand axes are considered as potential therapeutic targets. This review provides a survey of chemokine receptor expression in cancer and evaluates the potential of chemokine receptor imaging as a tool for molecular characterization of cancer.

  2. Seminal Plasma Proteins as Androgen Receptor Corregulators Promote Prostate Cancer Growth

    Science.gov (United States)

    2016-12-01

    that SgI did not interact with other steroid hormone receptors, including estrogen receptors and glucocorticoid receptor, and did not significantly...estrogen receptor-β, or glucocorticoid receptor. Figure 6. Co-precipitation of AR and SgI. Cell lysates from 293T transfected with pSG5-AR and pSG5-SgI...results suggest that SgI may require not only zinc, as in the case of its physi- ological action [12-16], but also AR to function as a modulator of

  3. Novel Transformations of Trenbolone Acetate Metabolites Suggest Incomplete Environmental Risk Assessment for Trenbolone

    Science.gov (United States)

    Kolodziej, E. P.; Jones, G.; Cwiertny, D. M.; Qu, S.

    2013-12-01

    account for these possibilities. The implications of this data suggest that improved environmental risk assessment should include a more complete characterization of transformation products and identification of possible non-target receptor interactions as part of exposure assessment process.

  4. Discriminative Stimulus Effects of the GABAB Receptor-Positive Modulator rac-BHFF: Comparison with GABAB Receptor Agonists and Drugs of Abuse

    Science.gov (United States)

    Cheng, Kejun; Rice, Kenner C.

    2013-01-01

    GABAB receptor-positive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction. They may have fewer side effects than GABAB receptor agonists, because selective enhancement of activated receptors could have effects different from nonselective activation of all receptors. To examine this, pigeons were trained to discriminate the GABAB receptor-positive modulator (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) from its vehicle. The discriminative stimulus effects of rac-BHFF were not mimicked by the GABAB receptor agonists baclofen and γ-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose self-administration has been reported to be attenuated by GABAB receptor-positive modulators. The discriminative stimulus effects of rac-BHFF were not antagonized by the GABAB receptor antagonist 3-aminopropyl (diethoxymethyl)phosphinic acid (CGP35348) but were attenuated by the less efficacious GABAB receptor-positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930), suggesting the possibility that rac-BHFF produces its discriminative stimulus effects by directly activating GABAB2 subunits of GABAB receptors. At a dose 10-fold lower than the training dose, rac-BHFF enhanced the discriminative stimulus effects of baclofen, but not of GHB. This study provides evidence that the effects of GABAB receptor-positive modulators are not identical to those of GABAB receptor agonists. In addition, the results suggest that positive modulation of GABAB receptors does not produce discriminative stimulus effects similar to those of benzodiazepines, alcohol, cocaine, and nicotine. Finally, the finding that rac-BHFF enhanced effects of baclofen but not of GHB is consistent with converging evidence that the populations of GABAB receptors mediating the effects of baclofen and GHB are not identical. PMID:23275067

  5. Toll-like receptor 2 or toll-like receptor 4 deficiency does not modify lupus in MRLlpr mice.

    Directory of Open Access Journals (Sweden)

    Simon J Freeley

    Full Text Available Systemic lupus erythematosus is an autoimmune disease with a high morbidity and nephritis is a common manifestation. Previous studies in murine lupus models have suggest a role for Toll-like receptor 2 and 4. We examined the role of these molecules in MRL lpr mice which is one of the most established and robust murine models. We compared disease parameters in Toll-like receptor 2 or Toll-like receptor 4 deficient mice with their littermate controls. We found no difference in the severity of glomerulonephritis as assessed by histology, serum creatinine and albuminuria when Toll-like receptor 2 or Toll-like receptor 4 deficient MRLlpr mice were compared with Toll-like receptor sufficient controls. We also found similar levels of anti-dsDNA and anti-ssDNA antibodies. These results show that Toll-like receptor 2 and Toll-like receptor 4 do not play a significant role in MRLlpr mice, and therefore they may not be important in human lupus.

  6. Helix 11 Dynamics is Critical for Constitutive Androstane Receptor Activity

    OpenAIRE

    Wright, Edward; Busby, Scott A.; Wisecarver, Sarah; Vincent, Jeremy; Griffin, Patrick R.; Fernandez, Elias J.

    2011-01-01

    The constitutive androstane receptor (CAR) transactivation can occur in the absence of exogenous ligand and this activity is enhanced by agonists TCPOBOP and meclizine. We use biophysical and cell-based assays to show that increased activity of CAR(TCPOBOP) relative to CAR(meclizine) corresponds to a higher affinity of CAR(TCPOBOP) for the steroid receptor coactivator-1. Additionally, steady-state fluorescence spectra suggest conformational differences between CAR(TCPOBOP):RXR and CAR(meclizi...

  7. Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein

    DEFF Research Database (Denmark)

    Jacobsen, Linda; Madsen, P; Moestrup, S K

    1996-01-01

    the corresponding cDNA. The gene, designated SORL1, maps to chromosome 11q 23/24 and encodes a 2214-residue type 1 receptor containing a furin cleavage site immediately preceding the N terminus determined in the purified protein. The receptor, designated sorLA-1, has a short cytoplasmic tail containing a tyrosine...... but not in several major organs. Both RAP and an antibody against a synthetic peptide derived from a sequence determined in the mature protein detected sorLA-1 in crude human brain extracts. The domain structure suggests that sorLA-1 is an endocytic receptor possibly implicated in the uptake of lipoproteins...

  8. Immunoprecipitation of the parathyroid hormone receptor

    International Nuclear Information System (INIS)

    Wright, B.S.; Tyler, G.A.; O'Brien, R.; Caporale, L.H.; Rosenblatt, M.

    1987-01-01

    An 125 I-labeled synthetic analog of bovine parathyroid hormone, [8-norleucine,18-norleucine,34-tyrosine]PTH-(1-34) amide ([Nle]PTH-(1-34)-NH 2 ), purified by high-pressure liquid chromatography (HPLC), was employed to label the parathyroid hormone (PTH) receptor in cell lines derived from PTH target tissues: the ROS 17/2.8 rat osteosarcoma of bone and the CV1 and COS monkey kidney lines. After incubation of the radioligand with intact cultured cells, the hormone was covalently attached to receptors by using either a photoaffinity technique or chemical (affinity) crosslinking. In each case, covalent labeling was specific, as evidenced by a reduction of labeling when excess competing nonradioactive ligand was present. After covalent attachment of radioligand, membranes were prepared form the cells and solubilized in the nonionic detergent Nonidet P-40 or octyl glucoside. Analysis of the immunoprecipitate on NaDod-SO 4 /polyacrylamide gel electrophoresis followed by autoradiography revealed the presence of a doublet of apparent molecular mass 69-70 kDa. Specifically labeled bands of approximate molecular mass 95 and 28 kDa were also observed. The anti-PTH IgG was affinity purified by passage over a PTH-Sepharose column and used to made an immunoaffinity column. These studies suggest that the use of an anti-PTH antiserum that binds receptor-bound hormone is likely to be a useful step in the further physicochemical characterization and purification of the PTH receptor

  9. Subunit Arrangement and Function in NMDA Receptors

    Energy Technology Data Exchange (ETDEWEB)

    Furukawa,H.; Singh, S.; Mancusso, R.; Gouaux, E.

    2005-01-01

    Excitatory neurotransmission mediated by NMDA (N-methyl-D-aspartate) receptors is fundamental to the physiology of the mammalian central nervous system. These receptors are heteromeric ion channels that for activation require binding of glycine and glutamate to the NR1 and NR2 subunits, respectively. NMDA receptor function is characterized by slow channel opening and deactivation, and the resulting influx of cations initiates signal transduction cascades that are crucial to higher functions including learning and memory. Here we report crystal structures of the ligand-binding core of NR2A with glutamate and that of the NR1-NR2A heterodimer with glutamate and glycine. The NR2A-glutamate complex defines the determinants of glutamate and NMDA recognition, and the NR1-NR2A heterodimer suggests a mechanism for ligand-induced ion channel opening. Analysis of the heterodimer interface, together with biochemical and electrophysiological experiments, confirms that the NR1-NR2A heterodimer is the functional unit in tetrameric NMDA receptors and that tyrosine 535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivation.

  10. Modelling of Arabidopsis LAX3 expression suggests auxin homeostasis.

    Science.gov (United States)

    Mellor, Nathan; Péret, Benjamin; Porco, Silvana; Sairanen, Ilkka; Ljung, Karin; Bennett, Malcolm; King, John

    2015-02-07

    Emergence of new lateral roots from within the primary root in Arabidopsis has been shown to be regulated by the phytohormone auxin, via the expression of the auxin influx carrier LAX3, mediated by the ARF7/19 IAA14 signalling module (Swarup et al., 2008). A single cell model of the LAX3 and IAA14 auxin response was formulated and used to demonstrate that hysteresis and bistability may explain the experimentally observed 'all-or-nothing' LAX3 spatial expression pattern in cortical cells containing a gradient of auxin concentrations. The model was tested further by using a parameter fitting algorithm to match model output with qRT-PCR mRNA expression data following exogenous auxin treatment. It was found that the model is able to show good agreement with the data, but only when the exogenous auxin signal is degraded over time, at a rate higher than that measured in the experimental medium, suggesting the triggering of an endogenous auxin homeostasis mechanism. Testing the model over a more physiologically relevant range of extracellular auxin shows bistability and hysteresis still occur when using the optimised parameters, providing the rate of LAX3 active auxin transport is sufficiently high relative to passive diffusion. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Improving therapeutic use of homework: suggestions from mental health clinicians.

    Science.gov (United States)

    Kelly, Peter J; Deane, Frank P

    2011-10-01

    The majority of mental health clinicians report the use of homework to support their case management, but practitioner surveys indicate that homework is not routinely used. To examine barriers that mental health case managers experience in implementing homework and to identify strategies to promote successful homework administration. One hundred thirty-four surveys were completed by mental health case managers. The survey examined their use of homework for individuals diagnosed with a severe mental health problem. It also asked them to identify barriers to regularly implement homework and describe strategies to promote more regular use of homework. On average, homework was used at 50% of clinical contacts. The primary reasons for not using homework included allocating insufficient time at appointments, perceived client resistance for using homework and concerns that the client was too unwell. Strategies used to overcome these difficulties included prioritising the use of homework and ensuring that homework assignments were achievable. Clinicians are able to identify a range of practical strategies to promote the use of homework. Discussion focuses on the application of the suggested strategies to promote regular use of homework. This includes discussion of possible training approaches to enhance systematic homework administration.

  12. Diatom centromeres suggest a mechanism for nuclear DNA acquisition.

    Science.gov (United States)

    Diner, Rachel E; Noddings, Chari M; Lian, Nathan C; Kang, Anthony K; McQuaid, Jeffrey B; Jablanovic, Jelena; Espinoza, Josh L; Nguyen, Ngocquynh A; Anzelmatti, Miguel A; Jansson, Jakob; Bielinski, Vincent A; Karas, Bogumil J; Dupont, Christopher L; Allen, Andrew E; Weyman, Philip D

    2017-07-18

    Centromeres are essential for cell division and growth in all eukaryotes, and knowledge of their sequence and structure guides the development of artificial chromosomes for functional cellular biology studies. Centromeric proteins are conserved among eukaryotes; however, centromeric DNA sequences are highly variable. We combined forward and reverse genetic approaches with chromatin immunoprecipitation to identify centromeres of the model diatom Phaeodactylum tricornutum We observed 25 unique centromere sequences typically occurring once per chromosome, a finding that helps to resolve nuclear genome organization and indicates monocentric regional centromeres. Diatom centromere sequences contain low-GC content regions but lack repeats or other conserved sequence features. Native and foreign sequences with similar GC content to P. tricornutum centromeres can maintain episomes and recruit the diatom centromeric histone protein CENH3, suggesting nonnative sequences can also function as diatom centromeres. Thus, simple sequence requirements may enable DNA from foreign sources to persist in the nucleus as extrachromosomal episomes, revealing a potential mechanism for organellar and foreign DNA acquisition.

  13. Dehumanizing Communication Reified among Undergraduates and Lecturers: Issues and Suggestions

    Directory of Open Access Journals (Sweden)

    Duvie Adanma Nnekwu

    2014-10-01

    Full Text Available This paper discusses dehumanizing communication reified among undergraduates and t lecturers. Dehumanization is the act of degrading people with respect to their best qualities and denial of humanness to others. On the other hand, communication is human interaction and learning. Communication becomes rude when it is deliberately directed resulting in dehumanizing communication. The paper, therefore, examines dehumanizing communication in terms of its being intentional and unintentional and dehumanizing communication between lecturers and students and among students. It also took a swipe on the effects of dehumanizing communication on students and lecturers as well as proffer solutions to mitigating effect of dehumanizing communication between lecturer and students and among students. The suggested solutions among others include inter-group dialogue programme among contending groups in the student community, establishment of multicultural centers on campus in order to bring contending groups together (i.e. lecturers and students of all races and ethnicity. A compulsory course on “pedagogy of positiveness” is also recommended in the university curriculum to instill in the students the value of respecting people who may be different. Keywords: Dehumanization, Intentional and Unintentional Communication, Reified, Lecturers, Undergraduates, Teaching and Learning, Classroom

  14. Cytological Findings Suggesting Sexuality in Phytomonas davidi (Protozoa: Kinetoplastida

    Directory of Open Access Journals (Sweden)

    Maria Auxiliadora de Sousa

    1997-03-01

    Full Text Available On few occasions, Phytomonas davidi (McGhee & Postell isolate cultures in LIT (liver infusion-tryptose medium around 27oC presented, as seen in Giemsa-stained smears, a set of peculiar morphological features, among them being noticeable the pairs of apposed cells attached by their posterior ends, where occurred a stained line and/or a dilatation, usually bulb-like in shape; sometimes this dilatation could occupy one of the cells or hold both together. In some pairs, the nucleus of each parasite seemed migrating towards the other, entering into such dilatation; in others, both nuclei were inside it, sometimes in close proximity or seeming fused; peculiar chromatin arrangements involving both nuclei were occasionally observed. Several mono or binucleate round forms bearing one or two flagella, as well as flagellate slender cells without nucleus were concomitantly seen there. In some instances, an intriguing small stained body occurred beside a single large nucleus, either in pairs presenting the bulb-like structure or in round cells. These cytological findings seemed steps of a dynamic process suggesting sexuality, since in several of them nuclear interactions following fusion of two parasites appeared to occur

  15. Elegy as a film genre. Adaptation — inspiration — suggestion

    Directory of Open Access Journals (Sweden)

    Rafał Koschany

    2011-01-01

    Full Text Available The question that this is article is concerned to answer is how the position of the film elegy can be best formally established — with its artistic representations, as well as its functioning in the genology of the genre. An attempt to provide definitive answers that emerge from interdisciplinary, film and literary discourse brings a number of substantial threads. Firstly, there is, indeed, no theoretical description of the elegy as a film genre, though the very name does appear in many titles. Secondly, it seems that a juxtaposition of available examples of film ad-aptations of elegies does not lead to any consistent conclusion, since, apart from the suggestion proposed by the author, they are different in terms of formal and thematic elements involved. Thirdly, any attempt at a genological profiling has to, somehow, refer to a more or less fixed literary genre and the relevant theory behind it. In a most general way, one can state, albeit with a number of reservations, that the elegiac film is characterized by a distinguishable style, often simply called the elegiac style, and the theme, very broadly associated with time and the theme of passing.

  16. Failures and suggestions in Earthquake forecasting and prediction

    Science.gov (United States)

    Sacks, S. I.

    2013-12-01

    Seismologists have had poor success in earthquake prediction. However, wide ranging observations from earlier great earthquakes show that precursory data can exist. In particular, two aspects seem promising. In agreement with simple physical modeling, b-values decrease in highly loaded fault zones for years before failure. Potentially more usefully, in high stress regions, breakdown of dilatant patches leading to failure can yield expelled water-related observations. The volume increase (dilatancy) caused by high shear stresses decreases the pore pressure. Eventually, water flows back in restoring the pore pressure, promoting failure and expelling the extra water. Of course, in a generally stressed region there may be many small patches that fail, such as observed before the 1975 Haicheng earthquake. Only a few days before the major event will most of the dilatancy breakdown occur in the fault zone itself such as for the Tangshan, 1976 destructive event. Observations of 'water release' effects have been observed before the 1923 great Kanto earthquake, the 1984 Yamasaki event, the 1975 Haicheng and the 1976 Tangshan earthquakes and also the 1995 Kobe earthquake. While there are obvious difficulties in water release observations, not least because there is currently no observational network anywhere, historical data does suggest some promise if we broaden our approach to this difficult subject.

  17. Foreign accents: suggested competencies for improving communicative pronunciation.

    Science.gov (United States)

    Sikorski, Lorna D

    2005-05-01

    In the past 20 years, many speech-language pathologists (SLPs) have joined their English as a Second Language (ESL) colleagues to address the pronunciation skills of second language speakers of English. This paper introduces SLPs to the ESL term "communicative pronunciation" as the underpinning for the commonly accepted terms "accent modification" or "accent reduction." Initially, professionals in both speech pathology and ESL felt that accent intervention was outside the scope of speech pathology practice, though that stance is softening. If an essential part of our mission as speech pathologists is to improve communicative competence for all persons, then making pronunciation more intelligible falls under that heading. This article on foreign accents limits discussion to: (1) the rationale for intervening with foreign accented adults; (2) an outline of a broader scope and definition of effective instruction for this population; (3) suggestions for trainer preparation; (4) recommendations for productive literature searches; and (5) a brief discussion of principles guiding assessment and instruction planning. The article includes relevant research and references outside the field of speech pathology that should stimulate future productive research efforts as well as more in-depth papers on specific instruction and assessment issues. While this article is intended to stand alone, readers may benefit from the content and references in another article in this issue by the same author.

  18. In vitro model suggests oxidative stress involved in keratoconus disease

    Science.gov (United States)

    Karamichos, D.; Hutcheon, A. E. K.; Rich, C. B.; Trinkaus-Randall, V.; Asara, J. M.; Zieske, J. D.

    2014-04-01

    Keratoconus (KC) affects 1:2000 people and is a disorder where cornea thins and assumes a conical shape. Advanced KC requires surgery to maintain vision. The role of oxidative stress in KC remains unclear. We aimed to identify oxidative stress levels between human corneal keratocytes (HCKs), fibroblasts (HCFs) and keratoconus cells (HKCs). Cells were cultured in 2D and 3D systems. Vitamin C (VitC) and TGF-β3 (T3) were used for 4 weeks to stimulate self-assembled extracellular matrix (ECM). No T3 used as controls. Samples were analyzed using qRT-PCR and metabolomics. qRT-PCR data showed low levels of collagen I and V, as well as keratocan for HKCs, indicating differentiation to a myofibroblast phenotype. Collagen type III, a marker for fibrosis, was up regulated in HKCs. We robustly detected more than 150 metabolites of the targeted 250 by LC-MS/MS per condition and among those metabolites several were related to oxidative stress. Lactate levels, lactate/malate and lactate/pyruvate ratios were elevated in HKCs, while arginine and glutathione/oxidized glutathione ratio were reduced. Similar patterns found in both 2D and 3D. Our data shows that fibroblasts exhibit enhanced oxidative stress compared to keratocytes. Furthermore the HKC cells exhibit the greatest level suggesting they may have a myofibroblast phenotype.

  19. Suggestion, persuasion and work: Psychotherapies in communist Europe.

    Science.gov (United States)

    Marks, Sarah

    2018-01-01

    This article traces what recent research and primary sources tell us about psychotherapy in Communist Europe, and how it survived both underground and above the surface. In particular, I will elaborate on the psychotherapeutic techniques that were popular across the different countries and language cultures of the Soviet sphere, with a particular focus upon the Cold War period. This article examines the literature on the mixed fortunes of psychoanalysis and group therapies in the region. More specifically, it focuses upon the therapeutic modalities such as work therapy, suggestion and rational therapy, which gained particular popularity in the Communist countries of Central and Eastern Europe. The latter two approaches had striking similarities with parallel developments in behavioural and cognitive therapies in the West. In part, this was because clinicians on both sides of the 'iron curtain' drew upon shared European traditions from the late nineteenth and early twentieth centuries. Nevertheless, this article argues that in the Soviet sphere, those promoting these approaches appropriated socialist thought as a source of inspiration and justification, or at the very least, as a convenient political shield.

  20. Demystifying Survey Research: Practical Suggestions for Effective Question Design

    Directory of Open Access Journals (Sweden)

    Deborah H. Charbonneau

    2007-12-01

    Full Text Available Objective ‐ Recent research has yielded several studies helpful for understanding the use of the survey technique in various library environments. Despite this, there has been limited discussion to guide library practitioners preparing survey questions. The aim of this article is to provide practical suggestions for effective questions when designing written surveys.Methods ‐ Advice and important considerations to help guide the process of developing survey questions are drawn from a review of the literature and personal experience.Results ‐ Basic techniques can be incorporated to improve survey questions, such as choosing appropriate question forms and incorporating the use of scales. Attention should be paid to the flow and ordering of the survey questions. Careful wording choices can also help construct clear, simple questions. Conclusion ‐ A well‐designed survey questionnaire can be a valuable source of data. By following some basic guidelines when constructing written survey questions, library and information professionals can have useful data collection instruments at their disposal.

  1. Current Situation in Vocational Schools: Issues and Some Suggested Solutions

    Directory of Open Access Journals (Sweden)

    Reha Metin ALKAN

    2014-12-01

    Full Text Available Vocational Schools which have undertaken various missions throughout history were established in order to train intermediate staff s with suff icient knowledge and skills in their fields, in accordance with the requirements of trade, industry and services sectors and they are the most important components of ‘vocational and technical education system' today. Analyzing the education given in the vocational schools in accordance with the national and international requirements, developing technologies and the needs of business world and making the necessary arrangements in line with these will contribute to the employability and preferability of graduates of these schools in an eff icient way. Many industrialists/businessmen in our country stated that they experienced serious problems in the supply of qualified staff with suff icient knowledge and skills needed in sectors. Although much progress has been achieved in this subject, it is a fact that there are still a lot of work to be done. In this study, current situation and main troubles in vocational schools are discussed in the light of the experiences gained at Hitit University Vocational School which was established about 40 years ago in Çorum and which is one of the first high schools in Turkey and some solutions are suggested in accordance with the problems mentioned.

  2. Molecular spectroscopic study for suggested mechanism of chrome tanned leather.

    Science.gov (United States)

    Nashy, Elshahat H A; Osman, Osama; Mahmoud, Abdel Aziz; Ibrahim, Medhat

    2012-03-01

    Collagen represents the structural protein of the extracellular matrix, which gives strength of hides and/or skin under tanning process. Chrome tan is the most important tanning agent all over the world. The methods for production of leather evolved over several centuries as art and engineering with little understanding of the underlying science. The present work is devoted to suggest the most probable mechanistic action of chrome tan on hide proteins. First the affect of Cr upon hide protein is indicated by the studied mechanical properties. Then the spectroscopic characterization of the hide protein as well as chrome tanned leather was carried out with Horizontal Attenuated Total Reflection (HATR) FT-IR. The obtained results indicate how the chromium can attached with the active sites of collagen. Molecular modeling confirms that chromium can react with amino as well as carboxylate groups. Four schemes were obtained to describe the possible interactions of chrome tan with hide proteins. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Outcomes and Suggestions of the Nuclear Security Summit

    International Nuclear Information System (INIS)

    Kim, Jae San; Jung, Myung Tak

    2014-01-01

    Through The third Nuclear Security Summit (NSS), the measurement for the nuclear security has become more strengthening and participating countries could recognize the importance of nuclear security than before. From the NSS sessions, the leaders of participating countries and international organizations (IAEA, UN, EU and INTERPOL) had an in-depth discussion about the seriousness of the nuclear terrorism, the urgency issues for strengthening the nuclear security, etc. What issues was discussed in NSS processes since 2010 and which facts become more important than ever for nuclear security? The purpose of this paper is to provide the substantive outcomes from the 1st to 3rd NSS and suggestions for consolidating the next NSS. The summit process has helped strengthen the nuclear security measures. In the following two years before 4th NSS, there will be various follow-up activities for making an effort to implementing national commitments, joint statement, continuous outreach with IAEA/UN and agreed measures in Hague. It should produce the substantial measures for enhancing the nuclear security that are aimed to the each country. And preemptively, it is necessary to understand the each nuclear security level by using the concrete questionnaire sheets substitute for the national progress report

  4. Self-directed attention, awareness of bodily states, and suggestibility.

    Science.gov (United States)

    Scheier, M F; Carver, C S; Gibbons, F X

    1979-09-01

    Two studies tested the hypothesis that self-directed attention would cause increased awareness of internal states and would thus reduce suggestibility effects. Experiment 1 applied this reasoning to the experience of an emotion. Males viewed moderately arousing slides of female nudes after being led to expect the slides to be either highly arousing or nonarousing. As predicted, ratings of the slides corresponded less with these experimentally-manipulated anticipations when self-focus was heightened by the presence of a mirror than when it was not. Experiment 2 examined a different internal experience: the perception of taste. Some subjects were led to expect a strong flavor as part of a test series, and other subjects were led to expect a weak flavor. Subjects high in private self-consciousness were less affected by this expectancy manipulation and more accurate in reporting their actual internal state than were subjects low in private self-consciousness. Discussion centers on the theoretical implications of the findings.

  5. Neurogenesis suggests independent evolution of opercula in serpulid polychaetes

    Directory of Open Access Journals (Sweden)

    Wanninger Andreas

    2009-11-01

    Full Text Available Abstract Background The internal phylogenetic relationships of Annelida, one of the key lophotrochozoan lineages, are still heavily debated. Recent molecular analyses suggest that morphologically distinct groups, such as the polychaetes, are paraphyletic assemblages, thus questioning the homology of a number of polychaete morphological characters. Serpulid polychaetes are typically recognized by having fused anterior ends bearing a tentacular crown and an operculum. The latter is commonly viewed as a modified tentacle (= radiole and is often used as an important diagnostic character in serpulid systematics. Results By reconstructing the developmental neuroanatomy of the serpulid polychaete Spirorbis cf. spirorbis (Spirorbinae, we found striking differences in the overall neural architecture, the innervation pattern, and the ontogenetic establishment of the nervous supply of the operculum and the radioles in this species. Accordingly, the spirorbin operculum might not be homologous to the radioles or to the opercula of other serpulid taxa such as Serpula and Pomatoceros and is thus probably not a part of the tentacular crown. Conclusion We demonstrate that common morphological traits such as the prostomial appendages may have evolved independently in respective serpulid sublineages and therefore require reassessment before being used in phylogenetic analyses. Our findings corroborate recent molecular studies that argue for a revision of serpulid systematics. In addition, our data on Spirorbis neurogenesis provide a novel set of characters that highlight the developmental plasticity of the segmented annelid nervous system.

  6. Two suggestions to ''improve the utilization of ISABELLE''

    International Nuclear Information System (INIS)

    Thorndike, A.

    1976-01-01

    Two suggestions are outlined which are aimed at improving the efficiency of work in experimental areas by improving the information available to experimenters. A very good communication system would make work as efficient as possible during times when the beam is off. Here are some ideas: (1) it should be a dedicated system that is always on or can be turned on from either position, and it should be impossible for the two ends to be on different channels; (2) tv is desirable so each individual can watch what the other is doing to avoid confusion; (3) slave CRT units would be desirable so both can watch a given waveform or other test signal; and (4) it should also be possible to monitor key voltages from either location. It seems reasonable that beam information would be stored in one or more files on a disc in the on-line computer system. Each experimenter's computer could then get whatever information was desired. Handling the information by computer is straightforward, and more or less standard systems for data-base management should be applicable. Having satisfactory sensors to monitor the information that is needed seems like more of a problem, but they are required in any case

  7. Trophic signatures of seabirds suggest shifts in oceanic ecosystems.

    Science.gov (United States)

    Gagne, Tyler O; Hyrenbach, K David; Hagemann, Molly E; Van Houtan, Kyle S

    2018-02-01

    Pelagic ecosystems are dynamic ocean regions whose immense natural capital is affected by climate change, pollution, and commercial fisheries. Trophic level-based indicators derived from fishery catch data may reveal the food web status of these systems, but the utility of these metrics has been debated because of targeting bias in fisheries catch. We analyze a unique, fishery-independent data set of North Pacific seabird tissues to inform ecosystem trends over 13 decades (1890s to 2010s). Trophic position declined broadly in five of eight species sampled, indicating a long-term shift from higher-trophic level to lower-trophic level prey. No species increased their trophic position. Given species prey preferences, Bayesian diet reconstructions suggest a shift from fishes to squids, a result consistent with both catch reports and ecosystem models. Machine learning models further reveal that trophic position trends have a complex set of drivers including climate, commercial fisheries, and ecomorphology. Our results show that multiple species of fish-consuming seabirds may track the complex changes occurring in marine ecosystems.

  8. Wheat yield vulnerability: relation to rainfall and suggestions for adaptation

    Directory of Open Access Journals (Sweden)

    Khalid Tafoughalti

    2018-04-01

    Full Text Available Wheat production is of paramount importance in the region of Meknes, which is mainly produced under rainfed conditions. It is the dominant cereal, the greater proportion being the soft type. During the past few decades, rainfall flaws have caused a number of cases of droughts. These flaws have seriously affecting wheat production. The main objective of this study is the assessment of rainfall variability at monthly, seasonal and annual scales and to determine their impact on wheat yields. To reduce this impact we suggested some mechanisms of adaptation. We used monthly rainfall records for three decades and wheat yields records of fifteen years. Rainfall variability is assessed utilizing the precipitation concentration index and the variation coefficient. The association between wheat yields and cumulative rainfall amounts of different scales was calculated based on a regression model to evaluate the impact of rainfall on wheat yields. Data analysis shown moderate seasonal and irregular annual rainfall distribution. Yields fluctuated from 210 to 4500 Kg/ha with 52% of coefficient of variation. The correlation results shows that soft wheat and hard wheat are strongly correlated with the period of January to March than with the whole growing-season. While they are adversely correlated with the mid-spring. This investigation concluded that synchronizing appropriate adaptation with the period of January to March was crucial to achieving success yield of wheat.

  9. Receptors for enterovirus 71.

    Science.gov (United States)

    Yamayoshi, Seiya; Fujii, Ken; Koike, Satoshi

    2014-07-01

    Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease (HFMD). Occasionally, EV71 infection is associated with severe neurological diseases, such as acute encephalitis, acute flaccid paralysis and cardiopulmonary failure. Several molecules act as cell surface receptors that stimulate EV71 infection, including scavenger receptor B2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), sialylated glycan, heparan sulfate and annexin II (Anx2). SCARB2 plays critical roles in attachment, viral entry and uncoating, and it can facilitate efficient EV71 infection. The three-dimensional structures of the mature EV71 virion, procapsid and empty capsid, as well as the exofacial domain of SCARB2, have been elucidated. This structural information has greatly increased our understanding of the early steps of EV71 infection. Furthermore, SCARB2 plays essential roles in the development of EV71 neurological disease in vivo. Adult mice are not susceptible to infection by EV71, but transgenic mice that express human SCARB2 become susceptible to EV71 infection and develop similar neurological diseases to those found in humans. This mouse model facilitates the in vivo investigation of many issues related to EV71. PSGL-1, sialylated glycan, heparan sulfate and Anx2 are attachment receptors, which enhance viral infection by retaining the virus on the cell surface. These molecules also contribute to viral infection in vitro either by interacting with SCARB2 or independently of SCARB2. However, the cooperative effects of these receptors, and their contribution to EV71 pathogenicity in vivo, remain to be elucidated.

  10. The interleukin-4 receptor: signal transduction by a hematopoietin receptor.

    Science.gov (United States)

    Keegan, A D; Pierce, J H

    1994-02-01

    Over the last several years, the receptors for numerous cytokines have been molecularly characterized. Analysis of their amino acid sequences shows that some of these receptors bear certain motifs in their extracellular domains that define a family of receptors called the Hematopoietin receptor superfamily. Significant advances in characterizing the structure, function, and mechanisms of signal transduction have been made for several members of this family. The purpose of this review is to discuss the recent advances made for one of the family members, the interleukin (IL) 4 receptor. Other receptor systems have recently been reviewed elsewhere. The IL-4 receptor consists of, at the minimum, the cloned 140 kDa IL-4-binding chain with the potential for associating with other chains. The IL-4 receptor transduces its signal by activating a tyrosine kinase that phosphorylates cellular substrates, including the receptor itself, and the 170 kDa substrate called 4PS. Phosphorylated 4PS interacts with the SH2 domain of the enzyme PI-3'-kinase and increases its enzymatic activity. These early events in the IL-4 receptor initiated signaling pathway may trigger a series of signals that will ultimately lead to an IL-4 specific biologic outcome.

  11. A possible new target in lung-cancer cells: The orphan receptor, bombesin receptor subtype-3.

    Science.gov (United States)

    Moreno, Paola; Mantey, Samuel A; Lee, Suk H; Ramos-Álvarez, Irene; Moody, Terry W; Jensen, Robert T

    2018-03-01

    Human bombesin receptors, GRPR and NMBR, are two of the most frequently overexpressed G-protein-coupled-receptors by lung-cancers. Recently, GRPR/NMBR are receiving considerable attention because they act as growth factor receptors often in an autocrine manner in different lung-cancers, affect tumor angiogenesis, their inhibition increases the cytotoxic potency of tyrosine-kinase inhibitors reducing lung-cancer cellular resistance/survival and their overexpression can be used for sensitive tumor localization as well as to target cytotoxic agents to the cancer. The orphan BRS-3-receptor, because of homology is classified as a bombesin receptor but has received little attention, despite the fact that it is also reported in a number of studies in lung-cancer cells and has growth effects in these cells. To address its potential importance, in this study, we examined the frequency/relative quantitative expression of human BRS-3 compared to GRPR/NMBR and the effects of its activation on cell-signaling/growth in 13 different human lung-cancer cell-lines. Our results showed that BRS-3 receptor is expressed in 92% of the cell-lines and that it is functional in these cells, because its activation stimulates phospholipase-C with breakdown of phosphoinositides and changes in cytosolic calcium, stimulates ERK/MAPK and stimulates cell growth by EGFR transactivation in some, but not all, the lung-cancer cell-lines. These results suggest that human BRS-3, similar to GRPR/NMBR, is frequently ectopically-expressed by lung-cancer cells in which, it is functional, affecting cell signaling/growth. These results suggest that similar to GRPR/NMBR, BRS-3 should receive increased attention as possible approach for the development of novel treatments and/or diagnosis in lung-cancer. Published by Elsevier Inc.

  12. Functional and molecular evidence for heteromeric association of P2Y1 receptor with P2Y2 and P2Y4 receptors in mouse granulocytes.

    Science.gov (United States)

    Ribeiro-Filho, Antonio Carlos; Buri, Marcus Vinicius; Barros, Carlos Castilho; Dreyfuss, Juliana Luporini; Nader, Helena Bonciani; Justo, Giselle Zenker; Craveiro, Rogério Bastos; Pesquero, João Bosco; Miranda, Antonio; Ferreira, Alice Teixeira; Paredes-Gamero, Edgar Julian

    2016-07-07

    All hematopoietic cells express P2 receptors, however pharmacological characteristics such as expression and affinity in granulocytes are unknown. Pharmacological characteristics of P2 receptors were evaluated by Ca(2+) measurements using Fura-2 fluorophore. P2 receptors expression were analyzed by flow cytometry and RT-PCR. P2 interaction were shown by coimmunoprecipitation, western blotting and FRET. Granulocytes were responsive to P2Y agonists, whereas P2X agonists were ineffective. Ca(2+) increase, elicited by ADP and UTP was dependent on intracellular stocks and sensitive to G-coupled receptor inhibition. Moreover, MRS2179, a specific antagonist of the P2Y1 receptor, abolished ADP response. Interestingly, ADP and UTP exhibited full heterologous desensitization, suggesting that these agonists interact with the same receptor. The heteromeric association between P2Y1 receptor and the P2Y2 and P2Y4 receptors was shown by immunoprecipitation and FRET analysis. Clear evidence of heteromeric association of P2Y receptors was found during the evaluation of P2 receptors present in mice granulocytes, which could impact in the classical pharmacology of P2Y receptors in granulocytes.

  13. Gestational Pityriasis Rosea: Suggestions for Approaching Affected Pregnant Women.

    Science.gov (United States)

    Monastirli, Alexandra; Pasmatzi, Efstathia; Badavanis, George; Tsambaos, Dionysios

    2016-12-01

    pityriasis rosea, for intrauterine fetal death. All miscarrying women reportedly revealed an aggressive course of widespread eruption and severe constitutional symptoms; all of them had HHV-6 DNA in the plasma, placenta, skin lesions, and fetal tissues, whereas HHV-7 DNA was detected in the plasma and skin lesions in 3 out of 8 (37.5%) miscarrying women. HHV-6 DNA was found only in the plasma of 2 out of 31 women (6.45%) with normal pregnancy, whereas HHV-7 DNA was detected in the plasma of 3 (9.45%) and in the skin lesions of 2 women (6.45%) with normal pregnancy. The total abortion rate in women who developed pityriasis rosea during their pregnancy (13%) does not differ from that observed in the general population. Nevertheless, it is markedly higher in cases affected during the first 15 gestational weeks (57%) (4,5). Surprisingly, this devastating impact of pityriasis rosea on the outcome of pregnancy is almost completely unknown not only to the public but also to many members of the medical community. It is also largely unknown that, particularly during the first 15 gestational weeks, all pregnant women should avoid any contact with patients known to have pityriasis rosea. Since we have received a considerable number of requests for consultation with pregnant women with pityriasis rosea over the last few years, our group has compiled suggestions approaching the affected patients: 1. If an eruption suggestive for pityriasis rosea occurs in a pregnant woman, the following factors should be excluded: a. Exposure to drugs prior to the development of the rash (biologic agents, captopril, clonidine, hydrochlorothiazide, atenolol, lamotrigine, nortriptyline, barbiturates, metronidazole, terbinafine, omeprazole, non-steroidal anti-inflammatory drugs, and isotretinoin), which are capable of inducing a pityriasis rosea-like eruption (6) and b. Disorders included in the differential diagnosis (syphilis and infections due to parvovirus, herpes virus, cytomegalovirus, and Epstein

  14. Frequency-dependent cannabinoid receptor-independent modulation of glycine receptors by endocannabinoid 2-AG

    Directory of Open Access Journals (Sweden)

    Natalia eLozovaya

    2011-07-01

    Full Text Available Endocannabinoids are known as retrograde messengers, being released from the postsynaptic neuron and acting on specific presynaptic G-protein-coupled cannabinoid (CB receptors to decrease neurotransmitter release. Also, at physiologically relevant concentrations cannabinoids can directly modulate the function of voltage-gated and receptor-operated ion channels. Using patch-clamp recording we analyzed the consequences of the direct action of an endocannabinoid, 2-arachidonoylglycerol (2-AG, on the functional properties of glycine receptor channels (GlyRs and ionic currents in glycinergic synapses. At physiologically relevant concentrations (0.1-1 µM, 2-AG directly affected the functions of recombinant homomeric alpha1H GlyR: it inhibited peak amplitude and dramatically enhanced desensitization. The action of 2-AG on GlyR-mediated currents developed rapidly, within ~300 milliseconds. Addition of 1 µM 2-AG strongly facilitated the depression of glycine-induced currents during repetitive (4-10 Hz application of short (2-ms duration pulses of glycine to outside-out patches. In brainstem slices from CB1 receptor-knockout mice, 2-AG significantly decreased the extent of facilitation of synaptic currents in hypoglossal motoneurons during repetitive (10-20 Hz stimulation. These observations suggest that endocannabinoids can modulate postsynaptic metaplasticity of glycinergic synaptic currents in a CB1 receptor-independent manner.

  15. ALMA suggests outflows in z ˜ 5.5 galaxies

    Science.gov (United States)

    Gallerani, S.; Pallottini, A.; Feruglio, C.; Ferrara, A.; Maiolino, R.; Vallini, L.; Riechers, D. A.; Pavesi, R.

    2018-01-01

    We present the first attempt to detect outflows from galaxies approaching the Epoch of Reionization (EoR) using a sample of nine star-forming (SFR = 31 ± 20 M⊙ yr- 1) z ∼ 5.5 galaxies for which the [C II]158 μm line has been previously obtained with Atacama Large Millimeter Array (ALMA). We first fit each line with a Gaussian function and compute the residuals by subtracting the best-fitting model from the data. We combine the residuals of all sample galaxies and find that the total signal is characterized by a flux excess of ∼0.5 mJy extended over ∼1000 km s-1. Although we cannot exclude that part of this signal is due to emission from faint satellite galaxies, we show that the most probable explanation for the detected flux excess is the presence of broad wings in the [C II] lines, signatures of starburst-driven outflows. We infer an average outflow rate of \\dot{M}=54± 23 M_{⊙} yr^{-1}, providing a loading factor η =\\dot{M}/SFR=1.7± 1.3 in agreement with observed local starbursts. Our interpretation is consistent with outcomes from zoomed hydrosimulations of Dahlia, a z ∼ 6 galaxy (SFR˜ 100 M_{⊙} yr^{-1}), whose feedback-regulated star formation results into an outflow rate \\dot{M}˜ 30 M_{⊙} yr^{-1}. The quality of the ALMA data is not sufficient for a detailed analysis of the [C II] line profile in individual galaxies. Nevertheless, our results suggest that starburst-driven outflows are in place in the EoR and provide useful indications for future ALMA campaigns. Deeper observations of the [C II] line in this sample are required to better characterize feedback at high-z and to understand the role of outflows in shaping early galaxy formation.

  16. Policy Implications and Suggestions on Administrative Measures of Urban Flood

    Science.gov (United States)

    Lee, S. V.; Lee, M. J.; Lee, C.; Yoon, J. H.; Chae, S. H.

    2017-12-01

    The frequency and intensity of floods are increasing worldwide as recent climate change progresses gradually. Flood management should be policy-oriented in urban municipalities due to the characteristics of urban areas with a lot of damage. Therefore, the purpose of this study is to prepare a flood susceptibility map by using data mining model and make a policy suggestion on administrative measures of urban flood. Therefore, we constructed a spatial database by collecting relevant factors including the topography, geology, soil and land use data of the representative city, Seoul, the capital city of Korea. Flood susceptibility map was constructed by applying the data mining models of random forest and boosted tree model to input data and existing flooded area data in 2010. The susceptibility map has been validated using the 2011 flood area data which was not used for training. The predictor importance value of each factor to the results was calculated in this process. The distance from the water, DEM and geology showed a high predictor importance value which means to be a high priority for flood preparation policy. As a result of receiver operating characteristic (ROC), random forest model showed 78.78% and 79.18% accuracy of regression and classification and boosted tree model showed 77.55% and 77.26% accuracy of regression and classification, respectively. The results show that the flood susceptibility maps can be applied to flood prevention and management, and it also can help determine the priority areas for flood mitigation policy by providing useful information to policy makers.

  17. Precise synaptic efficacy alignment suggests potentiation dominated learning

    Directory of Open Access Journals (Sweden)

    Christoph eHartmann

    2016-01-01

    Full Text Available Recent evidence suggests that parallel synapses from the same axonal branch onto the same dendritic branch have almost identical strength. It has been proposed that this alignment is only possible through learning rules that integrate activity over long time spans. However, learning mechanisms such as spike-timing-dependent plasticity (STDP are commonly assumed to be temporally local. Here, we propose that the combination of temporally local STDP and a multiplicative synaptic normalization mechanism is sufficient to explain the alignment of parallel synapses.To address this issue, we introduce three increasingly complex models: First, we model the idealized interaction of STDP and synaptic normalization in a single neuron as a simple stochastic process and derive analytically that the alignment effect can be described by a so-called Kesten process. From this we can derive that synaptic efficacy alignment requires potentiation-dominated learning regimes. We verify these conditions in a single-neuron model with independent spiking activities but more realistic synapses. As expected, we only observe synaptic efficacy alignment for long-term potentiation-biased STDP. Finally, we explore how well the findings transfer to recurrent neural networks where the learning mechanisms interact with the correlated activity of the network. We find that due to the self-reinforcing correlations in recurrent circuits under STDP, alignment occurs for both long-term potentiation- and depression-biased STDP, because the learning will be potentiation dominated in both cases due to the potentiating events induced by correlated activity. This is in line with recent results demonstrating a dominance of potentiation over depression during waking and normalization during sleep. This leads us to predict that individual spine pairs will be more similar in the morning than they are after sleep depriviation.In conclusion, we show that synaptic normalization in conjunction with

  18. Morphologic Features Suggestive of Endometriosis in Nondiagnostic Peritoneal Biopsies.

    Science.gov (United States)

    Harrison, Beth T; Mittal, Khush

    2015-11-01

    Endometriosis is a common disorder that causes significant morbidity from dysmenorrhea, pelvic pain, and subfertility. Establishment of a definitive diagnosis has important therapeutic implications; however, only approximately 50% of biopsies of laparoscopically suspicious areas provide a diagnosis of endometriosis. Histologic criteria for diagnosis require the presence of endometrial glands or endometrial-type stroma. We hypothesize that other frequently present, but nondiagnostic, histologic features of endometriosis suggest its presence in patients with nondiagnostic peritoneal biopsies. We performed a retrospective clinicopathologic study of morphologic and immunohistochemical features that may improve the histologic diagnosis of endometriosis on laparoscopic peritoneal biopsies. We compared diagnostic (n=88) and nondiagnostic (n=54) peritoneal biopsies from pathologically confirmed endometriosis cases with negative peritoneal biopsies (n=84) from early-stage gynecologic cancer cases. Statistical analysis utilized the Fisher exact test. Multiple morphologic features were significantly increased in nondiagnostic biopsies from patients with endometriosis in comparison with those from negative controls, including foamy macrophages (P=0.0001) and submesothelial stromal clusters (SSCs) (P=0.0008). SSCs ranged from subtle aggregates of spindle cells to nodules of whorled spindle cells with small vessels and extravasated red blood cells resembling stromal endometriosis. Immunohistochemical studies confirmed that ER and CD10-positive SSCs were present in a greater proportion of both nondiagnostic and diagnostic peritoneal biopsies and at a greater number of lesions per biopsy. The overall histologic detection rate of peritoneal biopsies for endometriosis was 62.0%, and inclusion of SSCs with or without foamy macrophages in the diagnostic criteria appreciably increased this rate to between 72.5% and 76.8%. We describe SSCs, which appear to be an early or less developed

  19. Genetic counselling in ALS: facts, uncertainties and clinical suggestions.

    Science.gov (United States)

    Chiò, Adriano; Battistini, Stefania; Calvo, Andrea; Caponnetto, Claudia; Conforti, Francesca L; Corbo, Massimo; Giannini, Fabio; Mandrioli, Jessica; Mora, Gabriele; Sabatelli, Mario; Ajmone, Clara; Mastro, Enza; Pain, Debora; Mandich, Paola; Penco, Silvana; Restagno, Gabriella; Zollino, Marcella; Surbone, Antonella

    2014-05-01

    The clinical approach to patients with amyotrophic lateral sclerosis (ALS) has been largely modified by the identification of novel genes, the detection of gene mutations in apparently sporadic patients, and the discovery of the strict genetic and clinical relation between ALS and frontotemporal dementia (FTD). As a consequence, clinicians are increasingly facing the dilemma on how to handle genetic counselling and testing both for ALS patients and their relatives. On the basis of existing literature on genetics of ALS and of other late-onset life-threatening disorders, we propose clinical suggestions to enable neurologists to provide optimal clinical and genetic counselling to patients and families. Genetic testing should be offered to ALS patients who have a first-degree or second-degree relative with ALS, FTD or both, and should be discussed with, but not offered to, all other ALS patients, with special emphasis on its major uncertainties. Presently, genetic testing should not be proposed to asymptomatic at-risk subjects, unless they request it or are enrolled in research programmes. Genetic counselling in ALS should take into account the uncertainties about the pathogenicity and penetrance of some genetic mutations; the possible presence of mutations of different genes in the same individual; the poor genotypic/phenotypic correlation in most ALS genes; and the phenotypic pleiotropy of some genes. Though psychological, social and ethical implications of genetic testing are still relatively unexplored in ALS, we recommend multidisciplinary counselling that addresses all relevant issues, including disclosure of tests results to family members and the risk for genetic discrimination.

  20. Pre-hospital Obstacles in Thrombolytic Therapy and Suggested Solutions

    Directory of Open Access Journals (Sweden)

    Betül Tekin Güveli

    2015-12-01

    Full Text Available INTRODUCTION: Acute ischemic stroke is frequently encountered in emergency neurology clinics. Especially when administered within 3 hours of symptom onset, thrombolytic therapy is important in reducing ischemic injury and neurological disability. In this study, we aimed to investigate the demographic and clinical characteristics according to application time, to identify situations which pose an obstacle to thrombolytic therapy and to review the thrombolytic therapy results in patients diagnosed with acute ischemic stroke. METHODS: The patients diagnosed with acute ischemic stroke were evaluated and their age, gender, complaints, risk factors, previous history of stroke, with whom they live, how they arrived at the hospital and their application time information were recorded. Those who were admitted within 3 hours of symptom onset were assessed as early, those admitted after 3 hours were assessed as late admission. Then the rate of thrombolytic therapy, final results and the clinical status in early admission patients and the reasons for delay in late admission patients were discussed. RESULTS: Among 361 acute ischemic stroke patients, the mean age was 66±14,1. 111 patients were admitted within 3 hours of symptom onset, 246 patients were admitted after three hours. Patients arriving to emergency room with 112 Ambulance Service were admitted earlier than those brought in by family, and this difference was statistically significant. The most common causes of time loss in late admissions were the patients being referred from other centers and the unawareness of family about the importance of the disease. There were 13 patients treated with thrombolytic therapy, and complications occurred in one patient. DISCUSSION AND CONCLUSION: Thrombolytic therapy is important in acute ischemic stroke for suitable patients.Our study suggested that the most important factors in spreading of performing the thrombolytic therapy are informing the public about

  1. Occupancy of dopamine D-2 receptors by antipsychotic drugs is related to nicotine addiction in young patients with schizophrenia

    NARCIS (Netherlands)

    de Haan, Lieuwe; Booij, Jan; Lavalaye, Jules; van Amelsvoort, Therese; Linszen, Don

    2006-01-01

    Rationale: Occupancy of dopamine D-2 receptors by antipsychotic drugs depends on the individual availability of D-2 receptors and on the dose and type of antipsychotic medication. It has been suggested that a low availability of these receptors may increase the risk for addictive behavior.

  2. Regulation of human penile smooth muscle tone byprostanoid receptors

    Science.gov (United States)

    Angulo, Javier; Cuevas, Pedro; La Fuente, Jose M; Pomerol, Jose M; Ruiz-Castañé, Eduardo; Puigvert, Ana; Gabancho, Sonia; Fernández, Argentina; Ney, Peter; Sáenz de Tejada, Iñigo

    2002-01-01

    We have characterized the prostanoid receptors involved in the regulation of human penile arterial and trabecular smooth muscle tone.Arachidonic acid induced relaxation of human corpus cavernosum strips (HCCS) that was blocked by the cyclo-oxygenase inhibitor, indomethacin, and augmented by the thromboxane receptor (TP) antagonist, SQ29548, suggesting that endogenous production of prostanoids regulates penile smooth muscle tone.TP-receptors mediate contraction of HCCS and penile resistance arteries (HPRA), since the agonist of these receptors, U46619, potently contracted HCCS (EC50 8.3±2.8 nM) and HPRA (EC50 6.2±2.2 nM), and the contractions produced by prostaglandin F2α at high concentrations (EC50 6460±3220 nM in HCCS and 8900±6700 nM in HPRA) were inhibited by the selective TP-receptor antagonist, SQ29548 (0.02 μM).EP-receptors are responsible for prostanoid-induced relaxant effects in HCCS because only prostaglandin E1 (PGE1), prostaglandin E2 and the EP2/EP4-receptor agonist, butaprost, produced consistent relaxation of this tissue (EC50 93.8±31.5, 16.3±3.8 and 1820±1284 nM, respectively). In HPRA, both prostacyclin and PGE1 (EC50 60.1±18.4 and 109.0±30.9 nM, respectively) as well as the selective IP receptor agonist, cicaprost, and butaprost (EC50 25.2±15.2 and 7050±6020 nM, respectively) caused relaxation, suggesting co-existence of IP- and EP-receptors (EP2 and/or EP4).In summary, endogenous production of prostanoids may regulate penile smooth muscle contractility by way of specific receptors. TP-receptors mediate contraction in HCCS and HPRA, while the relaxant effects of prostanoids are mediated by EP2- and/or EP4-receptors in HCCS and by EP- and IP-receptors in HPRA. PMID:11976264

  3. Adenosine–cannabinoid receptor interactions. Implications for striatal function

    Science.gov (United States)

    Ferré, Sergi; Lluís, Carme; Justinova, Zuzana; Quiroz, César; Orru, Marco; Navarro, Gemma; Canela, Enric I; Franco, Rafael; Goldberg, Steven R

    2010-01-01

    Adenosine and endocannabinoids are very ubiquitous non-classical neurotransmitters that exert a modulatory role on the transmission of other more ‘classical’ neurotransmitters. In this review we will focus on their common role as modulators of dopamine and glutamate neurotransmission in the striatum, the main input structure of the basal ganglia. We will pay particular attention to the role of adenosine A2A receptors and cannabinoid CB1 receptors. Experimental results suggest that presynaptic CB1 receptors interacting with A2A receptors in cortico-striatal glutamatergic terminals that make synaptic contact with dynorphinergic medium-sized spiny neurons (MSNs) are involved in the motor-depressant and addictive effects of cannabinoids. On the other hand, postsynaptic CB1 receptors interacting with A2A and D2 receptors in the dendritic spines of enkephalinergic MSNs and postsynaptic CB1 receptors in the dendritic spines of dynorphinergic MSN are probably involved in the cataleptogenic effects of cannabinoids. These receptor interactions most probably depend on the existence of a variety of heteromers of A2A, CB1 and D2 receptors in different elements of striatal spine modules. Drugs selective for the different striatal A2A and CB1 receptor heteromers could be used for the treatment of neuropsychiatric disorders and drug addiction and they could provide effective drugs with fewer side effects than currently used drugs. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x PMID:20590556

  4. Altered levels of laminin receptor mRNA in various human carcinoma cells that have different abilities to bind laminin

    DEFF Research Database (Denmark)

    Wewer, U M; Liotta, L A; Jaye, M

    1986-01-01

    of the receptor from different carcinoma sources and from normal placental tissue is in the range of 68-72 kDa. Isoelectric focusing and two-dimensional gel electrophoresis indicated that the receptor protein consists of one major polypeptide chain with a pI value of 6.4 +/- 0.2. Laminin receptor cDNA clones were...... bromide-generated octapeptide of purified placental laminin receptor. The laminin receptor mRNA is approximately 1700 bases long. The level of laminin receptor mRNA in a variety of human carcinoma-derived cell lines correlated with the number of laminin receptors on the cell surfaces of those cells....... This suggests that the amount of laminin receptor mRNA may be a rate-limiting control step in the biosynthesis of the laminin receptor, and hence in the regulation of cellular attachment to basement membranes via laminin....

  5. Designer lipid-like peptides: a class of detergents for studying functional olfactory receptors using commercial cell-free systems.

    Directory of Open Access Journals (Sweden)

    Karolina Corin

    Full Text Available A crucial bottleneck in membrane protein studies, particularly G-protein coupled receptors, is the notorious difficulty of finding an optimal detergent that can solubilize them and maintain their stability and function. Here we report rapid production of 12 unique mammalian olfactory receptors using short designer lipid-like peptides as detergents. The peptides were able to solubilize and stabilize each receptor. Circular dichroism showed that the purified olfactory receptors had alpha-helical secondary structures. Microscale thermophoresis suggested that the receptors were functional and bound their odorants. Blot intensity measurements indicated that milligram quantities of each olfactory receptor could be produced with at least one peptide detergent. The peptide detergents' capability was comparable to that of the detergent Brij-35. The ability of 10 peptide detergents to functionally solubilize 12 olfactory receptors demonstrates their usefulness as a new class of detergents for olfactory receptors, and possibly other G-protein coupled receptors and membrane proteins.

  6. Plasticity in neuromagnetic cortical responses suggests enhanced auditory object representation.

    Science.gov (United States)

    Ross, Bernhard; Jamali, Shahab; Tremblay, Kelly L

    2013-12-05

    Auditory perceptual learning persistently modifies neural networks in the central nervous system. Central auditory processing comprises a hierarchy of sound analysis and integration, which transforms an acoustical signal into a meaningful object for perception. Based on latencies and source locations of auditory evoked responses, we investigated which stage of central processing undergoes neuroplastic changes when gaining auditory experience during passive listening and active perceptual training. Young healthy volunteers participated in a five-day training program to identify two pre-voiced versions of the stop-consonant syllable 'ba', which is an unusual speech sound to English listeners. Magnetoencephalographic (MEG) brain responses were recorded during two pre-training and one post-training sessions. Underlying cortical sources were localized, and the temporal dynamics of auditory evoked responses were analyzed. After both passive listening and active training, the amplitude of the P2m wave with latency of 200 ms increased considerably. By this latency, the integration of stimulus features into an auditory object for further conscious perception is considered to be complete. Therefore the P2m changes were discussed in the light of auditory object representation. Moreover, P2m sources were localized in anterior auditory association cortex, which is part of the antero-ventral pathway for object identification. The amplitude of the earlier N1m wave, which is related to processing of sensory information, did not change over the time course of the study. The P2m amplitude increase and its persistence over time constitute a neuroplastic change. The P2m gain likely reflects enhanced object representation after stimulus experience and training, which enables listeners to improve their ability for scrutinizing fine differences in pre-voicing time. Different trajectories of brain and behaviour changes suggest that the preceding effect of a P2m increase relates to brain

  7. Suggestions on the development strategy of shale gas in China

    Directory of Open Access Journals (Sweden)

    Dazhong Dong

    2016-12-01

    Full Text Available From the aspects of shale gas resource condition, main exploration and development progress, important breakthrough in key technologies and equipment, this paper systematically summarized and analyzed current situation of shale gas development in China and pointed out five big challenges such as misunderstandings, lower implementation degree and higher economic uncertainty of shale gas resource, and still no breakthrough in exploration and development core technologies and equipment for shale gas buried depth more than 3500 m, higher cost and other non-technical factors that restrict the development pace. Aiming at the above challenges, we put forward five suggestions to promote the shale gas development in China: (1 Make strategies and set goals according to our national conditions and exploration and development stages. That is, make sure to realize shale gas annual production of 20 × 109 m3, and strives to reach 30 × 109 m3. (2 Attach importance to the research of accumulation and enrichment geological theory and exploration & development key engineering technologies for lower production and lower pressure marine shale gas reservoir, and at the same time orderly promote the construction of non-marine shale gas exploration & development demonstration areas. (3 The government should introduce further policies and set special innovation funds to support the companies to carry out research and development of related technologies and equipment, especially to strengthen the research and development of technology, equipment and process for shale gas bellow 3500 m in order to achieve breakthrough in deep shale gas. (4 Continue to promote the geological theory, innovation in technology and management, and strengthen cost control on drilling, fracturing and the whole process in order to realize efficient, economic and scale development of China's shale gas. (5 Reform the mining rights management system, establish information platform of shale

  8. Cellular mechanisms of the 5-HT7 receptor-mediated signaling

    Directory of Open Access Journals (Sweden)

    Daria eGuseva

    2014-10-01

    Full Text Available Serotonin (5-hydroxytryptamine or 5-HT is an important neurotransmitter regulating a wide range of physiological and pathological functions via activation of heterogeneously expressed 5-HT receptors. The 5-HT7 receptor is one of the most recently described members of the 5-HT receptor family. Functionally, 5-HT7 receptor is associated with a number of physiological and pathological responses, including serotonin-induced phase shifting of the circadian rhythm, control of memory as well as locomotor and exploratory activity. A large body of evidence indicates involvement of the 5-HT7 receptor in anxiety and depression, and recent studies suggest that 5-HT7 receptor can be highly relevant for the treatment of major depressive disorders. The 5-HT7 receptor is coupled to the stimulatory Gs-protein, and receptor stimulation results in activation of adenylyl cyclase (AC leading to a rise of cAMP concentration. In addition, this receptor is coupled to the G12-protein to activate small GTPases of the Rho family. This review focuses on molecular mechanisms responsible for the 5-HT7 receptor-mediated signaling. We provide detailed overview of signaling cascades controlled and regulated by the 5-HT7 receptor and discuss the functional impact of 5-HT7 receptor for the regulation of different cellular and subcellular processes.

  9. Role of insulin receptor phosphorylation in the insulinomimetic effects of hydrogen peroxide

    International Nuclear Information System (INIS)

    Hayes, G.R.; Lockwood, D.H.

    1987-01-01

    The oxidant H 2 O 2 has many insulin-like effects in rat adipocytes. To determine whether these effects could be mediated by the tyrosine kinase activity of the insulin receptor, the ability of H 2 O 2 to stimulate receptor phosphorylation in intact adipocytes and partially purified insulin receptors has been examined. Phosphorylation of the β subunit of the insulin receptor was increased. Stimulation of receptor phosphorylation was rapid, reaching maximal levels within 5 min, and preceded activation of glucose transport. Phosphoamino acid analysis of insulin receptors from H 2 O 2 -treated adipocytes showed that 32 P incorporation into phosphotyrosine and phosphoserine residues of the β subunit was enhanced. Furthermore, partially purified receptors from H 2 O 2 -treated cells exhibit increased tyrosine kinase activity, as measured by phosphorylation of the peptide Glu 80 Tyr 20 . To define the factors involved in H 2 O 2 's effect, the authors have examined receptor phosphorylation in fat cell homogenates and purified plasma membranes. Although insulin stimulated receptor phosphorylation in both of these systems, H 2 O 2 was only effective in the cell homogenates. These data demonstrate that, under certain conditions, H 2 O 2 stimulates insulin receptor phosphorylation and tyrosine kinase activity, suggesting that the insulin-like effects of H 2 O 2 may be mediated by stimulation of insulin receptor phosphorylation. This does not appear to be a direct effect of H 2 O 2 on the insulin receptor and requires nonplasma membrane cellular constituents

  10. A restricted population of CB1 cannabinoid receptors with neuroprotective activity

    Science.gov (United States)

    Chiarlone, Anna; Bellocchio, Luigi; Blázquez, Cristina; Resel, Eva; Soria-Gómez, Edgar; Cannich, Astrid; Ferrero, José J.; Sagredo, Onintza; Benito, Cristina; Romero, Julián; Sánchez-Prieto, José; Lutz, Beat; Fernández-Ruiz, Javier; Galve-Roperh, Ismael; Guzmán, Manuel

    2014-01-01

    The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies. PMID:24843137

  11. Melatonin Receptor Genes in Vertebrates

    Directory of Open Access Journals (Sweden)

    Hua Dong Yin

    2013-05-01

    Full Text Available Melatonin receptors are members of the G protein-coupled receptor (GPCR family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A and MT2 (or Mel1b or MTNR1B receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C, has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.

  12. Effects of microgravity on muscle and cerebral cortex: a suggested interaction

    Science.gov (United States)

    D'Amelio, F.; Fox, R. A.; Wu, L. C.; Daunton, N. G.; Corcoran, M. L.

    The ``slow'' antigravity muscle adductor longus was studied in rats after 14 days of spaceflight (SF). The techniques employed included standard methods for light microscopy, neural cell adhesion molecule (N-CAM) immunocytochemistry and electron microscopy. Light and electron microscopy revealed myofiber atrophy, segmental necrosis and regenerative myofibers. Regenerative myofibers were N-CAM immunoreactive (N-CAM-IR). The neuromuscular junctions showed axon terminals with a decrease or absence of synaptic vesicles, degenerative changes, vacant axonal spaces and changes suggestive of axonal sprouting. No alterations of muscle spindles was seen either by light or electron microscopy. These observations suggest that muscle regeneration and denervation and synaptic remodeling at the level of the neuromuscular junction may take place during spaceflight. In a separate study, GABA immunoreactivity (GABA-IR) was evaluated at the level of the hindlimb representation of the rat somatosensory cortex after 14 days of hindlimb unloading by tail suspension (``simulated'' microgravity). A reduction in number of GABA-immunoreactive cells with respect to the control animals was observed in layer Va and Vb. GABA-IR terminals were also reduced in the same layers, particularly those terminals surrounding the soma and apical dendrites of pyramidal cells in layer Vb. On the basis of previous morphological and behavioral studies of the neuromuscular system after spaceflight and hindlimb suspension it is suggested that after limb unloading there are alterations of afferent signaling and feedback information from intramuscular receptors to the cerebral cortex due to modifications in the reflex organization of hindlimb muscle groups. We propose that the changes observed in GABA immunoreactivity of cells and terminals is an expression of changes in their modulatory activity to compensate for the alterations in the afferent information.

  13. Hypocretin/Orexin Regulation of Dopamine Signaling and Cocaine Self-Administration Is Mediated Predominantly by Hypocretin Receptor 1

    OpenAIRE

    Prince, Courtney D.; Rau, Andrew R.; Yorgason, Jordan T.; Espa?a, Rodrigo A.

    2014-01-01

    Extensive evidence suggests that the hypocretins/orexins influence cocaine reinforcement and dopamine signaling via actions at hypocretin receptor 1. By comparison, the involvement of hypocretin receptor 2 in reward and reinforcement processes has received relatively little attention. Thus, although there is some evidence that hypocretin receptor 2 regulates intake of some drugs of abuse, it is currently unclear to what extent hypocretin receptor 2 participates in the regulation of dopamine s...

  14. Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor α signalling and results in tamoxifen insensitive proliferation.

    NARCIS (Netherlands)

    Moerkens, M.; Zhang, Y.; Wester, L.; Water, van de B.; Meerman, J.H.N.

    2014-01-01

    BACKGROUND Tamoxifen resistance is a major problem in the treatment of estrogen receptor (ER) α -positive breast cancer patients. Although the mechanisms behind tamoxifen resistance are still not completely understood, clinical data suggests that increased expression of receptor tyrosine kinases is

  15. Effects of Air Pollutants on Innate Immunity: The Role of Toll-like receptors and nucleotide-binding oligomerization domain-like receptors

    Science.gov (United States)

    Interactions between exposure to ambient air pollutants and respiratory pathogens have been shown to modify respiratory immune responses. Emerging data suggest key roles for toll-like receptor (TLR) and NOD-like receptor (NLR) signaling in pathogen-induced immune responses. Simil...

  16. Mechanisms underlying developmental changes in the expression of metabotropic glutamate receptors in cultured cerebellar granule cells: homologous desensitization and interactive effects involving N-methyl-D-aspartate receptors

    NARCIS (Netherlands)

    Aronica, E.; Dell'Albani, P.; Condorelli, D. F.; Nicoletti, F.; Hack, N.; Balázs, R.

    1993-01-01

    Glutamate receptors coupled to polyphosphoinositide (PPI) hydrolysis (metabotropic glutamate receptors, mGluR), are highly efficient during the early stages of postnatal life and are thought to be involved in developmental plasticity. The dramatic decrease with age in mGluR activity suggests the

  17. Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Goodman, M W; Burstein, E S

    2002-01-01

    The pharmacology of histamine H(3) receptors suggests the presence of distinct receptor isoforms or subtypes. We herein describe multiple, functionally distinct, alternatively spliced isoforms of the human H(3) receptor. Combinatorial splicing at three different sites creates at least six distinct...... receptor isoforms, of which isoforms 1, 2, and 4, encode functional proteins. Detailed pharmacology on isoforms 1 (unspliced receptor), and 2 (which has an 80 amino acid deletion within the third intracellular loop of the protein) revealed that both isoforms displayed robust responses to a series of known...... revealed a rank order of potency at both isoforms of clobenpropit>iodophenpropit>thioperamide, and these drugs are fivefold less potent at isoform 2 than isoform 1. To further explore the pharmacology of H(3) receptor function, we screened 150 clinically relevant neuropsychiatric drugs for H(3) receptor...

  18. BDNF downregulates 5-HT(2A) receptor protein levels in hippocampal cultures

    DEFF Research Database (Denmark)

    Trajkovska, V; Santini, M A; Marcussen, Anders Bue

    2009-01-01

    Both brain-derived neurotrophic factor (BDNF) and the serotonin receptor 2A (5-HT(2A)) have been related to depression pathology. Specific 5-HT(2A) receptor changes seen in BDNF conditional mutant mice suggest that BDNF regulates the 5-HT(2A) receptor level. Here we show a direct effect of BDNF...... on 5-HT(2A) receptor protein levels in primary hippocampal neuronal and mature hippocampal organotypic cultures exposed to different BDNF concentrations for either 1, 3, 5 or 7 days. In vivo effects of BDNF on hippocampal 5-HT(2A) receptor levels were further corroborated in (BDNF +/-) mice...... with reduced BDNF levels. In primary neuronal cultures, 7 days exposure to 25 and 50ng/mL BDNF resulted in downregulation of 5-HT(2A), but not of 5-HT(1A), receptor protein levels. The BDNF-associated downregulation of 5-HT(2A) receptor levels was also observed in mature hippocampal organotypic cultures...

  19. Attenuation of cocaine's reinforcing and discriminative stimulus effects via muscarinic M1 acetylcholine receptor stimulation

    DEFF Research Database (Denmark)

    Thomsen, Morgane; Conn, P Jeffrey; Lindsley, Craig

    2010-01-01

    Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine's abuse-related effects. Here, we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine's discriminative stimulus....... More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor subtype selectivity can blunt cocaine's discriminative stimulus and reinforcing effects; we hypothesized a critical role for the M(1) and/or M(4) receptor subtypes in this modulation. Mice were trained......) conferred lesser nonspecific rate-suppressing effects, with no rate suppression for TBPB. In mutant mice lacking M(1) and M(4) receptors, xanomeline failed to diminish cocaine discrimination while rate-decreasing effects were intact. Our data suggest that central M(1) receptor activation attenuates cocaine...

  20. Striatal μ-opioid receptor availability predicts cold pressor pain threshold in healthy human subjects

    DEFF Research Database (Denmark)

    Hagelberg, Nora; Aalto, Sargo; Tuominen, Lauri

    2012-01-01

    the potential associations between μ-opioid receptor BP(ND) and psychophysical measures. The results show that striatal μ-opioid receptor BP(ND) predicts cold pressor pain threshold, but not cold pressor pain tolerance or tactile sensitivity. This finding suggests that striatal μ-opioid receptor density......Previous PET studies in healthy humans have shown that brain μ-opioid receptor activation during experimental pain is associated with reductions in the sensory and affective ratings of the individual pain experience. The aim of this study was to find out whether brain μ-opioid receptor binding...... at the resting state, in absence of painful stimulation, can be a long-term predictor of experimental pain sensitivity. We measured μ-opioid receptor binding potential (BP(ND)) with μ-opioid receptor selective radiotracer [(11)C]carfentanil and positron emission tomography (PET) in 12 healthy male subjects...

  1. The N-terminal domain of GluR6-subtype glutamate receptor ion channels

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Janesh; Schuck, Peter; Jin, Rongsheng; Mayer, Mark L.; (NIH); (Burnham)

    2009-09-25

    The amino-terminal domain (ATD) of glutamate receptor ion channels, which controls their selective assembly into AMPA, kainate and NMDA receptor subtypes, is also the site of action of NMDA receptor allosteric modulators. Here we report the crystal structure of the ATD from the kainate receptor GluR6. The ATD forms dimers in solution at micromolar protein concentrations and crystallizes as a dimer. Unexpectedly, each subunit adopts an intermediate extent of domain closure compared to the apo and ligand-bound complexes of LIVBP and G protein-coupled glutamate receptors (mGluRs), and the dimer assembly has a markedly different conformation from that found in mGluRs. This conformation is stabilized by contacts between large hydrophobic patches in the R2 domain that are absent in NMDA receptors, suggesting that the ATDs of individual glutamate receptor ion channels have evolved into functionally distinct families.

  2. What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

    Energy Technology Data Exchange (ETDEWEB)

    Kufareva, Irina; Gustavsson, Martin; Zheng, Yi; Stephens, Bryan S.; Handel, Tracy M. (UCSD)

    2017-05-22

    Chemokines and their cell surface G protein–coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs. In parallel, chemokine receptor structures with small molecules reveal the complicated and diverse structural foundations of small molecule antagonism and allostery, highlight the inherent physicochemical challenges of receptor:chemokine interfaces, and suggest novel epitopes that can be exploited to overcome these challenges. The structures and models promote unique understanding of chemokine receptor biology, including the interpretation of two decades of experimental studies, and will undoubtedly assist future drug discovery endeavors.

  3. Discovery of benzamide analogues as a novel class of 5-HT3 receptor agonists

    DEFF Research Database (Denmark)

    Jørgensen, Charlotte Grube; Frølund, Bente Flensborg; Kehler, Jan

    2011-01-01

    A 5-HT(3) receptor agonist based on a benzamide scaffold was identified in a screening of a small commercial compound library, and an elaborate SAR study originating from this hit was performed. The design, synthesis, and functional characterisation of benzamide analogues at the 5-HT(3) A receptor...... yielded substantial information concerning the analogues as 5-HT(3) receptor agonists. However, the potencies of the derived analogues were not significantly improved over that of the initial hit. The benzamide scaffold constitutes a novel type of 5-HT(3) receptor agonist, as it does not possess...... a positively charged functionality, which is essential for the binding of all orthosteric ligands to the receptor. Preliminary investigations suggest that the compounds may exert their effects on 5-HT(3) receptors by binding to an allosteric site in the receptor complex....

  4. Novel Functional Properties of Drosophila CNS Glutamate Receptors

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yan; Dharkar, Poorva; Han, Tae-Hee; Serpe, Mihaela; Lee, Chi-Hon; Mayer, Mark L.

    2016-12-01

    Phylogenetic analysis reveals AMPA, kainate, and NMDA receptor families in insect genomes, suggesting conserved functional properties corresponding to their vertebrate counterparts. However, heterologous expression of the Drosophila kainate receptor DKaiR1D and the AMPA receptor DGluR1A revealed novel ligand selectivity at odds with the classification used for vertebrate glutamate receptor ion channels (iGluRs). DKaiR1D forms a rapidly activating and desensitizing receptor that is inhibited by both NMDA and the NMDA receptor antagonist AP5; crystallization of the KaiR1D ligand-binding domain reveals that these ligands stabilize open cleft conformations, explaining their action as antagonists. Surprisingly, the AMPA receptor DGluR1A shows weak activation by its namesake agonist AMPA and also by quisqualate. Crystallization of the DGluR1A ligand-binding domain reveals amino acid exchanges that interfere with binding of these ligands. The unexpected ligand-binding profiles of insect iGluRs allows classical tools to be used in novel approaches for the study of synaptic regulation.

  5. PTH receptor-1 signalling—mechanistic insights and therapeutic prospects

    Science.gov (United States)

    Cheloha, Ross W.; Gellman, Samuel H.; Vilardaga, Jean-Pierre; Gardella, Thomas J.

    2015-01-01

    Parathyroid hormone/parathyroid hormone-related protein receptor (PTH/PTHrP type 1 receptor; commonly known as PTHR1) is a family B G-protein-coupled receptor (GPCR) that regulates skeletal development, bone turnover and mineral ion homeostasis. PTHR1 transduces stimuli from PTH and PTHrP into the interior of target cells to promote diverse biochemical responses. Evaluation of the signalling properties of structurally modified PTHR1 ligands has helped to elucidate determinants of receptor function and mechanisms of downstream cellular and physiological responses. Analysis of PTHR1 responses induced by structurally modified ligands suggests that PTHR1 can continue to signal through a G-protein-mediated pathway within endosomes. Such findings challenge the longstanding paradigm in GPCR biology that the receptor is transiently activated at the cell membrane, followed by rapid deactivation and receptor internalization. Evaluation of structurally modified PTHR1 ligands has further led to the identification of ligand analogues that differ from PTH or PTHrP in the type, strength and duration of responses induced at the receptor, cellular and organism levels. These modified ligands, and the biochemical principles revealed through their use, might facilitate an improved understanding of PTHR1 function in vivo and enable the treatment of disorders resulting from defects in PTHR1 signalling. This Review discusses current understanding of PTHR1 modes of action and how these findings might be applied in future therapeutic agents. PMID:26303600

  6. Dopamine receptor gene expression by enkephalin neurons in rat forebrain

    Energy Technology Data Exchange (ETDEWEB)

    Le Moine, C.; Normand, E.; Guitteny, A.F.; Fouque, B.; Teoule, R.; Bloch, B. (Universite de Bordeaux II (France))

    1990-01-01

    In situ hybridization experiments were performed with brain sections from normal, control and haloperidol-treated rats to identify and map the cells expressing the D2 dopamine receptor gene. D2 receptor mRNA was detected with radioactive or biotinylated oligonucleotide probes. D2 receptor mRNA was present in glandular cells of the pituitary intermediate lobe and in neurons of the substantia nigra, ventral tegmental area, and forebrain, especially in caudate putamen, nucleus accumbens, olfactory tubercle, and piriform cortex. Hybridization with D2 and preproenkephalin A probes in adjacent sections, as well as combined hybridization with the two probes in the same sections, demonstrated that all detectable enkephalin neurons in the striatum contained the D2 receptor mRNA. Large neurons in caudate putamen, which were unlabeled with the preproenkephalin A probe and which may have been cholinergic, also expressed the D2 receptor gene. Haloperidol treatment (14 or 21 days) provoked an increase in mRNA content for D2 receptor and preproenkephalin A in the striatum. This suggests that the increase in D2 receptor number observed after haloperidol treatment is due to increased activity of the D2 gene. These results indicate that in the striatum, the enkephalin neurons are direct targets for dopamine liberated from mesostriatal neurons.

  7. Structure-function relationships for the interleukin 2 receptor system

    Directory of Open Access Journals (Sweden)

    Richard J. Robb

    1987-01-01

    Full Text Available Receptors for interleukin 2 (IL-2 esit in at least three forms which differ in their subunit compositio, their affinity for ligand and their ability to mediate a cellular reponse. Type I receptors occur following cellular acitivation and consist of the 55,000 m. w. glycoprotein Tac. These receptors bind IL-2 with a low affinity, do not internalize ligand and have not been definitively associated with any response. Type II receptors, on the other hand, conssit of one or more glycoproteins of 70,000 m. w. which have been termed "beta ([beta] chains." They bind IL-2 with an intermediate affinity and rapidly internalize the ligand. [Beta] proteins mediate many cellular IL-2-dependent reponses, including the short-term activation of natural killer cells and the induction of Tac protein expression. Type III receptors consist of a ternary complex of the Tac protein, the [beta] chain(s and IL-2. They are characterized by a paricularly high affinity for ligand association. Type III receptors also internalize ligand and mediate IL-2-dependent responses at low factor concentrations. The identification of two independent IL-2-binding molecules, Tac and [beta], thus provides the elusive molecular explanation for the differences in IL-2 receptor affinity and suggests the potential for selective therapeutic manipulation of IL-2 reponses.

  8. Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors

    Energy Technology Data Exchange (ETDEWEB)

    Jin,R.; Clark, S.; Weeks, A.; Dudman, J.; Gouaux, E.; Partin, K.

    2005-01-01

    Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer's disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1, 3-oxazino benzo-1, 4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the 'hinge' in the ligand-binding core 'clamshell' that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.

  9. Therapeutic Potential of 5-HT2C Receptor Ligands

    Directory of Open Access Journals (Sweden)

    Nanna H. Jensen

    2010-01-01

    Full Text Available Serotonin 2C receptors are G protein-coupled receptors expressed by GABAergic, glutamatergic, and dopaminergic neurons. Anatomically, they are present in various brain regions, including cortical areas, hippocampus, ventral midbrain, striatum, nucleus accumbens, hypothalamus, and amygdala. A large body of evidence supports a critical role of serotonin 2C receptors in mediating the interaction between serotonergic and dopaminergic systems, which is at the basis of their proposed involvement in the regulation of mood, affective behavior, and memory. In addition, their expression in specific neuronal populations in the hypothalamus would be critical for their role in the regulation of feeding behavior. Modulation of these receptors has therefore been proposed to be of interest in the search for novel pharmacological strategies for the treatment of various pathological conditions, including schizophrenia and mood disorders, as well as obesity. More precisely, blockade of serotonin 2C receptors has been suggested to provide antidepressant and anxiolytic benefit, while stimulation of these receptors may offer therapeutic benefit for the treatment of psychotic symptoms in schizophrenia and obesity. In addition, modulation of serotonin 2C receptors may offer cognitive-enhancing potential, albeit still a matter of debate. In the present review, the most compelling evidence from the literature is presented and tentative hypotheses with respect to existing controversies are outlined.

  10. NMDA Receptor Modulators in the Treatment of Drug Addiction

    Directory of Open Access Journals (Sweden)

    M. Foster Olive

    2013-02-01

    Full Text Available Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

  11. Luteininzing hormone releasing hormones analogs in combination with tamoxifen for the adjuvant treatment of premenopausal women with hormone receptor positive breast cancer.

    Science.gov (United States)

    Conte, Benedetta; Poggio, Francesca; Del Mastro, Lucia

    2017-09-01

    The role of ovarian function suppression (OFS) through luteinizing hormone-releasing hormone agonists (LHRHa) in addition to tamoxifen has been questioned until recently. In 2015, two large clinical trials led to a paradigm shift in the adjuvant endocrine treatment of premenopausal women, introducing the use of LHRHa plus tamoxifen (or aromatase inhibitor, AI) into current clinical practice. Areas covered: The present review aims to provide an in-depth overview of the role of LHRHa+tamoxifen for the adjuvant treatment of premenopausal women with hormone receptor positive breast cancer (HR+BC). Expert opinion: The addition of LHRHa to endocrine treatment (either tamoxifen or AI) is effective in premenopausal women who are at high risk of relapse. To date, no clear recommendations are available for the choice between LHRHa+tamoxifen and LHRH+AI. Although recent data showed better DFS with LHRHa+AI, other issues should be considered: 1) approximately 20 out of 100 women do not reach complete OFS with LHRHa+AI; 2) there is no extended endocrine therapy option that can be applied to women who received 5 years of LHRHa+AI and remained premenopausal at the end of the fifth year. Long-term results of the SOFT-TEXT study are needed to establish if LHRHa+AI is superior to LHRHa+tamoxifen.

  12. Prostaglandins and prostaglandin receptor antagonism in migraine

    DEFF Research Database (Denmark)

    Antonova, Maria

    2013-01-01

    Human models of headache may contribute to understanding of prostaglandins' role in migraine pathogenesis. The current thesis investigated the migraine triggering effect of prostaglandin E2 (PGE2) in migraine patients without aura, the efficacy of a novel EP4 receptor antagonist, BGC20....... The infusion of PGE2 caused the immediate migraine-like attacks and vasodilatation of the middle cerebral artery in migraine patients without aura. The highly specific and potent EP4 receptor antagonist, BGC20-1531, was not able to attenuate PGE2-induced headache and vasodilatation of both intra- and extra......-cerebral arteries. The intravenous infusion of PGF2α did not induce headache or statistically significant vasoconstriction of cerebral arteries in healthy volunteers. Novel data on PGE2-provoked immediate migraine-like attacks suggest that PGE2 may be one of the important final products in the pathogenesis...

  13. A novel subtype of endothelin receptors.

    Science.gov (United States)

    Sokolovsky, M; Ambar, I; Galron, R

    1992-10-15

    A new subtype of endothelin receptors with binding properties typical of "super-high" affinity sites, i.e. with affinities in the picomolar range, were identified and characterized in several rat brain regions and atrium. The pharmacological profile of these sites is indicative of the endothelin receptor type B (ETB-R). These sites differ from the "conventional" high affinity sites (nanomolar range) in several respects; they do not induce phosphoinositide hydrolysis (whereas the high affinity sites do), and they are affected differently by deglycosylation. Thus, there appear to be at least two subtypes of the ETB-R, namely ETB1-R (super-high affinity sites) and ETB2-R (high affinity sites). We suggest the possibility that the super-high affinity sites are related to the vasodilatation property of endothelins, whereas the high affinity sites participate in their vasoconstrictive action.

  14. Characterization of ouabain receptor in neuronal tissue

    International Nuclear Information System (INIS)

    Lichtstein, D.; Samuelov, S.

    1982-01-01

    This study shows that [ 3 H]ouabain binds specifically to a single, saturable binding site located on rat brain membranes with an affinity constant of 6.21 x 10 - 8 M. As expected from studies on the mechanics of the Na + , K + -ATPase, sodium increased while potassium and lithium decreased ouabain binding. The occupation of other neurotransmitter receptors did not affect [ 3 H]ouabain binding. Based on its ability to compete with [ 3 H]ouabain binding and to inhibit Na + , K + -ATPase, it is suggested that rat brain extract contains an endogeneous ouabain-like compound. The results are discussed with respect to the possibility that the ouabain receptor is a physiological regulatory site of the Na + , K + -ATPase activity. (author)

  15. Molecular Cloning, Genomic Organization and Developmental Regulation of a Novel Receptor from Drosophila melanogaster Structurally Related to Gonadotropin-Releasing Hormone Receptors from Vertebrates

    DEFF Research Database (Denmark)

    Hauser, Frank; Søndergaard, Leif; Grimmelikhuijzen, Cornelis J.P.

    1998-01-01

    of receptor mRNA, while adult flies contain higher levels, with males having about five times more receptor mRNA than female flies. Southern blot analyses show thatDrosophilacontains only one copy of the receptor gene, which is located at position 27A2-B1 of chromosome 2. This paper is the first report...... in the rat gene, suggesting that theDrosophilaand mammalian GnRH receptor genes are evolutionarily related. Northern blot analyses show that theDrosophilareceptor gene is progressively expressed during larval development with a prominent maximum at the 3rd instar larval stage. Pupae contain low amounts...

  16. Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB{sub 1} cannabinoid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Jäntti, Maria H., E-mail: maria.jantti@helsinki.fi [Department of Veterinary Biosciences, POB 66, FIN-00014 University of Helsinki (Finland); Mandrika, Ilona, E-mail: ilona@biomed.lu.lv [Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, Riga LV 1067 (Latvia); Kukkonen, Jyrki P., E-mail: jyrki.kukkonen@helsinki.fi [Department of Veterinary Biosciences, POB 66, FIN-00014 University of Helsinki (Finland)

    2014-03-07

    Highlights: • OX{sub 1} and OX{sub 2} orexin and CB{sub 1} cannabinoid receptor dimerization was investigated. • Bioluminescence resonance energy transfer method was used. • All receptors readily formed constitutive homo- and heteromeric complexes. - Abstract: Human OX{sub 1} orexin receptors have been shown to homodimerize and they have also been suggested to heterodimerize with CB{sub 1} cannabinoid receptors. The latter has been suggested to be important for orexin receptor responses and trafficking. In this study, we wanted to assess the ability of the other combinations of receptors to also form similar complexes. Vectors for expression of human OX{sub 1}, OX{sub 2} and CB{sub 1} receptors, C-terminally fused with either Renilla luciferase or GFP{sup 2} green fluorescent protein variant, were generated. The constructs were transiently expressed in Chinese hamster ovary cells, and constitutive dimerization between the receptors was assessed by bioluminescence energy transfer (BRET). Orexin receptor subtypes readily formed homo- and hetero(di)mers, as suggested by significant BRET signals. CB{sub 1} receptors formed homodimers, and they also heterodimerized with both orexin receptors. Interestingly, BRET efficiency was higher for homodimers than for almost all heterodimers. This is likely to be due to the geometry of the interaction; the putatively symmetric dimers may place the C-termini in a more suitable orientation in homomers. Fusion of luciferase to an orexin receptor and GFP{sup 2} to CB{sub 1} produced more effective BRET than the opposite fusions, also suggesting differences in geometry. Similar was seen for the OX{sub 1}–OX{sub 2} interaction. In conclusion, orexin receptors have a significant propensity to make homo- and heterodi-/oligomeric complexes. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB{sub 1} receptors, dimerization could be an effective way

  17. Aspects of dopamine and acetylcholine release induced by glutamate receptors

    International Nuclear Information System (INIS)

    Paes, Paulo Cesar de Arruda

    2002-01-01

    The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)

  18. Genetic interactions between neurofibromin and endothelin receptor B in mice.

    Directory of Open Access Journals (Sweden)

    Mugdha Deo

    Full Text Available When mutations in two different genes produce the same mutant phenotype, it suggests that the encoded proteins either interact with each other, or act in parallel to fulfill a similar purpose. Haploinsufficiency of Neurofibromin and over-expression of Endothelin 3 both cause increased numbers of melanocytes to populate the dermis during mouse development, and thus we are interested in how these two signaling pathways might intersect. Neurofibromin is mutated in the human genetic disease, neurofibromatosis type 1, which is characterized by the development of Schwann cell based tumors and skin hyper-pigmentation. Neurofibromin is a GTPase activating protein, while the Endothelin 3 ligand activates Endothelin receptor B, a G protein coupled receptor. In order to study the genetic interactions between endothelin and neurofibromin, we defined the deletion breakpoints of the classical Ednrb piebald lethal allele (Ednrb(s-l and crossed these mice to mice with a loss-of-function mutation in neurofibromin, Dark skin 9 (Dsk9. We found that Neurofibromin haploinsufficiency requires Endothelin receptor B to darken the tail dermis. In contrast, Neurofibromin haploinsufficiency increases the area of the coat that is pigmented in Endothelin receptor B null mice. We also found an oncogenic mutation in the G protein alpha subunit, GNAQ, which couples to Endothelin receptor B, in a uveal melanoma from a patient with neurofibromatosis type 1. Thus, this data suggests that there is a complex relationship between Neurofibromin and Endothelin receptor B.

  19. Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Minqian Shen

    2015-01-01

    Full Text Available The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis.

  20. Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury.

    Science.gov (United States)

    Li, Tuoyi; Yu, Bing; Liu, Zhixin; Li, Jingyuan; Ma, Mingliang; Wang, Yingbao; Zhu, Mingjiang; Yin, Huiyong; Wang, Xiaofeng; Fu, Yi; Yu, Fang; Wang, Xian; Fang, Xiaohong; Sun, Jinpeng; Kong, Wei

    2018-01-02

    Hyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. However, the mechanism underlying HHcy-aggravated vascular injury remains unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) receptor and in mice treated with an AT1 blocker. We find that homocysteine directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer analysis reveals distinct conformational changes of AT1 receptor upon binding to angiotensin II and homocysteine. Molecular dynamics and site-directed mutagenesis experiments suggest that homocysteine regulates the conformation of the AT1 receptor both orthosterically and allosterically by forming a salt bridge and a disulfide bond with its Arg 167 and Cys 289 residues, respectively. Together, these findings suggest that strategies aimed at blocking the AT1 receptor may mitigate HHcy-associated aneurysmal vascular injuries.

  1. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    of proliferation and angiogenesis. Specific histamine receptors have been identified on the surface of bone marrow cells, immune competent cells, endothelial cells, fibroblasts, and also on malignant cells. This has prompted research in regulation by specific histamine receptor agonists and antagonists. Results...... from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor...... antagonists as adjuvant single drugs to reduce trauma-, blood transfusion- and sepsis-induced immunosuppression has led to research in combined treatment regimens in major surgery, particularly, of patients operated on for malignant diseases....

  2. NK receptor interactions with MHC class I molecules in pregnancy.

    Science.gov (United States)

    Trowsdale, John; Moffett, Ashley

    2008-12-01

    Both HLA class I molecules and their receptors on Natural Killer cells, the KIR molecules, are highly polymorphic. It is generally believed that this variation is driven in response to the role of these receptors and counter-receptors in resistance to disease. Uterine NK cells are the major maternal leukocyte population present within the decidua, and they express KIR2D receptors for HLA-C, the only polymorphic class I molecule on trophoblast. Genetic and functional data suggest that the maternal KIR/fetal HLA-C interaction in pregnancy may affect the delivery of an optimal blood supply to mother and fetus. The drive for novelty in HLA-C and KIR2D allelic diversity may relate not only to survival from infections but also to reproductive success.

  3. Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

    DEFF Research Database (Denmark)

    Maolanon, Alex R.; Risgaard, Rune; Wang, Shuang Yan

    2017-01-01

    A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist...... efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit......-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission....

  4. Characteristics of the mouse genomic histamine H1 receptor gene

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Isao; Taniuchi, Ichiro; Kitamura, Daisuke [Kyushu Univ., Fukuoka (Japan)] [and others

    1996-08-15

    We report here the molecular cloning of a mouse histamine H1 receptor gene. The protein deduced from the nucleotide sequence is composed of 488 amino acid residues with characteristic properties of GTP binding protein-coupled receptors. Our results suggest that the mouse histamine H1 receptor gene is a single locus, and no related sequences were detected. Interspecific backcross analysis indicated that the mouse histamine H1 receptor gene (Hrh1) is located in the central region of mouse Chromosome 6 linked to microphthalmia (Mitfmi), ras-related fibrosarcoma oncogene 1 (Raf1), and ret proto-oncogene (Ret) in a region of homology with human chromosome 3p. 12 refs., 3 figs.

  5. Anti-N-Methyl-d-Aspartate Receptor Encephalitis

    Directory of Open Access Journals (Sweden)

    Te-Yu Hung

    2011-12-01

    Full Text Available Anti-N-methyl-d-aspartate (NMDA receptor encephalitis is a treatment-responsive encephalitis associated with anti-NMDA receptor antibodies, which bind to the NR1/NR2 heteromers of the NMDA receptors. It is a highly characteristic syndrome evolving in five stages: the prodromal phase (viral infection-like symptoms, psychotic phase, unresponsive phase, hyperkinetic phase, and gradual recovery phase. It has been considered as a paraneoplastic syndrome usually affecting childbearing-age female with ovarian tumors; however, recent reports suggest a much higher incidence of nonparaneoplastic cases in children. We report a 14-year-old girl with anti-NMDA receptor encephalitis without a detectable tumor who showed a nearly complete recovery after intensive immunotherapy.

  6. Microglia P2Y13 Receptors Prevent Astrocyte Proliferation Mediated by P2Y1 Receptors

    Directory of Open Access Journals (Sweden)

    Clara Quintas

    2018-05-01

    Full Text Available Cerebral inflammation is a common feature of several neurodegenerative diseases that requires a fine interplay between astrocytes and microglia to acquire appropriate phenotypes for an efficient response to neuronal damage. During brain inflammation, ATP is massively released into the extracellular medium and converted into ADP. Both nucleotides acting on P2 receptors, modulate astrogliosis through mechanisms involving microglia-astrocytes communication. In previous studies, primary cultures of astrocytes and co-cultures of astrocytes and microglia were used to investigate the influence of microglia on astroglial proliferation induced by ADPβS, a stable ADP analog. In astrocyte cultures, ADPβS increased cell proliferation through activation of P2Y1 and P2Y12 receptors, an effect abolished in co-cultures (of astrocytes with ∼12.5% microglia. The possibility that the loss of the ADPβS-mediated effect could have been caused by a microglia-induced degradation of ADPβS or by a preferential microglial localization of P2Y1 or P2Y12 receptors was excluded. Since ADPβS also activates P2Y13 receptors, the contribution of microglial P2Y13 receptors to prevent the proliferative effect of ADPβS in co-cultures was investigated. The results obtained indicate that P2Y13 receptors are low expressed in astrocytes and mainly expressed in microglia. Furthermore, in co-cultures, ADPβS induced astroglial proliferation in the presence of the selective P2Y13 antagonist MRS 2211 (3 μM and of the selective P2Y12 antagonist AR-C66096 (0.1 μM, suggesting that activation of microglial P2Y12 and P2Y13 receptors may induce the release of messengers that inhibit astroglial proliferation mediated by P2Y1,12 receptors. In this microglia-astrocyte paracrine communication, P2Y12 receptors exert opposite effects in astroglial proliferation as a result of its cellular localization: cooperating in astrocytes with P2Y1 receptors to directly stimulate proliferation and in

  7. Opportunistic activation of TRP receptors by endogenous lipids: exploiting lipidomics to understand TRP receptor cellular communication.

    Science.gov (United States)

    Bradshaw, Heather B; Raboune, Siham; Hollis, Jennifer L

    2013-03-19

    Transient receptor potential channels (TRPs) form a large family of ubiquitous non-selective cation channels that function as cellular sensors and in many cases regulate intracellular calcium. Identification of the endogenous ligands that activate these TRP receptors is still under intense investigation with the majority of these channels still remaining "orphans." That these channels respond to a variety of external stimuli (e.g. plant-derived lipids, changes in temperature, and changes in pH) provides a framework for their abilities as cellular sensors, however, the mechanism of direct activation is still under much debate and research. In the cases where endogenous ligands (predominately lipids) have shown direct activation of a channel, multiple ligands have been shown to activate the same channel suggesting that these receptors are "promiscuous" in nature. Lipidomics of a growing class of endogenous lipids, N-acyl amides, the most famous of which is N-arachidonoyl ethanolamine (the endogenous cannabinoid, Anandamide) is providing a novel set of ligands that have been shown to activate some members of the TRP family and have the potential to deorphanize many more. Here it is argued that activation of TRPV receptors, a subset of the larger family of TRPs, by multiple endogenous lipids that are structurally analogous is a model system to drive our understanding that many TRP receptors are not promiscuous, but are more characteristically "opportunistic" in nature; exploiting the structural similarity and biosynthesis of a narrow range of analogous endogenous lipids. In addition, this manuscript will compare the activation properties of TRPC5 to the activity profile of an "orphan" lipid, N-palmitoyl glycine; further demonstrating that lipidomics aimed at expanding our knowledge of the family of N-acyl amides has the potential to provide novel avenues of research for TRP receptors. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Venus Kinase Receptors: prospects in signalling and biological functions of these invertebrate receptors

    Directory of Open Access Journals (Sweden)

    Colette eDissous

    2014-05-01

    Full Text Available Venus Kinase Receptors (VKRs form a family of invertebrate receptor tyrosine kinases (RTKs initially discovered in the parasitic platyhelminth Schistosoma mansoni. VKRs are single transmembrane receptors which contain an extracellular Venus Flytrap (VFT structure similar to the ligand binding domain of G Protein Coupled Receptors of class C, and an intracellular Tyrosine Kinase domain close to that of Insulin Receptors. VKRs are found in a large variety of invertebrates from cnidarians to echinoderms, and are highly expressed in larval stages and in gonads, suggesting a role of these proteins in embryonic and larval development as well as in reproduction. Vkr gene silencing could demonstrate the function of these receptors in oogenesis as well as in spermatogenesis in Schistosoma .mansoni. VKRs are activated by amino-acids, and highly responsive to arginine. As many other RTKs, they form dimers when activated by ligands and induce intracellular pathways involved in protein synthesis and cellular growth, such as MAPK and PI3K/Akt/S6K pathways. VKRs are not present in vertebrates, nor in some invertebrate species. Questions remain open about the origin of this little-known RTK family in evolution and its role in emergence and specialization of Metazoa. What is the meaning of maintenance or loss of VKR in some phyla or species in terms of development and physiological functions? The presence of VKRs in invertebrates of economical and medical importance, such as pests, vectors of pathogens and platyhelminth parasites, and the implication of these RTKs in gametogenesis and reproduction processes are valuable reasons to consider VKRs as interesting targets in new programs for eradication/ control of pests and infectious diseases, with the main advantage in the case of parasite targeting that VKR counterparts are absent from the vertebrate host kinase panel.

  9. Protease-activated receptor 1-dependent neuronal damage involves NMDA receptor function.

    Science.gov (United States)

    Hamill, Cecily E; Mannaioni, Guido; Lyuboslavsky, Polina; Sastre, Aristide A; Traynelis, Stephen F

    2009-05-01

    Protease-activated receptor 1 (PAR1) is a G-protein coupled receptor that is expressed throughout the central nervous system. PAR1 activation by brain-derived as well as blood-derived proteases has been shown to have variable and complex effects in a variety of animal models of neuronal injury and inflammation. In this study, we have evaluated the effects of PAR1 on lesion volume in wild-type or PAR1-/- C57Bl/6 mice subjected to transient occlusion of the middle cerebral artery or injected with NMDA in the striatum. We found that removal of PAR1 reduced infarct volume following transient focal ischemia to 57% of control. Removal of PAR1 or application of a PAR1 antagonist also reduced the neuronal injury associated with intrastriatal injection of NMDA to 60% of control. To explore whether NMDA receptor potentiation by PAR1 activation contributes to the harmful effects of PAR1, we investigated the effect of NMDA receptor antagonists on the neuroprotective phenotype of PAR1-/- mice. We found that MK801 reduced penumbral but not core neuronal injury in mice subjected to transient middle cerebral artery occlusion or intrastriatal NMDA injection. Lesion volumes in both models were not significantly different between PAR1-/- mice treated with and without MK801. Use of the NMDA receptor antagonist and dissociative anesthetic ketamine also renders NMDA-induced lesion volumes identical in PAR1-/- mice and wild-type mice. These data suggest that the ability of PAR1 activation to potentiate NMDA receptor function may underlie its harmful actions during injury.

  10. Solubilization of rat brain phencyclidine receptors in an active binding form that is sensitive to N-methyl-D-aspartate receptor ligands.

    Science.gov (United States)

    Ambar, I; Kloog, Y; Sokolovsky, M

    1988-07-01

    Phencyclidine (PCP) receptors were successfully solubilized from rat forebrain membranes with 1% sodium cholate. Approximately 58% of the initial protein and 20-30% of the high-affinity PCP binding sites were solubilized. The high affinity toward PCP-like drugs, the stereo-selectivity of the sites, and the sensitivity to N-methyl-D-aspartate (NMDA) receptor ligands were preserved. Binding of the potent PCP receptor ligand N-[3H][1-(2-thienyl)cyclohexyl] piperidine ([3H]TCP) to the soluble receptors was saturable (KD = 35 nM), and PCP-like drugs inhibited [3H]TCP binding in a rank order of potency close to that observed for the membrane-bound receptors; the most potent inhibitors were TCP (Ki = 31 nM) and the anticonvulsant MK-801 (Ki = 50 nM). The NMDA receptor antagonist 2-amino-5-phosphonovaleric acid inhibited binding of [3H]TCP to the soluble receptors; glutamate or NMDA diminished this inhibition in a dose-dependent manner. Taken together, the results indicate that the soluble PCP receptor preparation contains the glutamate recognition sites and may represent a single receptor complex for PCP and NMDA, as suggested by electrophysiological data. The successful solubilization of the PCP receptors in an active binding form should now facilitate their purification.

  11. Dimerization of nuclear receptors.

    Science.gov (United States)

    Germain, Pierre; Bourguet, William

    2013-01-01

    Multicellular organisms require specific intercellular communication to properly organize the complex body plan during embryogenesis and maintain its properties and functions during the entire life. While growth factors, neurotransmitters, and peptide hormones bind to membrane receptors, thereby inducing the activity of intracellular kinase cascades or the JAK-STAT signaling pathways, other small signaling compounds such as steroid hormones, certain vitamins, and metabolic intermediates enter, or are generated, within the target cells and bind to members of a large family of nuclear receptors (NRs). NRs are ligand-inducible transcription factors that control a plethora of biological phenomena, thus orchestrating complex events like development, organ homeostasis, immune function, and reproduction. NR-NR interactions are of major importance in these regulatory processes, as NRs regulate their target genes by binding to cognate DNA response elements essentially as homo- or heterodimers. A number of structural and functional studies have provided significant insights as to how combinatorial NRs rely on protein-protein contacts that discriminate geometric features of their DNA response elements, thereby allowing both binding site diversity and physiological specificity. Here, we will review our current understanding of NR-NR interactions and provide protocols for a number of experimental approaches that are useful for their study. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.

    Science.gov (United States)

    Lindner, Robert; Sullivan, Catherine; Offor, Onyinye; Lezon-Geyda, Kimberly; Halligan, Kyle; Fischbach, Neal; Shah, Mansi; Bossuyt, Veerle; Schulz, Vincent; Tuck, David P; Harris, Lyndsay N

    2013-01-01

    Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1) and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA versus EA patients

  13. Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.

    Directory of Open Access Journals (Sweden)

    Robert Lindner

    Full Text Available Triple negative breast cancer (TNBC is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA. It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1 and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA

  14. Thyrotropin-luteinizing hormone/chorionic gonadotropin receptor extracellular domain chimeras as probes for thyrotropin receptor function

    International Nuclear Information System (INIS)

    Nagayama, Yuji; Wadsworth, H.L.; Chazenbalk, G.D.; Russo, D.; Seto, Pui; Rapoport, B.

    1991-01-01

    To define the sites in the extracellular domain of the human thyrotropin (TSH) receptor that are involved in TSH binding and signal transduction the authors constructed chimeric thyrotropin-luteinizing hormone/chorionic gonadotropin (TSH-LH/CG) receptors. The extracellular domain of the human TSH receptor was divided into five regions that were replaced, either singly or in various combinations, with homologous regions of the rat LH/CG receptor. The chimeric receptors were stably expressed in Chinese hamster ovary cells. The data obtained suggest that the carboxyl region of the extracellular domain (amino acid residues 261-418) and particularly the middle region (residues 171-260) play a role in signal transduction. The possibility is also raised of an interaction between the amino and carboxyl regions of the extracellular domain in the process of signal transduction. In summary, these studies suggest that the middle region and carboxyl half of the extracellular domain of the TSH receptor are involved in signal transduction and that the TSH-binding region is likely to span the entire extracellular domain, with multiple discontinuous contact sites

  15. Dopamine-galanin receptor heteromers modulate cholinergic neurotransmission in the rat ventral hippocampus

    Science.gov (United States)

    Moreno, Estefanía; Vaz, Sandra H.; Cai, Ning-Sheng; Ferrada, Carla; Quiroz, César; Barodia, Sandeep; Kabbani, Nadine; Canela, Enric I.; McCormick, Peter J.; Lluis, Carme; Franco, Rafael; Ribeiro, Joaquim A; Sebastião, Ana M.; Ferré, Sergi

    2011-01-01

    Previous studies have shown that dopamine and galanin modulate cholinergic transmission in the hippocampus, but little is known about the mechanisms involved and their possible interactions. By using resonance energy transfer techniques in transfected mammalian cells we demonstrated the existence of heteromers between the dopamine D1-like receptors (D1 and D5) and galanin Gal1, but not Gal2 receptors. Within the D1-Gal1 and D5-Gal1 receptor heteromers, dopamine receptor activation potentiated and dopamine receptor blockade counteracted MAPK activation induced by stimulation of Gal1 receptors, while Gal1 receptor activation or blockade did not modify D1-like receptor-mediated MAPK activation. Ability of a D1-like receptor antagonist to block galanin-induced MAPK activation (cross-antagonism) was used as a “biochemical fingerprint” of D1-like-Gal1 receptor heteromers, allowing their identification in the rat ventral hippocampus. The functional role of D1-like-Gal receptor heteromers was demonstrated in synaptosomes from rat ventral hippocampus, where galanin facilitated acetylcholine release, but only with co-stimulation of D1-like receptors. Electrophysiological experiments in rat ventral hippocampal slices showed that these receptor interactions modulate hippocampal synaptic transmission. Thus, a D1-like receptor agonist, that was ineffective when administered alone, turned an inhibitory effect of galanin into an excitatory effect, an interaction that required cholinergic neurotransmission. Altogether, our results strongly suggest that D1-like-Gal1 receptor heteromers act as processors that integrate signals of two different neurotransmitters, dopamine and acetylcholine, to modulate hippocampal cholinergic neurotransmission. PMID:21593325

  16. Differences in both glycosylation and binding properties between rat and mouse liver prolactin receptors.

    Science.gov (United States)

    Lascols, O; Cherqui, G; Munier, A; Picard, J; Capeau, J

    1994-05-01

    To investigate whether glycanic chains of prolactin receptors (PRL-R) play a role in hormone binding activity, comparison was made of rat and mouse liver solubilized receptors with respect to both their affinity for the hormone and their glycosylation properties. As compared with rat receptors, mouse receptors exhibited a 2-fold higher affinity for human growth hormone (hGH), the hormone being bound by both tissues with a lactogenic specificity. Along with this increased affinity, mouse receptors had a 2 lower M(r) relative to rat receptors (62 kDa versus 64 kDa as measured on hGH cross-linked receptors). These differences could be ascribed to different glycosylation properties of the receptors from the two species, as supported by the followings. 1) After treatment with endoglycosidase F (endo F), rat and mouse PRL-R no longer exhibited any difference in their M(r) (54 kDa for both cross-linked receptors). 2) Neuraminidase treatment increased by 37% the binding of hGH to mouse receptors, but was ineffective on the hormone-binding to rat receptors. Conversely, wheat germ agglutinin (WGA), another sialic acid specific probe, decreased hGH binding to rat receptors by 25%, but had no effect on this process for mouse ones. 3) Marked differences were observed in the recoveries of rat and mouse hormone-receptor (HR) complexes from ricin-1- (RCA1-), concanavalin A- (ConA-) and WGA-immobilized lectins. These differences were reduced (RCA1 and ConA) or abolished (WGA) after rat and mouse receptor desialylation by neuraminidase, a treatment which decreased the M(r) of both receptors by 2 kDa. Taken together, these results strongly suggest that the PRL-R from rat and mouse liver contain biantennary N-linked oligosaccharidic chains with distinct type of sialylation, which may account for their differential hormone-binding affinities.

  17. Recent Methods for Measuring Dopamine D3 receptor Occupancy In Vivo: Importance for Drug Development

    Directory of Open Access Journals (Sweden)

    Bernard eLe Foll

    2014-07-01

    Full Text Available There is considerable interest in developing highly selective dopamine D3 receptor ligands for a variety of mental health disorders. Dopamine D3 receptors have been implicated in Parkinson’s Disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10-15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from preclinical studies. Recently, with the advent of [11C]-(+-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [11C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [11C]-(+-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [11C]-(+-PHNO binding by region of interest. This novel methodology can be used in preclinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [11C]-(+-PHNO can provide insights into the function of D3 receptors in addiction is also presented.

  18. THIP, a hypnotic and antinociceptive drug, enhances a tonic GABAA receptor mediated conductance in mouse neocortex

    DEFF Research Database (Denmark)

    Drasbek, Kim Ryun; Jensen, Kimmo

    2006-01-01

    THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a selective GABA(A) receptor agonist with a preference for delta-subunit containing GABA(A) receptors. THIP is currently being tested in human trials for its hypnotic effects, displaying advantageous tolerance and addiction properties. Sinc...... suggest that THIP activates an extrasynaptic GABA(A) receptor-mediated conductance in the neocortex, which may alter the cortical network activity....

  19. Allosteric modulation of retinal GABA receptors by ascorbic acid

    Science.gov (United States)

    Calero, Cecilia I.; Vickers, Evan; Moraga Cid, Gustavo; Aguayo, Luis G.; von Gersdorff, Henrique; Calvo, Daniel J.

    2011-01-01

    Summary Ionotropic γ-aminobutyric acid receptors (GABAA and GABAC) belong to the cys-loop receptor family of ligand-gated ion channels. GABAC receptors are highly expressed in the retina, mainly localized at the axon terminals of bipolar cells. Ascorbic acid, an endogenous redox agent, modulates the function of diverse proteins, and basal levels of ascorbic acid in the retina are very high. However, the effect of ascorbic acid on retinal GABA receptors has not been studied. Here we show that the function of GABAC and GABAA receptors is regulated by ascorbic acid. Patch-clamp recordings from bipolar cell terminals in goldfish retinal slices revealed that GABAC receptor-mediated currents activated by tonic background levels of extracellular GABA, and GABAC currents elicited by local GABA puffs, are both significantly enhanced by ascorbic acid. In addition, a significant rundown of GABA-puff evoked currents was observed in the absence of ascorbic acid. GABA-evoked Cl- currents mediated by homomeric ρ1 GABAC receptors expressed in Xenopus laevis oocytes were also potentiated by ascorbic acid in a concentration-dependent, stereospecific, reversible, and voltage-independent manner. Studies involving the chemical modification of sulfhydryl groups showed that the two cys-loop cysteines and histidine 141, all located in the ρ1 subunit extracellular domain, each play a key role in the modulation of GABAC receptors by ascorbic acid. Additionally, we show that retinal GABAA IPSCs and heterologously expressed GABAA receptor currents are similarly augmented by ascorbic acid. Our results suggest that ascorbic acid may act as an endogenous agent capable of potentiating GABAergic neurotransmission in the CNS. PMID:21715633

  20. Function of the cytoplasmic tail of human calcitonin receptor-like receptor in complex with receptor activity-modifying protein 2

    Energy Technology Data Exchange (ETDEWEB)

    Kuwasako, Kenji, E-mail: kuwasako@fc.miyazaki-u.ac.jp [Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan); Kitamura, Kazuo; Nagata, Sayaka; Hikosaka, Tomomi [Division of Circulation and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan); Kato, Johji [Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan)

    2010-02-12

    Receptor activity-modifying protein 2 (RAMP2) enables calcitonin receptor-like receptor (CRLR) to form an adrenomedullin (AM)-specific receptor. Here we investigated the function of the cytoplasmic C-terminal tail (C-tail) of human (h)CRLR by co-transfecting its C-terminal mutants into HEK-293 cells stably expressing hRAMP2. Deleting the C-tail from CRLR disrupted AM-evoked cAMP production or receptor internalization, but did not affect [{sup 125}I]AM binding. We found that CRLR residues 428-439 are required for AM-evoked cAMP production, though deleting this region had little effect on receptor internalization. Moreover, pretreatment with pertussis toxin (100 ng/mL) led to significant increases in AM-induced cAMP production via wild-type CRLR/RAMP2 complexes. This effect was canceled by deleting CRLR residues 454-457, suggesting Gi couples to this region. Flow cytometric analysis revealed that CRLR truncation mutants lacking residues in the Ser/Thr-rich region extending from Ser{sup 449} to Ser{sup 467} were unable to undergo AM-induced receptor internalization and, in contrast to the effect on wild-type CRLR, overexpression of GPCR kinases-2, -3 and -4 failed to promote internalization of CRLR mutants lacking residues 449-467. Thus, the hCRLR C-tail is crucial for AM-evoked cAMP production and internalization of the CRLR/RAMP2, while the receptor internalization is dependent on the aforementioned GPCR kinases, but not Gs coupling.

  1. Characterization of serotonergic receptors in rabbit, porcine and human conjunctivae.

    Science.gov (United States)

    Turner, Helen C; Alvarez, Lawrence J; Candia, Oscar A; Bernstein, Audrey M

    2003-10-01

    To characterize the serotonin (5-HT) receptors linked to the modulation of adenylyl cyclase activity in rabbit, porcine and human conjunctivae. Serotonin receptor-subtype expression was examined using reverse transcription-polymerase chain reaction (RT-PCR) and receptor subtype-specific polyclonal antibodies for the immunofluorescent labeling of conjunctival cryosections. In addition, measurements of the effects of serotonergics on the short-circuit current (I(sc)) across rabbit and porcine conjunctivae were contrasted. RT-PCR assays indicated the expression of 5-HT(1B ) and 5-HT(1D) receptors, subtypes negatively coupled to adenylyl cyclase, in the rabbit conjunctiva. This approach also suggested the co-expression of 5-HT(1B), 5-HT(1D), 5-HT(1F), 5-HT(4) and 5-HT(7) mRNA's in the porcine conjunctiva, and 5-HT( 1D), 5-HT(1F) and 5-HT(7) in the human conjunctiva. Since the 5-HT(4) and 5-HT(7) receptors are positively linked to adenylyl cyclase, these results implied that the porcine and human tissues exhibited subtypes both positively and negatively linked to the enzyme. However, immunohistochemical observations, using currently available antibodies solely localized the 5-HT(7) moiety in the porcine and human epithelia, suggested that the 1B/1D forms may be minor elements. Consistent with this prospect, 5-HT was a stimulant of the transepithelial I(sc) across the porcine conjunctiva, an opposite response from earlier findings that demonstrated inhibitory effects by 5-HT on the rabbit I(sc), which are now explained by the localization of the 1B/1D receptors in the rabbit stratified epithelium. The 5-HT receptors expressed by mammalian conjunctivae are not identical. In terms of 5-HT receptor expression, the porcine tissue may be a more appropriate model for human, than is the rabbit, in that 5-HT may serve as a secretagogue in the human epithelium.

  2. Umami taste in mice uses multiple receptors and transduction pathways.

    Science.gov (United States)

    Yasumatsu, Keiko; Ogiwara, Yoko; Takai, Shingo; Yoshida, Ryusuke; Iwatsuki, Ken; Torii, Kunio; Margolskee, Robert F; Ninomiya, Yuzo

    2012-03-01

    The distinctive umami taste elicited by l-glutamate and some other amino acids is thought to be initiated by G-protein-coupled receptors. Proposed umami receptors include heteromers of taste receptor type 1, members 1 and 3 (T1R1+T1R3), and metabotropic glutamate receptors 1 and 4 (mGluR1 and mGluR4). Multiple lines of evidence support the involvement of T1R1+T1R3 in umami responses of mice. Although several studies suggest the involvement of receptors other than T1R1+T1R3 in umami, the identity of those receptors remains unclear. Here, we examined taste responsiveness of umami-sensitive chorda tympani nerve fibres from wild-type mice and mice genetically lacking T1R3 or its downstream transduction molecule, the ion channel TRPM5. Our results indicate that single umami-sensitive fibres in wild-type mice fall into two major groups: sucrose-best (S-type) and monopotassium glutamate (MPG)-best (M-type). Each fibre type has two subtypes; one shows synergism between MPG and inosine monophosphate (S1, M1) and the other shows no synergism (S2, M2). In both T1R3 and TRPM5 null mice, S1-type fibres were absent, whereas S2-, M1- and M2-types remained. Lingual application of mGluR antagonists selectively suppressed MPG responses of M1- and M2-type fibres. These data suggest the existence of multiple receptors and transduction pathways for umami responses in mice. Information initiated from T1R3-containing receptors may be mediated by a transduction pathway including TRPM5 and conveyed by sweet-best fibres, whereas umami information from mGluRs may be mediated by TRPM5-independent pathway(s) and conveyed by glutamate-best fibres.

  3. Receptor studies in biological psychiatry

    International Nuclear Information System (INIS)

    Fujiwara, Yutaka

    1992-01-01

    Recent advances in the pharmacological treatment of endogenous psychosis have led to the development of biological studies in psychiatry. Studies on neurotransmitter receptors were reviewed in order to apply positron-emission tomograph (PET) for biological psychiatry. The dopamine (DA) hypothesis for schizophrenia was advanced on the basis of the observed effects of neuroleptics and methamphetamine, and DA(D 2 ) receptor supersensitivity measured by PET and receptor binding in the schizophrenic brain. The clinical potencies of neuroleptics for schizophrenia were correlated with their abilities to inhibit the D 2 receptor, and not other receptors. The σ receptor was expected to be a site of antipsychotic action. However, the potency of drugs action on it was not correlated with clinical efficacy. Haloperidol binds with high affinity to the σ receptor, which may mediate acute dystonia, an extrapyramidal side effect of neuroleptics. Behavioral and neurochemical changes induced by methamphetamine treatment were studied as an animal model of schizophrenia, and both a decrease of D 2 receptor density and an increase of DA release were detected. The monoamine hypothesis for manic-depressive psychosis was advanced on the basis of the effect of reserpine, monoamine oxidase inhibitor and antidepressants. 3 H-clonidine binding sites were increased in platelet membranes of depressive patients, 3 H-imipramine binding sites were decreased. The GABA A receptor is the target site for the action of anxiolytics and antiepileptics such as benzodiazepines and barbiturates. Recent developments in molecular biology techniques have revealed the structure of receptor proteins, which are classified into two receptor families, the G-protein coupled type (D 2 ) and the ion-channel type (GABA A ). (J.P.N.)

  4. Scavenger receptor B2 as a receptor for hand, foot and Mouth disease and severe neurological diseases

    Directory of Open Access Journals (Sweden)

    Seiya eYamayoshi

    2012-02-01

    Full Text Available Enterovirus 71 (EV71 is one of the major causative agents of hand, foot and mouth disease (HFMD. Infection with EV71 is occasionally associated with severe neurological diseases such as acute encephalitis, acute flaccid paralysis and cardiopulmonary failure. Because cellular receptors for viruses play an important role in cell, tissue and species tropism, it is important to identify and characterize the receptor molecule. Recently, cellular receptors and host factors that stimulate EV71 infection have been identified. Several lines of evidence suggest that scavenger receptor class B, member 2 (SCARB2 plays critical roles in efficient EV71 infection and the development of disease in humans. In this review, we will summarize the findings of recent studies on EV71 infection and on the roles of SCARB2.

  5. Scavenger receptor b2 as a receptor for hand, foot, and mouth disease and severe neurological diseases.

    Science.gov (United States)

    Yamayoshi, Seiya; Fujii, Ken; Koike, Satoshi

    2012-01-01

    Enterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease (HFMD). Infection with EV71 is occasionally associated with severe neurological diseases such as acute encephalitis, acute flaccid paralysis, and cardiopulmonary failure. Because cellular receptors for viruses play an important role in cell, tissue, and species tropism, it is important to identify and characterize the receptor molecule. Recently, cellular receptors and host factors that stimulate EV71 infection have been identified. Several lines of evidence suggest that scavenger receptor class B, member 2 (SCARB2) plays critical roles in efficient EV71 infection and the development of disease in humans. In this review, we will summarize the findings of recent studies on EV71 infection and on the roles of SCARB2.

  6. Functional expression of the 5-HT1c receptor in neuronal and nonneuronal cells

    International Nuclear Information System (INIS)

    Julius, D.; MacDermott, A.B.; Jessel, T.M.; Huang, K.; Molineaux, S.; Schieren, I.; Axel, R.

    1988-01-01

    The isolation of the genes encoding the multiple serotonin receptor subtypes and the ability to express these receptors in new cellular environments will help to elucidate the molecular mechanisms of action of serotonin in the mammalian brain. The cloning of most neurotransmitter receptors has required the purification of receptor, the determination of partial protein sequence, and the synthesis of oligonucleotide probes with which to obtain cDNA or genomic clones. However, the serotonin receptors have not been purified and antibodies have not been generated. The authors therefore designed a cDNA expression system that permits the identification of functional cDNA clones encoding serotonin receptors in the absence of protein sequence information. They have combined cloning in RNA expression vectors with an electrophysiological assay in oocytes to isolate a functional cDNA clone encoding the entire 5-HT 1c receptor. The sequence of this clone reveals that the 5-HT 1c receptor belongs to a family of G-protein-coupled receptors that are thought to traverse the membrane seven times. Mouse fibroblasts transformed with this clone bind serotonergic ligands and respond to serotonin with an elevation in intracellular calcium. Moreover, in situ hybridization and Northern blot analysis indicate that the 5-HT 1c receptor mRNA is expressed in a wide variety of neurons in the rat central nervous system, suggesting that this receptor plays a prominent role in neuronal function

  7. Insulin receptor internalization defect in an insulin-resistant mouse melanoma cell line

    International Nuclear Information System (INIS)

    Androlewicz, M.J.; Straus, D.S.; Brandenburg, D.F.

    1989-01-01

    Previous studies from this laboratory demonstrated that the PG19 mouse melanoma cell line does not exhibit a biological response to insulin, whereas melanoma x mouse embryo fibroblast hybrids do respond to insulin. To investigate the molecular basis of the insulin resistance of the PG19 melanoma cells, insulin receptors from the insulin-resistant melanoma cells and insulin-sensitive fibroblast x melanoma hybrid cells were analyzed by the technique of photoaffinity labeling using the photoprobe 125 I-NAPA-DP-insulin. Photolabeled insulin receptors from the two cell types have identical molecular weights as determined by SDS gel electrophoresis under reducing and nonreducing conditions, indicating that the receptors on the two cell lines are structurally similar. Insulin receptor internalization studies revealed that the hybrid cells internalize receptors to a high degree at 37 degree C, whereas the melanoma cells internalize receptors to a very low degree or not at all. The correlation between ability to internalize insulin receptors and sensitivity to insulin action in this system suggests that uptake of the insulin-receptor complex may be required for insulin action in these cells. Insulin receptors from the two cell lines autophosphorylate in a similar insulin-dependent manner both in vitro and in intact cells, indicating that insulin receptors on the melanoma and hybrid cells have functional tyrosine protein kinase activity. Therefore, the block in insulin action in the PG19 melanoma cells appears to reside at a step beyond insulin-stimulated receptor autophosphorylation

  8. Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer's Disease.

    Science.gov (United States)

    Rodríguez-Ruiz, Mar; Moreno, Estefanía; Moreno-Delgado, David; Navarro, Gemma; Mallol, Josefa; Cortés, Antonio; Lluís, Carme; Canela, Enric I; Casadó, Vicent; McCormick, Peter J; Franco, Rafael

    2017-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D 1 , histamine H 3 , and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by co-immunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H 3 receptor agonists, via negative cross-talk, and H 3 receptor antagonists, via cross-antagonism, decreased D 1 receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D 1 receptor-mediated excitotoxic cell death. Both D 1 and H 3 receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D 1 -H 3 receptor heteromer function. Likely due to heteromerization, H 3 receptors act as allosteric regulator for D 1 and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D 1 or H 3 receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D 1 -H 3 -NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H 3 receptor antagonists reduced NMDA or D 1 receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H 3 receptor antagonists reverted the toxicity induced by ß 1-42 -amyloid peptide. Thus, histamine H 3 receptors in D 1 -H 3 -NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.

  9. Peptide Receptor Radionuclide Therapy & Oncology

    NARCIS (Netherlands)

    H. Bergsma (Hendrik)

    2017-01-01

    markdownabstractNeuroendocrine tumors (NETs) are rare neoplasms with differences in clinical presentation, course and prognosis. Most of the NETs express the somatostatine receptor, which can be utilized for imaging and therapy. Radiolabeled somatostatin analogs can be used for peptide receptor

  10. Coronavirus spike-receptor interactions

    NARCIS (Netherlands)

    Mou, H.

    2015-01-01

    Coronaviruses cause important diseases in humans and animals. Coronavirus infection starts with the virus binding with its spike proteins to molecules present on the surface of host cells that act as receptors. This spike-receptor interaction is highly specific and determines the virus’ cell, tissue

  11. Dithiothreitol activation of the insulin receptor/kinase does not involve subunit dissociation of the native α2β2 insulin receptor subunit complex

    International Nuclear Information System (INIS)

    Sweet, L.J.; Wilden, P.A.; Pessin, J.E.

    1986-01-01

    The subunit composition of the dithiothreitol- (DTT) activated insulin receptor/kinase was examined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and gel filtration chromatography under denaturing or nondenaturing conditions. Pretreatment of 32 P-labeled insulin receptors with 50 mM DTT followed by gel filtration chromatography in 0.1% SDS demonstrated the dissociation of the α 2 β 2 insulin receptor complex (M/sub r/ 400,000) into the monomeric 95,000 β subunit. In contrast, pretreatment of the insulin receptors with 1-50 mM DTT followed by gel filtration chromatography in 0.1% Triton X-100 resulted in no apparent alteration in mobility compared to the untreated insulin receptors. Resolution of this complex by nonreducing SDS-polyacrylamide gel electrophoresis and autoradiography demonstrated the existence of the α 2 β 2 heterotetrameric complex with essentially no αβ heterodimeric or free monomeric β subunit species present. This suggests that the insulin receptor can reoxidize into the M/sub r/ 400,000 complex after the removal of DTT by gel filtration chromatography. To prevent reoxidation, the insulin receptors were pretreated with 50 mM DTT. Under the conditions the insulin receptors migrated as the M/sub r/ 400,000 α 2 β 2 complex. These results demonstrate that treatment of the insulin receptors with high concentrations of DTT, followed by removal of DTT by gel filtration, results in reoxidation of the reduced α 2 β 2 insulin receptor complex. Further, these results document that although the DTT stimulation of the insulin receptor/kinase does involve reduction of the insulin receptor subunits, it does not result in dissociation of the native α 2 β 2 insulin receptor subunit complex

  12. Ciliary neurotrophic factor receptor regulation of adult forebrain neurogenesis.

    Science.gov (United States)

    Lee, Nancy; Batt, Myra K; Cronier, Brigitte A; Jackson, Michele C; Bruno Garza, Jennifer L; Trinh, Dennis S; Mason, Carter O; Spearry, Rachel P; Bhattacharya, Shayon; Robitz, Rachel; Nakafuku, Masato; MacLennan, A John

    2013-01-16

    Appropriately targeted manipulation of endogenous neural stem progenitor (NSP) cells may contribute to therapies for trauma, stroke, and neurodegenerative disease. A prerequisite to such therapies is a better understanding of the mechanisms regulating adult NSP cells in vivo. Indirect data suggest that endogenous ciliary neurotrophic factor (CNTF) receptor signaling may inhibit neuronal differentiation of NSP cells. We challenged subventricular zone (SVZ) cells in vivo with low concentrations of CNTF to anatomically characterize cells containing functional CNTF receptors. We found that type B "stem" cells are highly responsive, whereas type C "transit-amplifying" cells and type A neuroblasts are remarkably unresponsive, as are GFAP(+) astrocytes found outside the SVZ. CNTF was identified in a subset of type B cells that label with acute BrdU administration. Disruption of in vivo CNTF receptor signaling in SVZ NSP cells, with a "floxed" CNTF receptor α (CNTFRα) mouse line and a gene construct driving Cre recombinase (Cre) expression in NSP cells, led to increases in SVZ-associated neuroblasts and new olfactory bulb neurons, as well as a neuron subtype-specific, adult-onset increase in olfactory bulb neuron populations. Adult-onset receptor disruption in SVZ NSP cells with a recombinant adeno-associated virus (AAV-Cre) also led to increased neurogenesis. However, the maintenance of type B cell populations was apparently unaffected by the receptor disruption. Together, the data suggest that endogenous CNTF receptor signaling in type B stem cells inhibits adult neurogenesis, and further suggest that the regulation may occur in a neuron subtype-specific manner.

  13. Neurobeachin regulates neurotransmitter receptor trafficking to synapses

    NARCIS (Netherlands)

    Nair, R.; Lauks, J.; Jung, S; Cooke, N.E.; de Wit, H.; Brose, N.; Kilimann, M.W.; Verhage, M.; Rhee, J.

    2013-01-01

    The surface density of neurotransmitter receptors at synapses is a key determinant of synaptic efficacy. Synaptic receptor accumulation is regulated by the transport, postsynaptic anchoring, and turnover of receptors, involving multiple trafficking, sorting, motor, and scaffold proteins. We found

  14. Probing Biased Signaling in Chemokine Receptors

    DEFF Research Database (Denmark)

    Amarandi, Roxana Maria; Hjortø, Gertrud Malene; Rosenkilde, Mette Marie

    2016-01-01

    The chemokine system mediates leukocyte migration during homeostatic and inflammatory processes. Traditionally, it is described as redundant and promiscuous, with a single chemokine ligand binding to different receptors and a single receptor having several ligands. Signaling of chemokine receptor...

  15. Dopamine Receptors and Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Shin Hisahara

    2011-01-01

    Full Text Available Parkinson's disease (PD is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS. In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist.

  16. Ryanodine receptor channelopathies

    Science.gov (United States)

    Betzenhauser, Matthew J.

    2010-01-01

    Ryanodine receptors (RyR) are intracellular Ca2+-permeable channels that provide the sarcoplasmic reticulum Ca2+ release required for skeletal and cardiac muscle contractions. RyR1 underlies skeletal muscle contraction, and RyR2 fulfills this role in cardiac muscle. Over the past 20 years, numerous mutations in both RyR isoforms have been identified and linked to skeletal and cardiac diseases. Malignant hyperthermia, central core disease, and catecholaminergic polymorphic ventricular tachycardia have been genetically linked to mutations in either RyR1 or RyR2. Thus, RyR channelopathies are both of interest because they cause significant human diseases and provide model systems that can be studied to elucidate important structure–function relationships of these ion channels. PMID:20179962

  17. Recombinant Collagen Engineered to Bind to Discoidin Domain Receptor Functions as a Receptor Inhibitor*

    Science.gov (United States)

    An, Bo; Abbonante, Vittorio; Xu, Huifang; Gavriilidou, Despoina; Yoshizumi, Ayumi; Bihan, Dominique; Farndale, Richard W.; Kaplan, David L.; Balduini, Alessandra; Leitinger, Birgit; Brodsky, Barbara

    2016-01-01

    A bacterial collagen-like protein Scl2 has been developed as a recombinant collagen model system to host human collagen ligand-binding sequences, with the goal of generating biomaterials with selective collagen bioactivities. Defined binding sites in human collagen for integrins, fibronectin, heparin, and MMP-1 have been introduced into the triple-helical domain of the bacterial collagen and led to the expected biological activities. The modular insertion of activities is extended here to the discoidin domain receptors (DDRs), which are collagen-activated receptor tyrosine kinases. Insertion of the DDR-binding sequence from human collagen III into bacterial collagen led to specific receptor binding. However, even at the highest testable concentrations, the construct was unable to stimulate DDR autophosphorylation. The recombinant collagen expressed in Escherichia coli does not contain hydroxyproline (Hyp), and complementary synthetic peptide studies showed that replacement of Hyp by Pro at the critical Gly-Val-Met-Gly-Phe-Hyp position decreased the DDR-binding affinity and consequently required a higher concentration for the induction of receptor activation. The ability of the recombinant bacterial collagen to bind the DDRs without inducing kinase activation suggested it could interfere with the interactions between animal collagen and the DDRs, and such an inhibitory role was confirmed in vitro and with a cell migration assay. This study illustrates that recombinant collagen can complement synthetic peptides in investigating structure-activity relationships, and this system has the potential for the introduction or inhibition of specific biological activities. PMID:26702058

  18. Molecular characterization of opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Howard, A.D.

    1986-01-01

    The aim of this research was to purify and characterize active opioid receptors and elucidate molecular aspects of opioid receptor heterogeneity. Purification to apparent homogeneity of an opioid binding protein from bovine caudate was achieved by solubilization in the non-ionic detergent, digitonin, followed by sequential chromatography on the opiate affinity matrix, ..beta..-naltrexylethylenediamine-CH-Sepharose 4B, and on the lectine affinity matrix, wheat germ agglutinin-agarose. Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE) followed by autoradiography revealed that radioiodinated purified receptor gave a single band. Purified receptor preparations showed a specific activity of 12,000-15,000 fmol of opiate bound per mg of protein. Radioiodinated human beta-endorphin (/sup 125/I-beta-end/sub H/) was used as a probe to investigate the ligand binding subunits of mu and delta opioid receptors. /sup 125/I-beta-end/sub H/ was shown to bind to a variety of opioid receptor-containing tissues with high affinity and specificity with preference for mu and delta sites, and with little, if any, binding to kappa sites. Affinity crosslinking techniques were employed to covalently link /sup 125/I-beta-end/sub H/ to opioid receptors, utilizing derivatives of bis-succinimidyl esters that are bifunctional crosslinkers with specificities for amino and sulfhydryl groups. This, and competition experiments with high type-selective ligands, permitted the assignment of two labeled peptides to their receptor types, namely a peptide of M/sub r/ = 65,000 for mu receptors and one of M/sub r/ = 53,000 for delta receptors.

  19. Animal lectins: potential receptors for ginseng polysaccharides

    Directory of Open Access Journals (Sweden)

    So Hee Loh

    2017-01-01

    Full Text Available Panax ginseng Meyer, belonging to the genus Panax of the family Araliaceae, is known for its human immune system-related effects, such as immune-boosting effects. Ginseng polysaccharides (GPs are the responsible ingredient of ginseng in immunomodulation, and are classified as acidic and neutral GPs. Although GPs participate in various immune reactions including the stimulation of immune cells and production of cytokines, the precise function of GPs together with its potential receptor(s and their signal transduction pathways have remained largely unknown. Animal lectins are carbohydrate-binding proteins that are highly specific for sugar moieties. Among many different biological functions in vivo, animal lectins especially play important roles in the immune system by recognizing carbohydrates that are found exclusively on pathogens or that are inaccessible on host cells. This review summarizes the immunological activities of GPs and the diverse roles of animal lectins in the immune system, suggesting the possibility of animal lectins as the potential receptor candidates of GPs and giving insights into the development of GPs as therapeutic biomaterials for many immunological diseases.

  20. Glucocorticoid Regulation of the Vitamin D Receptor

    Science.gov (United States)

    Hidalgo, Alejandro A.; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    Many studies indicate calcitriol has potent anti-tumor activity in different types of cancers. However, high levels of vitamin D can produce hypercalcemia in some patients. Glucocorticoids are used to ameliorate hypercalcemia and to enhance calcitriol anti-tumor activity. Calcitriol in combination with the glucocorticoid dexamethasone (Dex) increased vitamin D receptor (VDR) protein levels and ligand binding in squamous cell carcinoma VII (SCC). In this study we found that both calcitriol and Dex induce VDR- and glucocorticoid receptor (GR)-mediated transcription respectively, indicating both hormone receptors are active in SCC. Pre-treatment with Dex increases VDR-mediated transcription at the human CYP24A1 promoter. Whereas, pre-treatment with other steroid hormones, including dihydrotestosterone and R1881, has no effect on VDR-mediated transcription. Real-time PCR indicates treatment with Dex increases Vdr transcripts in a time-dependent manner, suggesting Dex may directly regulate expression of Vdr. Numerous putative glucocorticoid response elements (GREs) were found in the Vdr gene. Chromatin immunoprecipitation (ChIP) assay demonstrated GR binding at several putative GREs located within the mouse Vdr gene. However, none of the putative GREs studied increase GR-mediated transcription in luciferase reporter assays. In an attempt to identify the response element responsible for Vdr transcript regulation, future studies will continue to analyze newly identified GREs more distal from the Vdr gene promoter. PMID:20398752

  1. G protein-coupled receptors form stable complexes with inwardly rectifying potassium channels and adenylyl cyclase.

    Science.gov (United States)

    Lavine, Natalie; Ethier, Nathalie; Oak, James N; Pei, Lin; Liu, Fang; Trieu, Phan; Rebois, R Victor; Bouvier, Michel; Hebert, Terence E; Van Tol, Hubert H M

    2002-11-29

    A large number of studies have demonstrated co-purification or co-immunoprecipitation of receptors with G proteins. We have begun to look for the presence of effector molecules in these receptor complexes. Co-expression of different channel and receptor permutations in COS-7 and HEK 293 cells in combination with co-immunoprecipitation experiments established that the dopamine D(2) and D(4), and beta(2)-adrenergic receptors (beta(2)-AR) form stable complexes with Kir3 channels. The D(4)/Kir3 and D(2) receptor/Kir3 interaction does not occur when the channel and receptor are expressed separately and mixed prior to immunoprecipitation, indicating that the interaction is not an artifact of the experimental protocol and reflects a biosynthetic event. The observed complexes are stable in that they are not disrupted by receptor activation or modulation of G protein alpha subunit function. However, using a peptide that binds Gbetagamma (betaARKct), we show that Gbetagamma is critical for dopamine receptor-Kir3 complex formation, but not for maintenance of the complex. We also provide evidence that Kir3 channels and another effector, adenylyl cyclase, are stably associated with the beta(2)-adrenergic receptor and can be co-immunoprecipitated by anti-receptor antibodies. Using bioluminescence resonance energy transfer, we have shown that in living cells under physiological conditions, beta(2)AR interacts directly with Kir3.1/3.4 and Kir3.1/3.2c heterotetramers as well as with adenylyl cyclase. All of these interactions are stable in the presence of receptor agonists, suggesting that these signaling complexes persist during signal transduction. In addition, we provide evidence that the receptor-effector complexes are also found in vivo. The observation that several G protein-coupled receptors form stable complexes with their effectors suggests that this arrangement might be a general feature of G protein-coupled signal transduction.

  2. Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness

    DEFF Research Database (Denmark)

    Zhang, Chi; Cherifi, Ibtissem; Nygaard, Mads

    2015-01-01

    PRLR(I146L) is the first identified gain-of-function variant of the prolactin receptor (PRLR) that was proposed to be associated with benign breast tumorigenesis. Structural investigations suggested this hydrophobic core position in the extracellular D2 domain to be linked to receptor dimerization...

  3. Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes

    DEFF Research Database (Denmark)

    Andersen, Christian Brix Folsted; Madsen, Mette; Storm, Tina

    2010-01-01

    of how Cbl indirectly induces ligand-receptor coupling. Finally, the comparison of Ca(2+)-binding CUB domains and the low-density lipoprotein (LDL) receptor-type A modules suggests that the electrostatic pairing of a basic ligand arginine/lysine residue with Ca(2+)-coordinating acidic aspartates...

  4. Comment on "Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2".

    OpenAIRE

    Vassalli, A.; Li, S.; Tafti, M.

    2015-01-01

    Did hypocretin receptor 2 autoantibodies cause narcolepsy with hypocretin deficiency in Pandemrix-vaccinated children, as suggested by Ahmed et al.? Using newly developed mouse models to report and inactivate hypocretin receptor expression, Vassalli et al. now show that hypocretin neurons (whose loss causes narcolepsy) do not express hypocretin autoreceptors, raising questions to the interpretation of Ahmed et al.'s findings.

  5. Mu-opioid receptor knockout mice show diminished food-anticipatory activity

    NARCIS (Netherlands)

    Kas, Martien J H; van den Bos, Ruud; Baars, Annemarie M; Lubbers, Marianne; Lesscher, Heidi M B; Hillebrand, Jacquelien J G; Schuller, Alwin G; Pintar, John E; Spruijt, Berry M

    We have previously suggested that during or prior to activation of anticipatory behaviour to a coming reward, mu-opioid receptors are activated. To test this hypothesis schedule induced food-anticipatory activity in mu-opioid receptor knockout mice was measured using running wheels. We hypothesized

  6. How does the estrogen receptor work?

    International Nuclear Information System (INIS)

    Gross, Jennifer M; Yee, Douglas

    2002-01-01

    In breast cancer, interruption of estrogen receptor (ER)-α function is an effective therapeutic strategy. Despite the clinical benefit of interruption of ER-α function, the precise biological action of ER-α in breast tumors is not completely understood. Results of a recent study show that ER-α promotes growth of breast cancer cells by targeting expression of signaling components of the insulin-like growth factor system. Intriguingly, the authors of this study raise the possibility that unliganded ER-α itself may affect gene expression and breast cancer biology, and they suggest a potential mechanism for ER-α to stimulate proliferation in breast cancer

  7. Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments

    Science.gov (United States)

    Richter, David; Moraga, Ignacio; Winkelmann, Hauke; Birkholz, Oliver; Wilmes, Stephan; Schulte, Markos; Kraich, Michael; Kenneweg, Hella; Beutel, Oliver; Selenschik, Philipp; Paterok, Dirk; Gavutis, Martynas; Schmidt, Thomas; Garcia, K. Christopher; Müller, Thomas D.; Piehler, Jacob

    2017-07-01

    The spatiotemporal organization of cytokine receptors in the plasma membrane is still debated with models ranging from ligand-independent receptor pre-dimerization to ligand-induced receptor dimerization occurring only after receptor uptake into endosomes. Here, we explore the molecular and cellular determinants governing the assembly of the type II interleukin-4 receptor, taking advantage of various agonists binding the receptor subunits with different affinities and rate constants. Quantitative kinetic studies using artificial membranes confirm that receptor dimerization is governed by the two-dimensional ligand-receptor interactions and identify a critical role of the transmembrane domain in receptor dimerization. Single molecule localization microscopy at physiological cell surface expression levels, however, reveals efficient ligand-induced receptor dimerization by all ligands, largely independent of receptor binding affinities, in line with the similar STAT6 activation potencies observed for all IL-4 variants. Detailed spatiotemporal analyses suggest that kinetic trapping of receptor dimers in actin-dependent microcompartments sustains robust receptor dimerization and signalling.

  8. Species differences in the localization and number of CNS beta adrenergic receptors: Rat versus guinea pig

    International Nuclear Information System (INIS)

    Booze, R.M.; Crisostomo, E.A.; Davis, J.N.

    1989-01-01

    The localization and number of beta adrenergic receptors were directly compared in the brains of rats and guinea pigs. The time course of association and saturability of [125I]cyanopindolol (CYP) binding to slide-mounted tissue sections was similar in rats (Kd = 17 pM) and guinea pigs (Kd = 20 pM). The beta-1 and beta-2 receptor subtypes were examined through the use of highly selective unlabeled receptor antagonists, ICI 118,551 (50 nM) and ICI 89,406 (70 nM). Dramatic species differences between rats and guinea pigs were observed in the neuroanatomical regional localization of the beta adrenergic receptor subtypes. For example, in the thalamus prominent beta-1 and beta-2 receptor populations were identified in the rat; however, the entire thalamus of the guinea pig had few, if any, beta adrenergic receptors of either subtype. Hippocampal area CA1 had high levels of beta-2 adrenergic receptors in both rats and guinea pigs but was accompanied by a widespread distribution of beta-2 adrenergic receptors only in rats. Quantitative autoradiographic analyses of 25 selected neuroanatomical regions (1) confirmed the qualitative differences in CNS beta adrenergic receptor localization, (2) determined that guinea pigs had significantly lower levels of beta adrenergic receptors than rats and (3) indicated a differential pattern of receptor subtypes between the two species. Knowledge of species differences in receptor patterns may be useful in designing effective experiments as well as in exploring the relationships between receptor and innervation patterns. Collectively, these data suggest caution be used in extrapolation of the relationships of neurotransmitters and receptors from studies of a single species

  9. Classification of Dopamine Receptor Genes in Vertebrates: Nine Subtypes in Osteichthyes.

    Science.gov (United States)

    Yamamoto, Kei; Fontaine, Romain; Pasqualini, Catherine; Vernier, Philippe

    2015-01-01

    Dopamine neurotransmission regulates various brain functions, and its regulatory roles are mediated by two families of G protein-coupled receptors: the D1 and D2 receptor families. In mammals, the D1 family comprises two receptor subtypes (D1 and D5), while the D2 family comprises three receptor subtypes (D2, D3 and D4). Phylogenetic analyses of dopamine receptor genes strongly suggest that the common ancestor of Osteichthyes (bony jawed vertebrates) possessed four subtypes in the D1 family and five subtypes in the D2 family. Mammals have secondarily lost almost half of the ancestral dopamine receptor genes, whereas nonmammalian species kept many of them. Although the mammalian situation is an exception among Osteichthyes, the current classification and characterization of dopamine receptors are based on mammalian features, which have led to confusion in the identification of dopamine receptor subtypes in nonmammalian species. Here we begin by reviewing the history of the discovery of dopamine receptors in vertebrates. The recent genome sequencing of coelacanth, gar and elephant shark led to the proposal of a refined scenario of evolution of dopamine receptor genes. We also discuss a current problem of nomenclature of dopamine receptors. Following the official nomenclature of mammalian dopamine receptors from D1 to D5, we propose to name newly identified receptor subtypes from D6 to D9 in order to facilitate the use of an identical name for orthologous genes among different species. To promote a nomenclature change which allows distinguishing the two dopamine receptor families, a nomenclature consortium is needed. This comparative perspective is crucial to correctly interpret data obtained in animal studies on dopamine-related brain disorders, and more fundamentally, to understand the characteristics of dopamine neurotransmission in vertebrates. © 2015 S. Karger AG, Basel.

  10. Estrogen-related receptor β (ERRβ) - renaissance receptor or receptor renaissance?

    Science.gov (United States)

    Divekar, Shailaja D; Tiek, Deanna M; Fernandez, Aileen; Riggins, Rebecca B

    2016-01-01

    Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα and ERRγ at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ, however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRβ in mouse, man, and other species, highlighting unique aspects of ERRβ biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor.

  11. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-06-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of (/sup 3/H)Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in (14C)iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress (an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures), although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results.

  12. AMP is an adenosine A1 receptor agonist.

    Science.gov (United States)

    Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J

    2012-02-17

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

  13. Oxazaphosphorine bioactivation and detoxification: the role of xenobiotic receptors

    Directory of Open Access Journals (Sweden)

    Duan Wang

    2012-04-01

    Full Text Available Oxazaphosphorines, with the most representative members including cyclophosphamide, ifosfamide, and trofosfamide, constitute a class of alkylating agents that have a broad spectrum of anticancer activity against many malignant ailments including both solid tumors such as breast cancer and hematological malignancies such as leukemia and lymphoma. Most oxazaphosphorines are prodrugs that require hepatic cytochrome P450 enzymes to generate active alkylating moieties before manifesting their chemotherapeutic effects. Meanwhile, oxazaphosphorines can also be transformed into non-therapeutic byproducts by various drug-metabolizing enzymes. Clinically, oxazaphosphorines are often administered in combination with other chemotherapeutics in adjuvant treatments. As such, the therapeutic efficacy, off-target toxicity, and unintentional drug–drug interactions of oxazaphosphorines have been long-lasting clinical concerns and heightened focuses of scientific literatures. Recent evidence suggests that xenobiotic receptors may play important roles in regulating the metabolism and clearance of oxazaphosphorines. Drugs as modulators of xenobiotic receptors can affect the therapeutic efficacy, cytotoxicity, and pharmacokinetics of coadministered oxazaphosphorines, providing a new molecular mechanism of drug–drug interactions. Here, we review current advances regarding the influence of xenobiotic receptors, particularly, the constitutive androstane receptor, the pregnane X receptor and the aryl hydrocarbon receptor, on the bioactivation and detoxification of oxazaphosphorines, with a focus on cyclophosphamide and ifosfamide.

  14. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    International Nuclear Information System (INIS)

    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-01-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of [ 3 H]Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in [14C]iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress [an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures], although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results

  15. Predicting receptor functionality of signaling lymphocyte activation molecule for measles virus hemagglutinin by docking simulation.

    Science.gov (United States)

    Suzuki, Yoshiyuki

    2017-05-01

    Predicting susceptibility of various species to a virus assists assessment of risk of interspecies transmission. Evaluation of receptor functionality may be useful in screening for susceptibility. In this study, docking simulation was conducted for measles virus hemagglutinin (MV-H) and immunoglobulin-like variable domain of signaling lymphocyte activation molecule (SLAM-V). It was observed that the docking scores for MV-H and SLAM-V correlated with the activity of SLAM as an MV receptor. These results suggest that the receptor functionality may be predicted from the docking scores of virion surface proteins and cellular receptor molecules. © 2017 The Societies and John Wiley & Sons Australia, Ltd.

  16. Potential cellular receptors involved in hepatitis C virus entry into cells

    Directory of Open Access Journals (Sweden)

    Muellhaupt Beat

    2005-04-01

    Full Text Available Abstract Hepatitis C virus (HCV infects hepatocytes and leads to permanent, severe liver damage. Since the genomic sequence of HCV was determined, progress has been made towards understanding the functions of the HCV-encoded proteins and identifying the cellular receptor(s responsible for adsorption and penetration of the virus particle into the target cells. Several cellular receptors for HCV have been proposed, all of which are associated with lipid and lipoprotein metabolism. This article reviews the cellular receptors for HCV and suggests a general model for HCV entry into cells, in which lipoproteins play a crucial role.

  17. Regulation of dopamine D2 receptors in a novel cell line (SUP1)

    International Nuclear Information System (INIS)

    Ivins, K.J.; Luedtke, R.R.; Artymyshyn, R.P.; Molinoff, P.B.

    1991-01-01

    A prolactin-secreting cell line, SUP1, has been established from rat pituitary tumor 7315a. In radioligand binding experiments, the D2 receptor antagonist (S)-(-)-3- 125 I iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2- pyrrolidinyl)methyl]benzamide ( 125 I IBZM) labeled a single class of sites in homogenates of SUP1 cells (Kd = 0.6 nM; Bmax = 45 fmol/mg of protein). The sites displayed a pharmacological profile consistent with that of D2 receptors. Inhibition of the binding of 125 I IBZM by dopamine was sensitive to GTP, suggesting that D2 receptors in SUP1 cells are coupled to guanine nucleotide-binding protein(s). In the presence of isobutylmethylxanthine, dopamine decreased the level of cAMP accumulation in SUP1 cells. Dopamine also inhibited prolactin secretion from SUP1 cells. Both the inhibition of cAMP accumulation and the inhibition of prolactin secretion were blocked by D2 receptor antagonists, suggesting that these effects of dopamine were mediated by an interaction with D2 receptors. The regulation of D2 receptors in SUP1 cells by D2 receptor agonists was investigated. Exposure of SUP1 cells to dopamine or to the D2 receptor agonist N-propylnorapomorphine led to increased expression of D2 receptors, with no change in the affinity of the receptors for 125 I IBZM. An increase in the density of D2 receptors in SUP1 cells was evident within 7 hr of exposure to dopamine. Spiroperidol, a D2 receptor antagonist, blocked the effect of dopamine on receptor density. These results suggest that exposure of D2 receptors in SUP1 cells to agonists leads to an up-regulation of D2 receptors. Dopamine retained the ability to inhibit cAMP accumulation in SUP1 cells exposed to dopamine for 24 hr, suggesting that D2 receptors in SUP1 cells are not desensitized by prolonged exposure to agonist

  18. Corticosteroids decrease glomerular angiotensin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Douglas, J.G.

    1987-03-01

    Angiotensin II (ANG II) receptors of glomerular mesangial cells are regulated in vivo by changes in Na balance, effects that are presumed to be secondary to changes in circulating ANG II. However, since changes in ANG II were accompanied by parallel changes in plasma aldosterone in all models tested, it is possible that aldosterone may have also participated in the modulation of glomerular ANG II receptors. To test this hypothesis, short-term aldosterone infusions within the physiological range were employed to favor actions that would be mediated through a high-affinity mineralocorticoid receptor. The glucocorticoid, dexamethasone, was also tested to determine the mineralocorticoid specificity of the response. Two infusion rates were associated with a decrease in glomerular /sup 125/I ANG II receptor density of 33 and 45%, respectively. Serum potassium and urinary Na/K ratio were lower in the aldosterone group. Spironolactone abolished the effect of aldosterone consistent with an action mediated through a specific mineralocorticoid receptor. These studies support the hypothesis that corticosteroids modulate glomerular ANG II receptors and validate the complexity of glomerular receptor modulation. The downregulation observed would be expected to diminish the ability of ANG II to influence glomerular hemodynamics in models such as mineralocorticoid and glucocorticoid-induced hypertension.

  19. Lysophospholipid receptors in drug discovery.

    Science.gov (United States)

    Kihara, Yasuyuki; Mizuno, Hirotaka; Chun, Jerold

    2015-05-01

    Lysophospholipids (LPs), including lysophosphatidic acid (LPA), sphingosine 1-phospate (S1P), lysophosphatidylinositol (LPI), and lysophosphatidylserine (LysoPS), are bioactive lipids that transduce signals through their specific cell-surface G protein-coupled receptors, LPA1-6, S1P1-5, LPI1, and LysoPS1-3, respectively. These LPs and their receptors have been implicated in both physiological and pathophysiological processes such as autoimmune diseases, neurodegenerative diseases, fibrosis, pain, cancer, inflammation, metabolic syndrome, bone formation, fertility, organismal development, and other effects on most organ systems. Advances in the LP receptor field have enabled the development of novel small molecules targeting LP receptors for several diseases. Most notably, fingolimod (FTY720, Gilenya, Novartis), an S1P receptor modulator, became the first FDA-approved medicine as an orally bioavailable drug for treating relapsing forms of multiple sclerosis. This success is currently being followed by multiple, mechanistically related compounds targeting S1P receptor subtypes, which are in various stages of clinical development. In addition, an LPA1 antagonist, BMS-986020 (Bristol-Myers Squibb), is in Phase 2 clinical development for treating idiopathic pulmonary fibrosis, as a distinct compound, SAR100842 (Sanofi) for the treatment of systemic sclerosis and related fibrotic diseases. This review summarizes the current state of drug discovery in the LP receptor field. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Exome Sequencing of Bilateral Testicular Germ Cell Tumors Suggests Independent Development Lineages

    Directory of Open Access Journals (Sweden)

    Sigmund Brabrand

    2015-02-01

    Full Text Available Intratubular germ cell neoplasia, the precursor of testicular germ cell tumors (TGCTs, is hypothesized to arise during embryogenesis from developmentally arrested primordial germ cells (PGCs or gonocytes. In early embryonal life, the PGCs migrate from the yolk sac to the dorsal body wall where the cell population separates before colonizing the genital ridges. However, whether the malignant transformation takes place before or after this separation is controversial. We have explored the somatic exome-wide mutational spectra of bilateral TGCT to provide novel insight into the in utero critical time frame of malignant transformation and TGCT pathogenesis. Exome sequencing was performed in five patients with bilateral TGCT (eight tumors, of these three patients in whom both tumors were available (six tumors and two patients each with only one available tumor (two tumors. Selected loci were explored by Sanger sequencing in 71 patients with bilateral TGCT. From the exome-wide mutational spectra, no identical mutations in any of the three bilateral tumor pairs were identified. Exome sequencing of all eight tumors revealed 87 somatic non-synonymous mutations (median 10 per tumor; range 5-21, some in already known cancer genes such as CIITA, NEB, platelet-derived growth factor receptor α (PDGFRA, and WHSC1. SUPT6H was found recurrently mutated in two tumors. We suggest independent development lineages of bilateral TGCT. Thus, malignant transformation into intratubular germ cell neoplasia is likely to occur after the migration of PGCs. We reveal possible drivers of TGCT pathogenesis, such as mutated PDGFRA, potentially with therapeutic implications for TGCT patients.