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Sample records for affect receptor clustering

  1. Synaptic Bistability Due to Nucleation and Evaporation of Receptor Clusters

    KAUST Repository

    Burlakov, V. M.; Emptage, N.; Goriely, A.; Bressloff, P. C.

    2012-01-01

    interacting receptors and is stabilized against clustering by a high nucleation barrier. The other state contains a receptor gas in equilibrium with a large cluster of immobile receptors, which is stabilized by the turnover rate of receptors into and out

  2. Synaptic Bistability Due to Nucleation and Evaporation of Receptor Clusters

    KAUST Repository

    Burlakov, V. M.

    2012-01-10

    We introduce a bistability mechanism for long-term synaptic plasticity based on switching between two metastable states that contain significantly different numbers of synaptic receptors. One state is characterized by a two-dimensional gas of mobile interacting receptors and is stabilized against clustering by a high nucleation barrier. The other state contains a receptor gas in equilibrium with a large cluster of immobile receptors, which is stabilized by the turnover rate of receptors into and out of the synapse. Transitions between the two states can be initiated by either an increase (potentiation) or a decrease (depotentiation) of the net receptor flux into the synapse. This changes the saturation level of the receptor gas and triggers nucleation or evaporation of receptor clusters. © 2012 American Physical Society.

  3. The affective discourse dynamics of metaphor clustering The affective discourse dynamics of metaphor clustering

    Directory of Open Access Journals (Sweden)

    Lynne Cameron

    2010-05-01

    Full Text Available

    Metaphor is examined in the very different iscourse contexts of the classroom and of reconciliation talk to highlight the neglected affective dimension. The distribution of metaphors across discourse shows clustering at certain points, often where speakers are engaged in critical interpersonal discourse activity. Clusters in classroom talk co-occur with sequences of agenda management where teachers prepare students for upcoming lessons and with giving feedback to students, both of which require careful management of interpersonal and affective issues. Clusters in reconciliation talk co-occur with discourse management and with two situations with significant affective dynamics: appropriation of metaphor and exploration of alternative scenarios.

    Metaphor is examined in the very different iscourse contexts of the classroom and of reconciliation talk to highlight the neglected affective dimension. The distribution of metaphors across discourse shows clustering at certain points, often where speakers are engaged in critical interpersonal discourse activity. Clusters in classroom talk co-occur with sequences of agenda management where teachers prepare students for upcoming lessons and with giving feedback to students, both of which require careful management of interpersonal and affective issues. Clusters in reconciliation talk co-occur with discourse management and with two situations with significant affective dynamics: appropriation of metaphor and exploration of alternative scenarios.

  4. The formation of acetylcholine receptor clusters visualized with quantum dots

    Directory of Open Access Journals (Sweden)

    Peng H Benjamin

    2009-07-01

    Full Text Available Abstract Background Motor innervation of skeletal muscle leads to the assembly of acetylcholine receptor (AChR clusters in the postsynaptic membrane at the vertebrate neuromuscular junction (NMJ. Synaptic AChR aggregation, according to the diffusion-mediated trapping hypothesis, involves the establishment of a postsynaptic scaffold that "traps" freely diffusing receptors into forming high-density clusters. Although this hypothesis is widely cited to explain the formation of postsynaptic AChR clusters, direct evidence at molecular level is lacking. Results Using quantum dots (QDs and live cell imaging, we provide new measurements supporting the diffusion-trap hypothesis as applied to AChR cluster formation. Consistent with published works, experiments on cultured Xenopus myotomal muscle cells revealed that AChRs at clusters that formed spontaneously (pre-patterned clusters, also called hot spots and at those induced by nerve-innervation or by growth factor-coated latex beads were very stable whereas diffuse receptors outside these regions were mobile. Moreover, despite the restriction of AChR movement at sites of synaptogenic stimulation, individual receptors away from these domains continued to exhibit free diffusion, indicating that AChR clustering at NMJ does not involve an active attraction of receptors but is passive and diffusion-driven. Conclusion Single-molecular tracking using QDs has provided direct evidence that the clustering of AChRs in muscle cells in response to synaptogenic stimuli is achieved by two distinct cellular processes: the Brownian motion of receptors in the membrane and their trapping and immobilization at the synaptic specialization. This study also provides a clearer picture of the "trap" that it is not a uniformly sticky area but consists of discrete foci at which AChRs are immobilized.

  5. The glycocalyx promotes cooperative binding and clustering of adhesion receptors.

    Science.gov (United States)

    Xu, Guang-Kui; Qian, Jin; Hu, Jinglei

    2016-05-18

    Cell adhesion plays a pivotal role in various biological processes, e.g., immune responses, cancer metastasis, and stem cell differentiation. The adhesion behaviors depend subtly on the binding kinetics of receptors and ligands restricted at the cell-substrate interfaces. Although much effort has been directed toward investigating the kinetics of adhesion molecules, the role of the glycocalyx, anchored on cell surfaces as an exterior layer, is still unclear. In this paper, we propose a theoretical approach to study the collective binding kinetics of a few and a large number of binders in the presence of the glycocalyx, representing the cases of initial and mature adhesions of cells, respectively. The analytical results are validated by finding good agreement with our Monte Carlo simulations. In the force loading case, the on-rate and affinity increase as more bonds form, whereas this cooperative effect is not observed in the displacement loading case. The increased thickness and stiffness of the glycocalyx tend to decrease the affinity for a few bonds, while they have less influence on the affinity for a large number of bonds. Moreover, for a flexible membrane with thermally-excited shape fluctuations, the glycocalyx is exhibited to promote the formation of bond clusters, mainly due to the cooperative binding of binders. This study helps to understand the cooperative kinetics of adhesion receptors under physiologically relevant loading conditions and sheds light on the novel role of the glycocalyx in cell adhesion.

  6. γ1-Containing GABA-A Receptors Cluster at Synapses Where they Mediate Slower Synaptic Currents than γ2-Containing GABA-A Receptors

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    Christine L. Dixon

    2017-06-01

    Full Text Available GABA-A receptors (GABAARs are pentameric ligand-gated ion channels that are assembled mainly from α (α1–6, β (β1–3 and γ (γ1–3 subunits. Although GABAARs containing γ2L subunits mediate most of the inhibitory neurotransmission in the brain, significant expression of γ1 subunits is seen in the amygdala, pallidum and substantia nigra. However, the location and function of γ1-containing GABAARs in these regions remains unclear. In “artificial” synapses, where the subunit composition of postsynaptic receptors is specifically controlled, γ1 incorporation slows the synaptic current decay rate without affecting channel deactivation, suggesting that γ1-containing receptors are not clustered and therefore activated by diffuse neurotransmitter. However, we show that γ1-containing receptors are localized at neuronal synapses and form clusters in both synaptic and extrasynaptic regions. In addition, they exhibit rapid membrane diffusion and a higher frequency of exchange between synaptic and perisynaptic populations compared to γ2L-containing GABAARs. A point mutation in the large intracellular domain and a pharmacological analysis reveal that when a single non-conserved γ2L residue is mutated to its γ1 counterpart (T349L, the synaptic current decay is slowed from γ2L- to γ1-like without changing the clustering or diffusion properties of the receptors. In addition, previous fast perfusion and single channel kinetic experiments revealed no difference in the intrinsic closing rates of γ2L- and γ1-containing receptors when expressed in HEK293 cells. These observations together with Monte Carlo simulations of synaptic function confirm that decreased clustering does not control γ1-containing GABAAR kinetics. Rather, they suggest that γ1- and γ2L-containing receptors exhibit differential synaptic current decay rates due to differential gating dynamics when localized at the synapse.

  7. Identifying At-Risk Students in General Chemistry via Cluster Analysis of Affective Characteristics

    Science.gov (United States)

    Chan, Julia Y. K.; Bauer, Christopher F.

    2014-01-01

    The purpose of this study is to identify academically at-risk students in first-semester general chemistry using affective characteristics via cluster analysis. Through the clustering of six preselected affective variables, three distinct affective groups were identified: low (at-risk), medium, and high. Students in the low affective group…

  8. How the Clustering of Phonological Neighbors Affects Visual Word Recognition

    Science.gov (United States)

    Yates, Mark

    2013-01-01

    In recent years, a new scientific field known as network science has been emerging. Network science is concerned with understanding the structure and properties of networks. One concept that is commonly used in describing a network is how the nodes in the network cluster together. The current research applied the idea of clustering to the study of…

  9. Bisphenol A affects androgen receptor function via multiple mechanisms.

    Science.gov (United States)

    Teng, Christina; Goodwin, Bonnie; Shockley, Keith; Xia, Menghang; Huang, Ruili; Norris, John; Merrick, B Alex; Jetten, Anton M; Austin, Christopher P; Tice, Raymond R

    2013-05-25

    Bisphenol A (BPA), is a well-known endocrine disruptor compound (EDC) that affects the normal development and function of the female and male reproductive system, however the mechanisms of action remain unclear. To investigate the molecular mechanisms of how BPA may affect ten different nuclear receptors, stable cell lines containing individual nuclear receptor ligand binding domain (LBD)-linked to the β-Gal reporter were examined by a quantitative high throughput screening (qHTS) format in the Tox21 Screening Program of the NIH. The results showed that two receptors, estrogen receptor alpha (ERα) and androgen receptor (AR), are affected by BPA in opposite direction. To confirm the observed effects of BPA on ERα and AR, we performed transient transfection experiments with full-length receptors and their corresponding response elements linked to luciferase reporters. We also included in this study two BPA analogs, bisphenol AF (BPAF) and bisphenol S (BPS). As seen in African green monkey kidney CV1 cells, the present study confirmed that BPA and BPAF act as ERα agonists (half maximal effective concentration EC50 of 10-100 nM) and as AR antagonists (half maximal inhibitory concentration IC50 of 1-2 μM). Both BPA and BPAF antagonized AR function via competitive inhibition of the action of synthetic androgen R1881. BPS with lower estrogenic activity (EC50 of 2.2 μM), did not compete with R1881 for AR binding, when tested at 30 μM. Finally, the effects of BPA were also evaluated in a nuclear translocation assays using EGPF-tagged receptors. Similar to 17β-estradiol (E2) which was used as control, BPA was able to enhance ERα nuclear foci formation but at a 100-fold higher concentration. Although BPA was able to bind AR, the nuclear translocation was reduced. Furthermore, BPA was unable to induce functional foci in the nuclei and is consistent with the transient transfection study that BPA is unable to activate AR. Published by Elsevier Ireland Ltd.

  10. Calcium Domains around Single and Clustered IP3 Receptors and Their Modulation by Buffers

    Science.gov (United States)

    Rüdiger, S.; Nagaiah, Ch.; Warnecke, G.; Shuai, J.W.

    2010-01-01

    Abstract We study Ca2+ release through single and clustered IP3 receptor channels on the ER membrane under presence of buffer proteins. Our computational scheme couples reaction-diffusion equations and a Markovian channel model and allows our investigating the effects of buffer proteins on local calcium concentrations and channel gating. We find transient and stationary elevations of calcium concentrations around active channels and show how they determine release amplitude. Transient calcium domains occur after closing of isolated channels and constitute an important part of the channel's feedback. They cause repeated openings (bursts) and mediate increased release due to Ca2+ buffering by immobile proteins. Stationary domains occur during prolonged activity of clustered channels, where the spatial proximity of IP3Rs produces a distinct [Ca2+] scale (0.5–10 μM), which is smaller than channel pore concentrations (>100 μM) but larger than transient levels. While immobile buffer affects transient levels only, mobile buffers in general reduce both transient and stationary domains, giving rise to Ca2+ evacuation and biphasic modulation of release amplitude. Our findings explain recent experiments in oocytes and provide a general framework for the understanding of calcium signals. PMID:20655827

  11. Interaction of epidermal growth factor receptors with the cytoskeleton is related to receptor clustering

    NARCIS (Netherlands)

    van Belzen, N.; Spaargaren, M.; Verkleij, A. J.; Boonstra, J.

    1990-01-01

    Recently it has been established that cytoskeleton-associated epidermal growth factor (EGF) receptors are predominantly of the high-affinity class and that EGF induces a recruitment of low-affinity receptors to the cytoskeleton. The nature of this EGF-induced receptor-cytoskeleton interaction,

  12. The function of Shp2 tyrosine phosphatase in the dispersal of acetylcholine receptor clusters

    Directory of Open Access Journals (Sweden)

    Madhavan Raghavan

    2008-07-01

    Full Text Available Abstract Background A crucial event in the development of the vertebrate neuromuscular junction (NMJ is the postsynaptic enrichment of muscle acetylcholine (ACh receptors (AChRs. This process involves two distinct steps: the local clustering of AChRs at synapses, which depends on the activation of the muscle-specific receptor tyrosine kinase MuSK by neural agrin, and the global dispersal of aneural or "pre-patterned" AChR aggregates, which is triggered by ACh or by synaptogenic stimuli. We and others have previously shown that tyrosine phosphatases, such as the SH2 domain-containing phosphatase Shp2, regulate AChR cluster formation in muscle cells, and that tyrosine phosphatases also mediate the dispersal of pre-patterned AChR clusters by synaptogenic stimuli, although the specific phosphatases involved in this latter step remain unknown. Results Using an assay system that allows AChR cluster assembly and disassembly to be studied separately and quantitatively, we describe a previously unrecognized role of the tyrosine phosphatase Shp2 in AChR cluster disassembly. Shp2 was robustly expressed in embryonic Xenopus muscle in vivo and in cultured myotomal muscle cells, and treatment of the muscle cultures with an inhibitor of Shp2 (NSC-87877 blocked the dispersal of pre-patterned AChR clusters by synaptogenic stimuli. In contrast, over-expression in muscle cells of either wild-type or constitutively active Shp2 accelerated cluster dispersal. Significantly, forced expression in muscle of the Shp2-activator SIRPα1 (signal regulatory protein α1 also enhanced the disassembly of AChR clusters, whereas the expression of a truncated SIRPα1 mutant that suppresses Shp2 signaling inhibited cluster disassembly. Conclusion Our results suggest that Shp2 activation by synaptogenic stimuli, through signaling intermediates such as SIRPα1, promotes the dispersal of pre-patterned AChR clusters to facilitate the selective accumulation of AChRs at developing NMJs.

  13. Prediction of in vitro and in vivo oestrogen receptor activity using hierarchical clustering

    Science.gov (United States)

    In this study, hierarchical clustering classification models were developed to predict in vitro and in vivo oestrogen receptor (ER) activity. Classification models were developed for binding, agonist, and antagonist in vitro ER activity and for mouse in vivo uterotrophic ER bindi...

  14. Mechanism of acetylcholine receptor cluster formation induced by DC electric field.

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    Hailong Luke Zhang

    Full Text Available BACKGROUND: The formation of acetylcholine receptor (AChR cluster is a key event during the development of the neuromuscular junction. It is induced through the activation of muscle-specific kinase (MuSK by the heparan-sulfate proteoglycan agrin released from the motor axon. On the other hand, DC electric field, a non-neuronal stimulus, is also highly effective in causing AChRs to cluster along the cathode-facing edge of muscle cells. METHODOLOGY/PRINCIPAL FINDINGS: To understand its molecular mechanism, quantum dots (QDs were used to follow the movement of AChRs as they became clustered under the influence of electric field. From analyses of trajectories of AChR movement in the membrane, it was concluded that diffuse receptors underwent Brownian motion until they were immobilized at sites of cluster formation. This supports the diffusion-mediated trapping model in explaining AChR clustering under the influence of this stimulus. Disrupting F-actin cytoskeleton assembly and interfering with rapsyn-AChR interaction suppressed this phenomenon, suggesting that these are integral components of the trapping mechanism induced by the electric field. Consistent with the idea that signaling pathways are activated by this stimulus, the localization of tyrosine-phosphorylated forms of AChR β-subunit and Src was observed at cathodal AChR clusters. Furthermore, disrupting MuSK activity through the expression of a kinase-dead form of this enzyme abolished electric field-induced AChR clustering. CONCLUSIONS: These results suggest that DC electric field as a physical stimulus elicits molecular reactions in muscle cells in the form of cathodal MuSK activation in a ligand-free manner to trigger a signaling pathway that leads to cytoskeletal assembly and AChR clustering.

  15. True Molecular Scale Visualization of Variable Clustering Properties of Ryanodine Receptors

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    Isuru Jayasinghe

    2018-01-01

    Full Text Available Summary: Signaling nanodomains rely on spatial organization of proteins to allow controlled intracellular signaling. Examples include calcium release sites of cardiomyocytes where ryanodine receptors (RyRs are clustered with their molecular partners. Localization microscopy has been crucial to visualizing these nanodomains but has been limited by brightness of markers, restricting the resolution and quantification of individual proteins clustered within. Harnessing the remarkable localization precision of DNA-PAINT (<10 nm, we visualized punctate labeling within these nanodomains, confirmed as single RyRs. RyR positions within sub-plasmalemmal nanodomains revealed how they are organized randomly into irregular clustering patterns leaving significant gaps occupied by accessory or regulatory proteins. RyR-inhibiting protein junctophilin-2 appeared highly concentrated adjacent to RyR channels. Analyzing these molecular maps showed significant variations in the co-clustering stoichiometry between junctophilin-2 and RyR, even between nearby nanodomains. This constitutes an additional level of complexity in RyR arrangement and regulation of calcium signaling, intrinsically built into the nanodomains. : Jayasinghe et al. resolve the distribution of single ryanodine receptors (RyRs within intracellular signaling domains in cardiac myocytes with DNA-PAINT, a super-resolution microscopy approach. Individual RyRs are resolved within irregular cluster arrays. Quantitative imaging reveals significant variation in the co-clustering stoichiometry between RyRs and the regulatory protein junctophilin-2. Keywords: nanodomains, DNA-PAINT, single-molecule localization microscopy, ryanodine receptor, super-resolution imaging, junctophilin, heart

  16. Analyzing the factors affecting network lifetime cluster-based wireless sensor network

    International Nuclear Information System (INIS)

    Malik, A.S.; Qureshi, A.

    2010-01-01

    Cluster-based wireless sensor networks enable the efficient utilization of the limited energy resources of the deployed sensor nodes and hence prolong the node as well as network lifetime. Low Energy Adaptive Clustering Hierarchy (Leach) is one of the most promising clustering protocol proposed for wireless sensor networks. This paper provides the energy utilization and lifetime analysis for cluster-based wireless sensor networks based upon LEACH protocol. Simulation results identify some important factors that induce unbalanced energy utilization between the sensor nodes and hence affect the network lifetime in these types of networks. These results highlight the need for a standardized, adaptive and distributed clustering technique that can increase the network lifetime by further balancing the energy utilization among sensor nodes. (author)

  17. Cysteine 295 indirectly affects Ni coordination of carbon monoxide dehydrogenase-II C-cluster

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Takahiro; Takao, Kyosuke; Yoshida, Takashi [Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502 (Japan); Wada, Kei [Organization for Promotion of Tenure Track, University of Miyazaki, Miyazaki 889-1692 (Japan); Daifuku, Takashi; Yoneda, Yasuko [Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502 (Japan); Fukuyama, Keiichi [Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043 (Japan); Sako, Yoshihiko, E-mail: sako@kais.kyoto-u.ac.jp [Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502 (Japan)

    2013-11-08

    Highlights: •CODH-II harbors a unique [Ni-Fe-S] cluster. •We substituted the ligand residues of Cys{sup 295} and His{sup 261}. •Dramatic decreases in Ni content upon substitutions were observed. •All substitutions did not affect Fe-S clusters assembly. •CO oxidation activity was decreased by the substitutions. -- Abstract: A unique [Ni–Fe–S] cluster (C-cluster) constitutes the active center of Ni-containing carbon monoxide dehydrogenases (CODHs). His{sup 261}, which coordinates one of the Fe atoms with Cys{sup 295}, is suggested to be the only residue required for Ni coordination in the C-cluster. To evaluate the role of Cys{sup 295}, we constructed CODH-II variants. Ala substitution for the Cys{sup 295} substitution resulted in the decrease of Ni content and didn’t result in major change of Fe content. In addition, the substitution had no effect on the ability to assemble a full complement of [Fe–S] clusters. This strongly suggests Cys{sup 295} indirectly and His{sup 261} together affect Ni-coordination in the C-cluster.

  18. Cysteine 295 indirectly affects Ni coordination of carbon monoxide dehydrogenase-II C-cluster

    International Nuclear Information System (INIS)

    Inoue, Takahiro; Takao, Kyosuke; Yoshida, Takashi; Wada, Kei; Daifuku, Takashi; Yoneda, Yasuko; Fukuyama, Keiichi; Sako, Yoshihiko

    2013-01-01

    Highlights: •CODH-II harbors a unique [Ni-Fe-S] cluster. •We substituted the ligand residues of Cys 295 and His 261 . •Dramatic decreases in Ni content upon substitutions were observed. •All substitutions did not affect Fe-S clusters assembly. •CO oxidation activity was decreased by the substitutions. -- Abstract: A unique [Ni–Fe–S] cluster (C-cluster) constitutes the active center of Ni-containing carbon monoxide dehydrogenases (CODHs). His 261 , which coordinates one of the Fe atoms with Cys 295 , is suggested to be the only residue required for Ni coordination in the C-cluster. To evaluate the role of Cys 295 , we constructed CODH-II variants. Ala substitution for the Cys 295 substitution resulted in the decrease of Ni content and didn’t result in major change of Fe content. In addition, the substitution had no effect on the ability to assemble a full complement of [Fe–S] clusters. This strongly suggests Cys 295 indirectly and His 261 together affect Ni-coordination in the C-cluster

  19. Activation-Dependent Rapid Postsynaptic Clustering of Glycine Receptors in Mature Spinal Cord Neurons

    Science.gov (United States)

    Eto, Kei; Murakoshi, Hideji; Watanabe, Miho; Hirata, Hiromi; Moorhouse, Andrew J.; Ishibashi, Hitoshi

    2017-01-01

    Abstract Inhibitory synapses are established during development but continue to be generated and modulated in strength in the mature nervous system. In the spinal cord and brainstem, presynaptically released inhibitory neurotransmitter dominantly switches from GABA to glycine during normal development in vivo. While presynaptic mechanisms of the shift of inhibitory neurotransmission are well investigated, the contribution of postsynaptic neurotransmitter receptors to this shift is not fully elucidated. Synaptic clustering of glycine receptors (GlyRs) is regulated by activation-dependent depolarization in early development. However, GlyR activation induces hyperpolarization after the first postnatal week, and little is known whether and how presynaptically released glycine regulates postsynaptic receptors in a depolarization-independent manner in mature developmental stage. Here we developed spinal cord neuronal culture of rodents using chronic strychnine application to investigate whether initial activation of GlyRs in mature stage could change postsynaptic localization of GlyRs. Immunocytochemical analyses demonstrate that chronic blockade of GlyR activation until mature developmental stage resulted in smaller clusters of postsynaptic GlyRs that could be enlarged upon receptor activation for 1 h in the mature stage. Furthermore, live cell-imaging techniques show that GlyR activation decreases its lateral diffusion at synapses, and this phenomenon is dependent on PKC, but neither Ca2+ nor CaMKII activity. These results suggest that the GlyR activation can regulate receptor diffusion and cluster size at inhibitory synapses in mature stage, providing not only new insights into the postsynaptic mechanism of shifting inhibitory neurotransmission but also the inhibitory synaptic plasticity in mature nervous system. PMID:28197549

  20. Repeated stressful experiences differently affect brain dopamine receptor subtypes

    International Nuclear Information System (INIS)

    Puglisi-Allegra, S.; Cabib, S.; Kempf, E.; Schleef, C.

    1991-01-01

    The binding of tritiated spiperone (D2 antagonist) and tritiated SCH 23390 (D1 antagonist), in vivo, was investigated in the caudatus putamen (CP) and nucleus accumbens septi (NAS) of mice submitted to ten daily restraint stress sessions. Mice sacrificed 24 hr after the last stressful experience presented a 64% decrease of D2 receptor density (Bmax) but no changes in D1 receptor density in the NAS. In the CP a much smaller (11%) reduction of D2 receptor density was accompanied by a 10% increase of D1 receptors. These results show that the two types of dopamine (DA) receptors adapt in different or even opposite ways to environmental pressure, leading to imbalance between them

  1. Too Little, Too Late: How the Tidal Evolution of Hot Jupiters Affects Transit Surveys of Clusters

    Science.gov (United States)

    Debes, John H.; Jackson, Brian

    2010-01-01

    The tidal evolution of hot Jupiters may change the efficiency of transit surveys of stellar clusters. The orbital decay that hot Jupiters suffer may result in their destruction, leaving fewer transiting planets in older clusters. We calculate the impact tidal evolution has for different assumed stellar populations, including that of 47 Tuc, a globular cluster that was the focus of an intense HST search for transits. We find that in older clusters one expects to detect fewer transiting planets by a factor of two for surveys sensitive to Jupiter-like planets in orbits out to 0.5 AU, and up to a factor of 25 for surveys sensitive to Jupiter-like planets in orbits out to 0.08 AU. Additionally, tidal evolution affects the distribution of transiting planets as a function of semi-major axis, producing larger orbital period gaps for transiting planets as the age of the cluster increases. Tidal evolution can explain the lack of detected exoplanets in 47 Tuc without invoking other mechanisms. Four open clusters residing within the Kepler fields of view have ages that span 0.4-8 Gyr-if Kepler can observe a significant number of planets in these clusters, it will provide key tests for our tidal evolution hypothesis. Finally, our results suggest that observers wishing to discover transiting planets in clusters must have sufficient accuracy to detect lower mass planets, search larger numbers of cluster members, or have longer observation windows to be confident that a significant number of transits will occur for a population of stars.

  2. Cognitive-affective depression and somatic symptoms clusters are differentially associated with maternal parenting and coparenting.

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    Lamela, Diogo; Jongenelen, Inês; Morais, Ana; Figueiredo, Bárbara

    2017-09-01

    Both depressive and somatic symptoms are significant predictors of parenting and coparenting problems. However, despite clear evidence of their co-occurrence, no study to date has examined the association between depressive-somatic symptoms clusters and parenting and coparenting. The current research sought to identify and cross-validate clusters of cognitive-affective depressive symptoms and nonspecific somatic symptoms, as well as to test whether clusters would differ on parenting and coparenting problems across three independent samples of mothers. Participants in Studies 1 and 3 consisted of 409 and 652 community mothers, respectively. Participants in Study 2 consisted of 162 mothers exposed to intimate partner violence. All participants prospectively completed self-report measures of depressive and nonspecific somatic symptoms and parenting (Studies 1 and 2) or coparenting (Study 3). Across studies, three depression-somatic symptoms clusters were identified: no symptoms, high depression and low nonspecific somatic symptoms, and high depression and nonspecific somatic symptoms. The high depression-somatic symptoms cluster was associated with the highest levels of child physical maltreatment risk (Study 1) and overt-conflict coparenting (Study 3). No differences in perceived maternal competence (Study 2) and cooperative and undermining coparenting (Study 3) were found between the high depression and low somatic symptoms cluster and the high depression-somatic symptoms cluster. The results provide novel evidence for the strong associations between clusters of depression and nonspecific somatic symptoms and specific parenting and coparenting problems. Cluster stability across three independent samples suggest that they may be generalizable. The results inform preventive approaches and evidence-based psychotherapeutic treatments. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Sex Steroid Hormone Receptor Expression Affects Ovarian Cancer Survival

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Skovbjerg Arildsen, Nicolai; Malander, Susanne

    2015-01-01

    BACKGROUND AND AIMS: Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival...... in epithelial ovarian cancer. METHODS: Immunohistochemical stainings for ERα, ERβ, PR, and AR were assessed in relation to survival in 118 serous and endometrioid ovarian cancers. Expression of the genes encoding the four receptors was studied in relation to prognosis in the molecular subtypes of ovarian cancer...... in ovarian cancer and support that tumors should be stratified based on molecular as well as histological subtypes in future studies investigating the role of endocrine treatment in ovarian cancer....

  4. Environmental polycyclic aromatic hydrocarbons affect androgen receptor activation in vitro

    DEFF Research Database (Denmark)

    Vinggaard, Anne Marie; Hnida, Christina; Larsen, John Christian

    2000-01-01

    Nine structurally different polycyclic aromatic hydrocarbons (PAHs) were tested for their ability to either agonize or antagonize the human androgen receptor (hAR) in a sensitive reporter gene assay based on CHO cells transiently cotransfected with a hAR vector and an MMTV-LUC vector. Benz...

  5. Multivariate cluster analysis of dynamic iodine-123 iodobenzamide SPET dopamine D2receptor images in schizophrenia

    International Nuclear Information System (INIS)

    Acton, P.D.; Pilowsky, L.S.; Costa, D.C.; Ell, P.J.

    1997-01-01

    This paper describes the application of a multivariate statistical technique to investigate striatal dopamine D 2 receptor concentrations measured by iodine-123 iodobenzamide ( 123 I-IBZM) single-photon emission tomography (SPET). This technique enables the automatic segmentation of dynamic nuclear medicine images based on the underlying time-activity curves present in the data. Once the time-activity curves have been extracted, each pixel can be mapped back on to the underlying distribution, considerably reducing image noise. Cluster analysis has been verified using computer simulations and phantom studies. The technique has been applied to SPET images of dopamine D 2 receptors in a total of 20 healthy and 20 schizophrenic volunteers (22 male, 18 female), using the ligand 123 I-IBZM. Following automatic image segmentation, the concentration of striatal dopamine D 2 receptors shows a significant left-sided asymmetry in male schizophrenics compared with male controls. The mean left-minus-right laterality index for controls is -1.52 (95% CI -3.72-0.66) and for patients 4.04 (95% CI 1.07-7.01). Analysis of variance shows a case-by-sex-by-side interaction, with F=10.01, P=0.005. We can now demonstrate that the previously observed male sex-specific D 2 receptor asymmetry in schizophrenia, which had failed to attain statistical significance, is valid. Cluster analysis of dynamic nuclear medicine studies provides a powerful tool for automatic segmentation and noise reduction of the images, removing much of the subjectivity inherent in region-of-interest analysis. The observed striatal D 2 asymmetry could reflect long hypothesized disruptions in dopamine-rich cortico-striatal-limbic circuits in schizophrenic males. (orig.). With 4 figs., 2 tabs

  6. Lipid raft integrity affects GABAA receptor, but not NMDA receptor modulation by psychopharmacological compounds.

    Science.gov (United States)

    Nothdurfter, Caroline; Tanasic, Sascha; Di Benedetto, Barbara; Uhr, Manfred; Wagner, Eva-Maria; Gilling, Kate E; Parsons, Chris G; Rein, Theo; Holsboer, Florian; Rupprecht, Rainer; Rammes, Gerhard

    2013-07-01

    Lipid rafts have been shown to play an important role for G-protein mediated signal transduction and the function of ligand-gated ion channels including their modulation by psychopharmacological compounds. In this study, we investigated the functional significance of the membrane distribution of NMDA and GABAA receptor subunits in relation to the accumulation of the tricyclic antidepressant desipramine (DMI) and the benzodiazepine diazepam (Diaz). In the presence of Triton X-100, which allowed proper separation of the lipid raft marker proteins caveolin-1 and flotillin-1 from the transferrin receptor, all receptor subunits were shifted to the non-raft fractions. In contrast, under detergent-free conditions, NMDA and GABAA receptor subunits were detected both in raft and non-raft fractions. Diaz was enriched in non-raft fractions without Triton X-100 in contrast to DMI, which preferentially accumulated in lipid rafts. Impairment of lipid raft integrity by methyl-β-cyclodextrine (MβCD)-induced cholesterol depletion did not change the inhibitory effect of DMI at the NMDA receptor, whereas it enhanced the potentiating effect of Diaz at the GABAA receptor at non-saturating concentrations of GABA. These results support the hypothesis that the interaction of benzodiazepines with the GABAA receptor likely occurs outside of lipid rafts while the antidepressant DMI acts on ionotropic receptors both within and outside these membrane microdomains.

  7. Calmodulin affects sensitization of Drosophila melanogaster odorant receptors

    Directory of Open Access Journals (Sweden)

    Latha eMukunda

    2016-02-01

    Full Text Available Flying insects have developed a remarkably sensitive olfactory system to detect faint and turbulent odor traces. This ability is linked to the olfactory receptors class of odorant receptors (ORs, occurring exclusively in winged insects. ORs form heteromeric complexes of an odorant specific receptor protein (OrX and a highly conserved co-receptor protein (Orco. The ORs form ligand gated ion channels that are tuned by intracellular signaling systems. Repetitive subthreshold odor stimulation of olfactory sensory neurons sensitizes insect ORs. This OR sensitization process requires Orco activity. In the present study we first asked whether OR sensitization can be monitored with heterologously expressed OR proteins. Using electrophysiological and calcium imaging methods we demonstrate that D. melanogaster OR proteins expressed in CHO cells show sensitization upon repeated weak stimulation. This was found for OR channels formed by Orco as well as by Or22a or Or56a and Orco. Moreover, we show that inhibition of calmodulin (CaM action on OR proteins, expressed in CHO cells, abolishes any sensitization. Finally, we investigated the sensitization phenomenon using an ex vivo preparation of olfactory sensory neurons (OSNs expressing Or22a inside the fly’s antenna. Using calcium imaging, we observed sensitization in the dendrites as well as in the soma. Inhibition of calmodulin with W7 disrupted the sensitization within the outer dendritic shaft, whereas the sensitization remained in the other OSN compartments. Taken together, our results suggest that CaM action is involved in sensitizing the OR complex and that this mechanisms accounts for the sensitization in the outer dendrites, whereas further mechanisms contribute to the sensitization observed in the other OSN compartments. The use of heterologously expressed OR proteins appears to be suitable for further investigations on the mechanistic basis of OR sensitization, while investigations on native

  8. Lipid raft localization of GABA A receptor and Na+, K+-ATPase in discrete microdomain clusters in rat cerebellar granule cells

    DEFF Research Database (Denmark)

    Dalskov, Stine-Mathilde; Immerdal, Lissi; Niels-Christiansen, Lise-Lotte W

    2005-01-01

    The microdomain localization of the GABA(A) receptor in rat cerebellar granule cells was studied by subcellular fractionation and fluorescence- and immunogold electron microscopy. The receptor resided in lipid rafts, prepared at 37 degrees C by extraction with the nonionic detergent Brij 98......, but the raft fraction, defined by the marker ganglioside GM(1) in the floating fractions following density gradient centrifugation, was heterogeneous in density and protein composition. Thus, another major raft-associated membrane protein, the Na(+), K(+)-ATPase, was found in discrete rafts of lower density......, reflecting clustering of the two proteins in separate membrane microdomains. Both proteins were observed in patchy "hot spots" at the cell surface as well as in isolated lipid rafts. Their insolubility in Brij 98 was only marginally affected by methyl-beta-cyclodextrin. In contrast, both the GABA(A) receptor...

  9. Activation and clustering of a Plasmodium falciparum var gene are affected by subtelomeric sequences.

    Science.gov (United States)

    Duffy, Michael F; Tang, Jingyi; Sumardy, Fransisca; Nguyen, Hanh H T; Selvarajah, Shamista A; Josling, Gabrielle A; Day, Karen P; Petter, Michaela; Brown, Graham V

    2017-01-01

    The Plasmodium falciparum var multigene family encodes the cytoadhesive, variant antigen PfEMP1. P. falciparum antigenic variation and cytoadhesion specificity are controlled by epigenetic switching between the single, or few, simultaneously expressed var genes. Most var genes are maintained in perinuclear clusters of heterochromatic telomeres. The active var gene(s) occupy a single, perinuclear var expression site. It is unresolved whether the var expression site forms in situ at a telomeric cluster or whether it is an extant compartment to which single chromosomes travel, thus controlling var switching. Here we show that transcription of a var gene did not require decreased colocalisation with clusters of telomeres, supporting var expression site formation in situ. However following recombination within adjacent subtelomeric sequences, the same var gene was persistently activated and did colocalise less with telomeric clusters. Thus, participation in stable, heterochromatic, telomere clusters and var switching are independent but are both affected by subtelomeric sequences. The var expression site colocalised with the euchromatic mark H3K27ac to a greater extent than it did with heterochromatic H3K9me3. H3K27ac was enriched within the active var gene promoter even when the var gene was transiently repressed in mature parasites and thus H3K27ac may contribute to var gene epigenetic memory. © 2016 Federation of European Biochemical Societies.

  10. Improved pan-specific prediction of MHC class I peptide binding using a novel receptor clustering data partitioning strategy

    DEFF Research Database (Denmark)

    Mattsson, Andreas Holm; Kringelum, Jens Vindahl; Garde, C.

    2016-01-01

    Pan-specific prediction of receptor-ligand interaction is conventionally done using machine-learning methods that integrates information about both receptor and ligand primary sequences. To achieve optimal performance using machine learning, dealing with overfitting and data redundancy is critical....... Most often so-called ligand clustering methods have been used to deal with these issues in the context of pan-specific receptor-ligand predictions, and the MHC system the approach has proven highly effective for extrapolating information from a limited set of receptors with well characterized binding...

  11. Spatial cluster analysis of nanoscopically mapped serotonin receptors for classification of fixed brain tissue

    Science.gov (United States)

    Sams, Michael; Silye, Rene; Göhring, Janett; Muresan, Leila; Schilcher, Kurt; Jacak, Jaroslaw

    2014-01-01

    We present a cluster spatial analysis method using nanoscopic dSTORM images to determine changes in protein cluster distributions within brain tissue. Such methods are suitable to investigate human brain tissue and will help to achieve a deeper understanding of brain disease along with aiding drug development. Human brain tissue samples are usually treated postmortem via standard fixation protocols, which are established in clinical laboratories. Therefore, our localization microscopy-based method was adapted to characterize protein density and protein cluster localization in samples fixed using different protocols followed by common fluorescent immunohistochemistry techniques. The localization microscopy allows nanoscopic mapping of serotonin 5-HT1A receptor groups within a two-dimensional image of a brain tissue slice. These nanoscopically mapped proteins can be confined to clusters by applying the proposed statistical spatial analysis. Selected features of such clusters were subsequently used to characterize and classify the tissue. Samples were obtained from different types of patients, fixed with different preparation methods, and finally stored in a human tissue bank. To verify the proposed method, samples of a cryopreserved healthy brain have been compared with epitope-retrieved and paraffin-fixed tissues. Furthermore, samples of healthy brain tissues were compared with data obtained from patients suffering from mental illnesses (e.g., major depressive disorder). Our work demonstrates the applicability of localization microscopy and image analysis methods for comparison and classification of human brain tissues at a nanoscopic level. Furthermore, the presented workflow marks a unique technological advance in the characterization of protein distributions in brain tissue sections.

  12. Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder.

    Directory of Open Access Journals (Sweden)

    René A W Frank

    2011-04-01

    Full Text Available Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic 'hub' genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders.

  13. Low power laser irradiation does not affect the generation of signals in a sensory receptor

    Energy Technology Data Exchange (ETDEWEB)

    Lundeberg, T.; Zhou, J.

    1989-01-01

    The effect of low power Helium-Neon (He-Ne) and Gallium-Arsenide (Ga-As) laser on the slowly adapting crustacean stretch receptor was studied. The results showed that low power laser irradiation did not affect the membrane potential of the stretch receptor. These results are discussed in relation to the use of low power laser irradiation on the skin overlaying acupuncture points in treatment of pain syndrome.

  14. Androgen receptor variation affects prostate cancer progression and drug resistance.

    Science.gov (United States)

    McCrea, Edel; Sissung, Tristan M; Price, Douglas K; Chau, Cindy H; Figg, William D

    2016-12-01

    Significant therapeutic progress has been made in treating prostate cancer in recent years. Drugs such as enzalutamide, abiraterone, and cabazitaxel have expanded the treatment armamentarium, although it is not completely clear which of these drugs are the most-effective option for individual patients. Moreover, such advances have been tempered by the development of therapeutic resistance. The purpose of this review is to summarize the current literature pertaining to the biochemical effects of AR variants and their consequences on prostate cancer therapies at both the molecular level and in clinical treatment. We address how these AR splice variants and mutations affect tumor progression and therapeutic resistance and discuss potential novel therapeutic strategies under development. It is hoped that these therapies can be administered with increasing precision as tumor genotyping methods become more sophisticated, thereby lending clinicians a better understanding of the underlying biology of prostate tumors in individual patients. Published by Elsevier Ltd.

  15. The Size of Activating and Inhibitory Killer Ig-like Receptor Nanoclusters Is Controlled by the Transmembrane Sequence and Affects Signaling

    Directory of Open Access Journals (Sweden)

    Anna Oszmiana

    2016-05-01

    Full Text Available Super-resolution microscopy has revealed that immune cell receptors are organized in nanoscale clusters at cell surfaces and immune synapses. However, mechanisms and functions for this nanoscale organization remain unclear. Here, we used super-resolution microscopy to compare the surface organization of paired killer Ig-like receptors (KIR, KIR2DL1 and KIR2DS1, on human primary natural killer cells and cell lines. Activating KIR2DS1 assembled in clusters two-fold larger than its inhibitory counterpart KIR2DL1. Site-directed mutagenesis established that the size of nanoclusters is controlled by transmembrane amino acid 233, a lysine in KIR2DS1. Super-resolution microscopy also revealed two ways in which the nanoscale clustering of KIR affects signaling. First, KIR2DS1 and DAP12 nanoclusters are juxtaposed in the resting cell state but coalesce upon receptor ligation. Second, quantitative super-resolution microscopy revealed that phosphorylation of the kinase ZAP-70 or phosphatase SHP-1 is favored in larger KIR nanoclusters. Thus, the size of KIR nanoclusters depends on the transmembrane sequence and affects downstream signaling.

  16. μ Opioid Receptor Expression after Morphine Administration Is Regulated by miR-212/132 Cluster.

    Directory of Open Access Journals (Sweden)

    Adrian Garcia-Concejo

    Full Text Available Since their discovery, miRNAs have emerged as a promising therapeutical approach in the treatment of several diseases, as demonstrated by miR-212 and its relation to addiction. Here we prove that the miR-212/132 cluster can be regulated by morphine, through the activation of mu opioid receptor (Oprm1. The molecular pathways triggered after morphine administration also induce changes in the levels of expression of oprm1. In addition, miR-212/132 cluster is actively repressing the expression of mu opioid receptor by targeting a sequence in the 3' UTR of its mRNA. These findings suggest that this cluster is closely related to opioid signaling, and function as a post-transcriptional regulator, modulating morphine response in a dose dependent manner. The regulation of miR-212/132 cluster expression is mediated by MAP kinase pathway, CaMKII-CaMKIV and PKA, through the phosphorylation of CREB. Moreover, the regulation of both oprm1 and of the cluster promoter is mediated by MeCP2, acting as a transcriptional repressor on methylated DNA after prolonged morphine administration. This mechanism explains the molecular signaling triggered by morphine as well as the regulation of the expression of the mu opioid receptor mediated by morphine and the implication of miR-212/132 in these processes.

  17. The medaka novel immune-type receptor (NITR gene clusters reveal an extraordinary degree of divergence in variable domains

    Directory of Open Access Journals (Sweden)

    Litman Gary W

    2008-06-01

    Full Text Available Abstract Background Novel immune-type receptor (NITR genes are members of diversified multigene families that are found in bony fish and encode type I transmembrane proteins containing one or two extracellular immunoglobulin (Ig domains. The majority of NITRs can be classified as inhibitory receptors that possess cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs. A much smaller number of NITRs can be classified as activating receptors by the lack of cytoplasmic ITIMs and presence of a positively charged residue within their transmembrane domain, which permits partnering with an activating adaptor protein. Results Forty-four NITR genes in medaka (Oryzias latipes are located in three gene clusters on chromosomes 10, 18 and 21 and can be organized into 24 families including inhibitory and activating forms. The particularly large dataset acquired in medaka makes direct comparison possible to another complete dataset acquired in zebrafish in which NITRs are localized in two clusters on different chromosomes. The two largest medaka NITR gene clusters share conserved synteny with the two zebrafish NITR gene clusters. Shared synteny between NITRs and CD8A/CD8B is limited but consistent with a potential common ancestry. Conclusion Comprehensive phylogenetic analyses between the complete datasets of NITRs from medaka and zebrafish indicate multiple species-specific expansions of different families of NITRs. The patterns of sequence variation among gene family members are consistent with recent birth-and-death events. Similar effects have been observed with mammalian immunoglobulin (Ig, T cell antigen receptor (TCR and killer cell immunoglobulin-like receptor (KIR genes. NITRs likely diverged along an independent pathway from that of the somatically rearranging antigen binding receptors but have undergone parallel evolution of V family diversity.

  18. Duplicated Gephyrin Genes Showing Distinct Tissue Distribution and Alternative Splicing Patterns Mediate Molybdenum Cofactor Biosynthesis, Glycine Receptor Clustering, and Escape Behavior in Zebrafish*

    Science.gov (United States)

    Ogino, Kazutoyo; Ramsden, Sarah L.; Keib, Natalie; Schwarz, Günter; Harvey, Robert J.; Hirata, Hiromi

    2011-01-01

    Gephyrin mediates the postsynaptic clustering of glycine receptors (GlyRs) and GABAA receptors at inhibitory synapses and molybdenum-dependent enzyme (molybdoenzyme) activity in non-neuronal tissues. Gephyrin knock-out mice show a phenotype resembling both defective glycinergic transmission and molybdenum cofactor (Moco) deficiency and die within 1 day of birth due to starvation and dyspnea resulting from deficits in motor and respiratory networks, respectively. To address whether gephyrin function is conserved among vertebrates and whether gephyrin deficiency affects molybdoenzyme activity and motor development, we cloned and characterized zebrafish gephyrin genes. We report here that zebrafish have two gephyrin genes, gphna and gphnb. The former is expressed in all tissues and has both C3 and C4 cassette exons, and the latter is expressed predominantly in the brain and spinal cord and harbors only C4 cassette exons. We confirmed that all of the gphna and gphnb splicing isoforms have Moco synthetic activity. Antisense morpholino knockdown of either gphna or gphnb alone did not disturb synaptic clusters of GlyRs in the spinal cord and did not affect touch-evoked escape behaviors. However, on knockdown of both gphna and gphnb, embryos showed impairments in GlyR clustering in the spinal cord and, as a consequence, demonstrated touch-evoked startle response behavior by contracting antagonistic muscles simultaneously, instead of displaying early coiling and late swimming behaviors, which are executed by side-to-side muscle contractions. These data indicate that duplicated gephyrin genes mediate Moco biosynthesis and control postsynaptic clustering of GlyRs, thereby mediating key escape behaviors in zebrafish. PMID:20843816

  19. Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis.

    Science.gov (United States)

    Mohammadi, M; Dionne, C A; Li, W; Li, N; Spivak, T; Honegger, A M; Jaye, M; Schlessinger, J

    1992-08-20

    Stimulation of growth factor receptors with tyrosine kinase activity is followed by rapid receptor dimerization, tyrosine autophosphorylation and phosphorylation of signalling molecules such as phospholipase C gamma (PLC gamma) and the ras GTPase-activating protein. PLC gamma and GTPase-activating protein bind to specific tyrosine-phosphorylated regions in growth factor receptors through their src-homologous SH2 domains. Growth factor-induced tyrosine phosphorylation of PLC gamma is essential for stimulation of phosphatidylinositol hydrolysis in vitro and in vivo. We have shown that a short phosphorylated peptide containing tyrosine at position 766 from a conserved region of the fibroblast growth factor (FGF) receptor is a binding site for the SH2 domain of PLC gamma (ref. 8). Here we show that an FGF receptor point mutant in which Tyr 766 is replaced by a phenylalanine residue (Y766F) is unable to associate with and tyrosine-phosphorylate PLC gamma or to stimulate hydrolysis of phosphatidylinositol. Nevertheless, the Y766F FGF receptor mutant can be autophosphorylated, and can phosphorylate several cellular proteins and stimulate DNA synthesis. Our data show that phosphorylation of the conserved Tyr 766 of the FGF receptor is essential for phosphorylation of PLC gamma and for hydrolysis of phosphatidylinositol, but that elimination of this hydrolysis does not affect FGF-induced mitogenesis.

  20. Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope

    DEFF Research Database (Denmark)

    Iversen, Astrid K N; Stewart-Jones, Guillaume; Learn, Gerald H

    2006-01-01

    two principal, diametrically opposed evolutionary pathways that exclusively affect T cell-receptor contact residues. One pathway was characterized by acquisition of CTL escape mutations and the other by selection for wild-type amino acids. The pattern of CTL responses to epitope variants shaped which...

  1. Potentiation of gamma aminobutyric acid receptors (GABAAR by Ethanol: How are inhibitory receptors affected?

    Directory of Open Access Journals (Sweden)

    Benjamin eFörstera

    2016-05-01

    Full Text Available In recent years there has been an increase in the understanding of ethanol actions on the type A -aminobutyric acid chloride channel (GABAAR, a member of the pentameric ligand gated ion channels (pLGICs. However, the mechanism by which ethanol potentiates the complex is still not fully understood and a number of publications have shown contradictory results. Thus many questions still remain unresolved requiring further studies for a better comprehension of this effect. The present review concentrates on the involvement of GABAAR in the acute actions of ethanol and specifically focuses on the immediate, direct or indirect, synaptic and extra-synaptic modulatory effects. To elaborate on the immediate, direct modulation of GABAAR by acute ethanol exposure, electrophysiological studies investigating the importance of different subunits, and data from receptor mutants will be examined. We will also discuss the nature of the putative binding sites for ethanol based on structural data obtained from other members of the pLGICs family. Finally, we will briefly highlight the glycine gated chloride channel (GlyR, another member of the pLGIC family, as a suitable target for the development of new pharmacological tools.

  2. Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4

    DEFF Research Database (Denmark)

    Jen, Angela; Parkyn, Celia J; Mootoosamy, Roy C

    2010-01-01

    For infectious prion protein (designated PrP(Sc)) to act as a template to convert normal cellular protein (PrP(C)) to its distinctive pathogenic conformation, the two forms of prion protein (PrP) must interact closely. The neuronal receptor that rapidly endocytoses PrP(C) is the low......-density lipoprotein receptor-related protein 1 (LRP1). We show here that on sensory neurons LRP1 is also the receptor that binds and rapidly endocytoses smaller oligomeric forms of infectious prion fibrils, and recombinant PrP fibrils. Although LRP1 binds two molecules of most ligands independently to its receptor...... both prion and LRP1 biology....

  3. clusters

    Indian Academy of Sciences (India)

    2017-09-27

    Sep 27, 2017 ... Author for correspondence (zh4403701@126.com). MS received 15 ... lic clusters using density functional theory (DFT)-GGA of the DMOL3 package. ... In the process of geometric optimization, con- vergence thresholds ..... and Postgraduate Research & Practice Innovation Program of. Jiangsu Province ...

  4. clusters

    Indian Academy of Sciences (India)

    environmental as well as technical problems during fuel gas utilization. ... adsorption on some alloys of Pd, namely PdAu, PdAg ... ried out on small neutral and charged Au24,26,27, Cu,28 ... study of Zanti et al.29 on Pdn (n = 1–9) clusters.

  5. Randomised trial on episodic cluster headache with an angiotensin II receptor blocker

    DEFF Research Database (Denmark)

    Tronvik, Erling; Wienecke, Troels; Monstad, Inge

    2013-01-01

    OBJECTIVES: The aim of this study was to evaluate the angiotensin II receptor antagonist candesartan as prophylactic medication in patients with episodic cluster headache. METHODS: This study comprised a prospective, placebo-controlled, double-blind, parallel-designed trial performed in seven cen...... the candesartan and placebo group was not significant with the pre-planned non-parametric ranking test, but a post-hoc exact Poisson test, which takes into account the temporal properties of the data, revealed a significant result ( P  ...... (primary efficacy variable) during the three-week treatment period was reduced from 14.3 ± 9.2 attacks in week 1 to 5.6 ± 7.0 attacks in week 3 (-61%) in the candesartan group and from 16.8 ± 14.1 attacks in week 1 to 10.5 ± 11.3 attacks in week 3 (-38%) in the placebo group. The difference between...

  6. Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder.

    Science.gov (United States)

    Dikeos, D G; Papadimitriou, G N; Avramopoulos, D; Karadima, G; Daskalopoulou, E G; Souery, D; Mendlewicz, J; Vassilopoulos, D; Stefanis, C N

    1999-12-01

    Dopamine neurotransmission has been implicated in the pathophysiology of schizophrenia and, more recently, affective disorders. Among the dopamine receptors, D3 can be considered as particularly related to affective disorders due to its neuroanatomical localization in the limbic region of the brain and its relation to the serotoninergic activity of the CNS. The possible involvement of dopamine receptor D3 in unipolar (UP) major depression was investigated by a genetic association study of the D3 receptor gene locus (DRD3) on 36 UP patients and 38 ethnically matched controls. An allelic association of DRD3 (Bal I polymorphism) and UP illness was observed, with the Gly-9 allele (allele '2', 206/98 base-pairs long) being more frequent in patients than in controls (49% vs 29%, P < 0.02). The genotypes containing this allele (1-2 and 2-2) were found in 75% of patients vs 50% of controls (P < 0.03, odds ratio = 3.00, 95% CI = 1.12-8.05). The effect of the genotype remained significant (P < 0.02) after sex and family history were controlled by a multiple linear regression analysis. These results further support the hypothesis that dopaminergic mechanisms may be implicated in the pathogenesis of affective disorder. More specifically, the '2' allele of the dopamine receptor D3 gene seems to be associated with unipolar depression and can be considered as a 'phenotypic modifier' for major psychiatric disorders.

  7. T-cell triggering thresholds are modulated by the number of antigen within individual T-cell receptor clusters

    Energy Technology Data Exchange (ETDEWEB)

    Manz, Boryana N. [Howard Hughes Medical Inst., Chevy Chase, MD (United States); Univ. of California, Berkeley, CA (United States); Jackson, Bryan L. [Howard Hughes Medical Inst., Chevy Chase, MD (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Petit, Rebecca S. [Howard Hughes Medical Inst., Chevy Chase, MD (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Dustin, Michael L. [New York School of Medicine, New York, NY (United States); Groves, Jay [Howard Hughes Medical Inst., Chevy Chase, MD (United States); Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2011-05-31

    T cells react to extremely small numbers of activating agonist peptides. Spatial organization of T-cell receptors (TCR) and their peptide-major histocompatibility complex (pMHC) ligands into microclusters is correlated with T-cell activation. In this study, we have designed an experimental strategy that enables control over the number of agonist peptides per TCR cluster, without altering the total number engaged by the cell. Supported membranes, partitioned with grids of barriers to lateral mobility, provide an effective way of limiting the total number of pMHC ligands that may be assembled within a single TCR cluster. Observations directly reveal that restriction of pMHC content within individual TCR clusters can decrease T-cell sensitivity for triggering initial calcium flux at fixed total pMHC density. Further analysis suggests that triggering thresholds are determined by the number of activating ligands available to individual TCR clusters, not by the total number encountered by the cell. Results from a series of experiments in which the overall agonist density and the maximum number of agonist per TCR cluster are independently varied in primary T cells indicate that the most probable minimal triggering unit for calcium signaling is at least four pMHC in a single cluster for this system. In conclusion, this threshold is unchanged by inclusion of coagonist pMHC, but costimulation of CD28 by CD80 can modulate the threshold lower.

  8. TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.

    Science.gov (United States)

    Ji, Rui; Tian, Shifu; Lu, Helen J; Lu, Qingjun; Zheng, Yan; Wang, Xiaomin; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

    2013-12-15

    TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.

  9. The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44.

    Science.gov (United States)

    Allcock, Richard J N; Barrow, Alexander D; Forbes, Simon; Beck, Stephan; Trowsdale, John

    2003-02-01

    We have characterized a cluster of single immunoglobulin variable (IgV) domain receptors centromeric of the major histocompatibility complex (MHC) on human chromosome 6. In addition to triggering receptor expressed on myeloid cells (TREM)-1 and TREM2, the cluster contains NKp44, a triggering receptor whose expression is limited to NK cells. We identified three new related genes and two gene fragments within a cluster of approximately 200 kb. Two of the three new genes lack charged residues in their transmembrane domain tails. Further, one of the genes contains two potential immunotyrosine Inhibitory motifs in its cytoplasmic tail, suggesting that it delivers inhibitory signals. The human and mouse TREM clusters appear to have diverged such that there are unique sequences in each species. Finally, each gene in the TREM cluster was expressed in a different range of cell types.

  10. The Swedish Automotive Cluster : How will it be affected by foreign acquisitions at the end of the value chain?

    OpenAIRE

    Sundqvist, Helena

    2011-01-01

    In this master thesis it is analyzed how the Swedish automotive cluster will be affected by foreign acquisitions at the end of the value chain. This is a relevant topic as the Swedish automotive industry is a very important industry in Sweden. It is of interest to evaluate how the recent shifts of ownership for the Swedish automotive manufacturers will affect the Swedish automotive cluster as a whole. It is also relevant from a theoretical point of view and this thesis draws on the extensive ...

  11. Sequencing and transcriptional analysis of the Streptococcus thermophilus histamine biosynthesis gene cluster: factors that affect differential hdcA expression

    DEFF Research Database (Denmark)

    Calles-Enríquez, Marina; Hjort, Benjamin Benn; Andersen, Pia Skov

    2010-01-01

    to produce histamine. The hdc clusters of S. thermophilus CHCC1524 and CHCC6483 were sequenced, and the factors that affect histamine biosynthesis and histidine-decarboxylating gene (hdcA) expression were studied. The hdc cluster began with the hdcA gene, was followed by a transporter (hdcP), and ended...... with the hdcB gene, which is of unknown function. The three genes were orientated in the same direction. The genetic organization of the hdc cluster showed a unique organization among the lactic acid bacterial group and resembled those of Staphylococcus and Clostridium species, thus indicating possible...... acquisition through a horizontal transfer mechanism. Transcriptional analysis of the hdc cluster revealed the existence of a polycistronic mRNA covering the three genes. The histidine-decarboxylating gene (hdcA) of S. thermophilus demonstrated maximum expression during the stationary growth phase, with high...

  12. Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis.

    Science.gov (United States)

    Ward, Diane M; Chen, Opal S; Li, Liangtao; Kaplan, Jerry; Bhuiyan, Shah Alam; Natarajan, Selvamuthu K; Bard, Martin; Cox, James E

    2018-05-17

    Ergosterol synthesis is essential for cellular growth and viability of the budding yeast Saccharomyces cerevisiae, and intracellular sterol distribution and homeostasis are therefore highly regulated in this species. Erg25 is an iron-containing C4-methyl sterol oxidase that contributes to the conversion of 4,4-dimethylzymosterol to zymosterol, a precursor of ergosterol. The ERG29 gene encodes an endoplasmic reticulum (ER)-associated protein, and here we identified a role for Erg29 in the methyl sterol oxidase step of ergosterol synthesis. ERG29 deletion resulted in lethality in respiring cells, but respiration-incompetent (Rho- or Rho0) cells survived, suggesting that Erg29 loss leads to accumulation of oxidized sterol metabolites that affect cell viability. Down-regulation of ERG29 expression in Δerg29 cells indeed led to accumulation of methyl sterol metabolites, resulting in increased mitochondrial oxidants and a decreased ability of mitochondria to synthesize iron-sulfur (Fe-S) clusters due to reduced levels of Yfh1, the mammalian frataxin homolog, which is involved in mitochondrial Fe metabolism. Using a high-copy genomic library, we identified suppressor genes that permitted growth of Δerg29 cells on respiratory substrates, and these included genes encoding the mitochondrial proteins Yfh1, Mmt1, Mmt2, and Pet20, which reversed all phenotypes associated with loss of ERG29. Of note, loss of Erg25 also resulted in accumulation of methyl sterol metabolites and also increased mitochondrial oxidants and degradation of Yfh1. We propose that accumulation of toxic intermediates of the methyl sterol oxidase reaction increase mitochondrial oxidants, which affect Yfh1 protein stability. These results indicate an interaction between sterols generated by ER proteins and mitochondrial iron metabolism. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Vocal Affect Recognition and Psychopathy: Converging Findings Across Traditional and Cluster Analytic Approaches to Assessing the Construct

    Science.gov (United States)

    Bagley, Amy D.; Abramowitz, Carolyn S.; Kosson, David S.

    2010-01-01

    Deficits in emotion processing have been widely reported to be central to psychopathy. However, few prior studies have examined vocal affect recognition in psychopaths, and these studies suffer from significant methodological limitations. Moreover, prior studies have yielded conflicting findings regarding the specificity of psychopaths’ affect recognition deficits. This study examined vocal affect recognition in 107 male inmates under conditions requiring isolated prosodic vs. semantic analysis of affective cues and compared subgroups of offenders identified via cluster analysis on vocal affect recognition. Psychopaths demonstrated deficits in vocal affect recognition under conditions requiring use of semantic cues and conditions requiring use of prosodic cues. Moreover, both primary and secondary psychopaths exhibited relatively similar emotional deficits in the semantic analysis condition compared to nonpsychopathic control participants. This study demonstrates that psychopaths’ vocal affect recognition deficits are not due to methodological limitations of previous studies and provides preliminary evidence that primary and secondary psychopaths exhibit generally similar deficits in vocal affect recognition. PMID:19413412

  14. Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein-Coupled Receptor 120

    DEFF Research Database (Denmark)

    Prihandoko, Rudi; Alvarez-Curto, Elisa; Hudson, Brian D

    2016-01-01

    of these phosphoacceptor sites to alanine completely prevented phosphorylation of mFFA4 but did not limit receptor coupling to extracellular signal regulated protein kinase 1 and 2 (ERK1/2) activation. Rather, an inhibitor of Gq/11proteins completely prevented receptor signaling to ERK1/2. By contrast, the recruitment...... activation. These unique observations define differential effects on signaling mediated by phosphorylation at distinct locations. This hallmark feature supports the possibility that the signaling outcome of mFFA4 activation can be determined by the pattern of phosphorylation (phosphorylation barcode...

  15. Medicinal utility of boron clusters. Receptor modulators bearing carborane as a hydrophobic pharmacophore

    International Nuclear Information System (INIS)

    Endo, Y.; Iijima, T.; Yaguchi, K.; Yoshimi, T.; Yamakoshi, Y.; Kawachi, E.; Kagechika, H.

    2000-01-01

    The hydrophobic character and spherical geometry of carboranes may allow their use as a hydrophobic pharmacophore in biologically active molecules. We report potent cellular nuclear receptor ligands with carborane such as retinoids and estrogens. These receptor ligands raise the possibility for therapeutic agents, and their membrane transport characteristics and concentration in cellular nucleus may provide potential use for BNCT. (author)

  16. Molecular basis of the γ-aminobutyric acid A receptor α3 subunit interaction with the clustering protein gephyrin

    DEFF Research Database (Denmark)

    Tretter, Verena; Kerschner, Bernd; Milenkovic, Ivan

    2011-01-01

    The multifunctional scaffolding protein gephyrin is a key player in the formation of the postsynaptic scaffold at inhibitory synapses, clustering both inhibitory glycine receptors (GlyRs) and selected GABA(A) receptor (GABA(A)R) subtypes. We report a direct interaction between the GABA(A)R α3...... subunit and gephyrin, mapping reciprocal binding sites using mutagenesis, overlay, and yeast two-hybrid assays. This analysis reveals that critical determinants of this interaction are located in the motif FNIVGTTYPI in the GABA(A)R α3 M3-M4 domain and the motif SMDKAFITVL at the N terminus...... of the gephyrin E domain. GABA(A)R α3 gephyrin binding-site mutants were unable to co-localize with endogenous gephyrin in transfected hippocampal neurons, despite being able to traffic to the cell membrane and form functional benzodiazepine-responsive GABA(A)Rs in recombinant systems. Interestingly, motifs...

  17. Corticotropin-Releasing Hormone Receptor Type 1 (CRHR1 Clustering with MAGUKs Is Mediated via Its C-Terminal PDZ Binding Motif.

    Directory of Open Access Journals (Sweden)

    Julia Bender

    Full Text Available The corticotropin-releasing hormone receptor type 1 (CRHR1 plays an important role in orchestrating neuroendocrine, behavioral, and autonomic responses to stress. To identify molecules capable of directly modulating CRHR1 signaling, we performed a yeast-two-hybrid screen using the C-terminal intracellular tail of the receptor as bait. We identified several members of the membrane-associated guanylate kinase (MAGUK family: postsynaptic density protein 95 (PSD95, synapse-associated protein 97 (SAP97, SAP102 and membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2. CRHR1 is co-expressed with the identified MAGUKs and with the additionally investigated PSD93 in neurons of the adult mouse brain and in primary hippocampal neurons, supporting the probability of a physiological interaction in vivo. The C-terminal PDZ (PSD-95, discs large, zona occludens 1 binding motif of CRHR1 is essential for its physical interaction with MAGUKs, as revealed by the CRHR1-STAVA mutant, which harbors a functionally impaired PDZ binding motif. The imitation of a phosphorylation at Thr413 within the PDZ binding motif also disrupted the interaction with MAGUKs. In contrast, distinct PDZ domains within the identified MAGUKs are involved in the interactions. Expression of CRHR1 in primary neurons demonstrated its localization throughout the neuronal plasma membrane, including the excitatory post synapse, where the receptor co-localized with PSD95 and SAP97. The co-expression of CRHR1 and respective interacting MAGUKs in HEK293 cells resulted in a clustered subcellular co-localization which required an intact PDZ binding motif. In conclusion, our study characterized the PDZ binding motif-mediated interaction of CRHR1 with multiple MAGUKs, which directly affects receptor function.

  18. Multivariate cluster analysis of dynamic iodine-123 iodobenzamide SPET dopamine D{sub 2}receptor images in schizophrenia

    Energy Technology Data Exchange (ETDEWEB)

    Acton, P.D. [Inst. of Nuclear Medicine, Univ. Coll. London Medical School, London (United Kingdom); Pilowsky, L.S. [Institute of Psychiatry, London (United Kingdom); Costa, D.C. [Inst. of Nuclear Medicine, Univ. Coll. London Medical School, London (United Kingdom); Ell, P.J. [Inst. of Nuclear Medicine, Univ. Coll. London Medical School, London (United Kingdom)

    1997-02-01

    This paper describes the application of a multivariate statistical technique to investigate striatal dopamine D{sub 2}receptor concentrations measured by iodine-123 iodobenzamide ({sup 123}I-IBZM) single-photon emission tomography (SPET). This technique enables the automatic segmentation of dynamic nuclear medicine images based on the underlying time-activity curves present in the data. Once the time-activity curves have been extracted, each pixel can be mapped back on to the underlying distribution, considerably reducing image noise. Cluster analysis has been verified using computer simulations and phantom studies. The technique has been applied to SPET images of dopamine D {sub 2}receptors in a total of 20 healthy and 20 schizophrenic volunteers (22 male, 18 female), using the ligand {sup 123}I-IBZM. Following automatic image segmentation, the concentration of striatal dopamine D {sub 2}receptors shows a significant left-sided asymmetry in male schizophrenics compared with male controls. The mean left-minus-right laterality index for controls is -1.52 (95% CI -3.72-0.66) and for patients 4.04 (95% CI 1.07-7.01). Analysis of variance shows a case-by-sex-by-side interaction, with F=10.01, P=0.005. We can now demonstrate that the previously observed male sex-specific D {sub 2}receptor asymmetry in schizophrenia, which had failed to attain statistical significance, is valid. Cluster analysis of dynamic nuclear medicine studies provides a powerful tool for automatic segmentation and noise reduction of the images, removing much of the subjectivity inherent in region-of-interest analysis. The observed striatal D {sub 2}asymmetry could reflect long hypothesized disruptions in dopamine-rich cortico-striatal-limbic circuits in schizophrenic males. (orig.). With 4 figs., 2 tabs.

  19. Large-scale dynamics associated with clustering of extratropical cyclones affecting Western Europe

    OpenAIRE

    Pinto, Joaquim G.; Gómara, Iñigo; Masato, Giacomo; Dacre, Helen F.; Woollings, Tim; Caballero, Rodrigo

    2014-01-01

    Some recent winters in Western Europe have been characterized by the occurrence of multiple extratropical cyclones following a similar path. The occurrence of such cyclone clusters leads to large socio-economic impacts due to damaging winds, storm surges, and floods. Recent studies have statistically characterized the clustering of extratropical cyclones over the North Atlantic and Europe and hypothesized potential physical mechanisms responsible for their formation. Here we analyze 4 months ...

  20. Endocrine disruptors induce cytochrome P450 by affecting transcriptional regulation via pregnane X receptor

    International Nuclear Information System (INIS)

    Mikamo, Eriko; Harada, Shingo; Nishikawa, Jun-ichi; Nishihara, Tsutomu

    2003-01-01

    Pregnane X receptor (PXR) is a nuclear receptor that regulates the expression of genes for cytochrome P450 3A (CYP3A), multidrug resistance 1 (MDR1), and organic anion-transporting peptide 2 (OATP2). These genes control the metabolism (CYP3A subfamily) and aspects of the pharmacokinetics (MDR1 and OATP2) of both endogenous and xenobiotic compounds. Since PXR is important in understanding the actions of endocrine disruptors (EDs), we determined the ability of suspected EDs to interact with PXR. In our study, 7 of 54 xenobiotics compounds interacted with PXR, including methoxychlor and benzophenone. All of the chemicals activated PXR in vitro and induced CYP3A mRNA in the male rat liver. In addition, CYP2C11 was also induced by some PXR agonists and converted methoxychlor into xenoestrogen. These findings suggest that some EDs affect sex hormone receptor indirectly by induction of metabolic enzyme via PXR, to produce rapidly higher concentrations of effective metabolites, leading to disturbance of the endocrine system

  1. Dopamine D4 Receptor Polymorphism and Sex Interact to Predict Children's Affective Knowledge

    Directory of Open Access Journals (Sweden)

    Sharon eBen-Israel

    2015-06-01

    Full Text Available Affective knowledge, the ability to understand others’ emotional states, is considered to be a fundamental part in efficient social interaction. Affective knowledge can be seen as related to cognitive empathy, and in the framework of Theory of Mind (ToM as affective ToM. Previous studies found that cognitive empathy and ToM are heritable, yet little is known regarding the specific genes involved in individual variability in affective knowledge. Investigating the genetic basis of affective knowledge is important for understanding brain mechanisms underlying socio-cognitive abilities. The 7-repeat (7R allele within the third exon of the Dopamine D4 receptor gene (DRD4-III has been a focus of interest, due to accumulated knowledge regarding its relevance to individual differences in prosocial behavior. A recent study suggests that an interaction between the DRD4-III polymorphism and sex is associated with cognitive empathy among adults. We aimed to examine the same association in two childhood age groups. Children (N = 280, age 3.5 years, N = 283, age 5 years participated as part of the Longitudinal Israel Study of Twins (LIST. Affective knowledge was assessed through children’s responses to an illustrated story describing different emotional situations, told in a laboratory setting. The findings suggest a significant interaction between sex and the DRD4-III polymorphism, replicated in both age groups. Boy carriers of the 7R allele had higher affective knowledge scores than girls, whereas in the absence of the 7R there was no significant sex effect on affective knowledge. The results support the importance of DRD4-III polymorphism and sex differences to social development. Possible explanations for differences from adult findings are discussed, as are pathways for future studies.

  2. Parameters that affect parallel processing for computational electromagnetic simulation codes on high performance computing clusters

    Science.gov (United States)

    Moon, Hongsik

    changing computer hardware platforms in order to provide fast, accurate and efficient solutions to large, complex electromagnetic problems. The research in this dissertation proves that the performance of parallel code is intimately related to the configuration of the computer hardware and can be maximized for different hardware platforms. To benchmark and optimize the performance of parallel CEM software, a variety of large, complex projects are created and executed on a variety of computer platforms. The computer platforms used in this research are detailed in this dissertation. The projects run as benchmarks are also described in detail and results are presented. The parameters that affect parallel CEM software on High Performance Computing Clusters (HPCC) are investigated. This research demonstrates methods to maximize the performance of parallel CEM software code.

  3. Lateral septum growth hormone secretagogue receptor affects food intake and motivation for sucrose reinforcement.

    Science.gov (United States)

    Terrill, Sarah J; Wall, Kaylee D; Medina, Nelson D; Maske, Calyn B; Williams, Diana L

    2018-03-28

    The hormone ghrelin promotes eating and is widely considered to be a hunger signal. Ghrelin receptors, growth hormone secretagogue receptors (GHSRs), are found in a number of specific regions throughout the brain, including the lateral septum (LS), an area not traditionally associated with the control of feeding. Here we investigated whether GHSRs in the LS play a role in the control of food intake. We examined the feeding effects of ghrelin and the GHSR antagonists ([D-Lys3]-GHRP-6 and JMV 2959), at doses subthreshold for effect when delivered to the lateral ventricle. Intra-LS ghrelin significantly increased chow intake during the mid-light phase, suggesting that pharmacologic activation of LS GHSRs promotes feeding. Conversely, GHSR antagonist delivered to the LS shortly before dark onset significantly reduced chow intake. These data support the hypothesis that exogenous and endogenous stimulation of GHSRs in the LS influence feeding. Ghrelin is known to affect motivation for food, and the dorsal subdivision of LS (dLS) has been shown to play a role in motivation. Thus, we investigated the role of dLS GHSRs in motivation for food reward by examining operant responding for sucrose on a progressive ratio (PR) schedule. Intra-dLS ghrelin increased PR responding for sucrose, while blockade of LS GHSRs did not affect responding in either a fed or fasted state. Together these findings for the first time substantiate the LS as a site of action for ghrelin signaling in the control of food intake.

  4. Rationale and design of the Affordability and Real-world Antiplatelet Treatment Effectiveness after Myocardial Infarction Study (ARTEMIS): A multicenter, cluster-randomized trial of P2Y12 receptor inhibitor copayment reduction after myocardial infarction.

    Science.gov (United States)

    Doll, Jacob A; Wang, Tracy Y; Choudhry, Niteesh K; Cannon, Christopher P; Cohen, David J; Fonarow, Gregg C; Henry, Timothy D; Bhandary, Durgesh D; Khan, Naeem; Davidson-Ray, Linda D; Anstrom, Kevin; Peterson, Eric D

    2016-07-01

    The use of oral P2Y12 receptor inhibitors after acute myocardial infarction (MI) can reduce risks of subsequent major adverse cardiovascular events (composite of all-cause death, recurrent MI, and stroke), yet medication persistence is suboptimal. Although copayment cost has been implicated as a factor influencing medication persistence, it remains unclear whether reducing or eliminating these costs can improve medication persistence and/or downstream clinical outcomes. ARTEMIS is a multicenter, cluster-randomized clinical trial designed to examine whether eliminating patient copayment for P2Y12 receptor inhibitor therapy affects medication persistence and clinical outcomes. We will enroll approximately 11,000 patients hospitalized for acute ST-elevation and non-ST-elevation MI at 300 hospitals. Choice and duration of treatment with a P2Y12 receptor inhibitor will be determined by the treating physician. Hospitals randomized to the copayment intervention will provide vouchers to cover patients' copayments for their P2Y12 receptor inhibitor for up to 1 year after discharge. The coprimary end points are 1-year P2Y12 receptor inhibitor persistence and major adverse cardiovascular events. Secondary end points include choice of P2Y12 receptor inhibitor, patient-reported outcomes, and postdischarge cost of care. ARTEMIS will be the largest randomized assessment of a medication copayment reduction intervention on medication persistence, clinical outcomes, treatment selection, and cost of care after acute MI. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Large-scale dynamics associated with clustering of extratropical cyclones affecting Western Europe

    Science.gov (United States)

    Pinto, Joaquim G.; Gómara, Iñigo; Masato, Giacomo; Dacre, Helen F.; Woollings, Tim; Caballero, Rodrigo

    2015-04-01

    Some recent winters in Western Europe have been characterized by the occurrence of multiple extratropical cyclones following a similar path. The occurrence of such cyclone clusters leads to large socio-economic impacts due to damaging winds, storm surges, and floods. Recent studies have statistically characterized the clustering of extratropical cyclones over the North Atlantic and Europe and hypothesized potential physical mechanisms responsible for their formation. Here we analyze 4 months characterized by multiple cyclones over Western Europe (February 1990, January 1993, December 1999, and January 2007). The evolution of the eddy driven jet stream, Rossby wave-breaking, and upstream/downstream cyclone development are investigated to infer the role of the large-scale flow and to determine if clustered cyclones are related to each other. Results suggest that optimal conditions for the occurrence of cyclone clusters are provided by a recurrent extension of an intensified eddy driven jet toward Western Europe lasting at least 1 week. Multiple Rossby wave-breaking occurrences on both the poleward and equatorward flanks of the jet contribute to the development of these anomalous large-scale conditions. The analysis of the daily weather charts reveals that upstream cyclone development (secondary cyclogenesis, where new cyclones are generated on the trailing fronts of mature cyclones) is strongly related to cyclone clustering, with multiple cyclones developing on a single jet streak. The present analysis permits a deeper understanding of the physical reasons leading to the occurrence of cyclone families over the North Atlantic, enabling a better estimation of the associated cumulative risk over Europe.

  6. Genome scan identifies a locus affecting gamma-globin expression in human beta-cluster YAC transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Lin, S.D.; Cooper, P.; Fung, J.; Weier, H.U.G.; Rubin, E.M.

    2000-03-01

    Genetic factors affecting post-natal g-globin expression - a major modifier of the severity of both b-thalassemia and sickle cell anemia, have been difficult to study. This is especially so in mice, an organism lacking a globin gene with an expression pattern equivalent to that of human g-globin. To model the human b-cluster in mice, with the goal of screening for loci affecting human g-globin expression in vivo, we introduced a human b-globin cluster YAC transgene into the genome of FVB mice . The b-cluster contained a Greek hereditary persistence of fetal hemoglobin (HPFH) g allele resulting in postnatal expression of human g-globin in transgenic mice. The level of human g-globin for various F1 hybrids derived from crosses between the FVB transgenics and other inbred mouse strains was assessed. The g-globin level of the C3HeB/FVB transgenic mice was noted to be significantly elevated. To map genes affecting postnatal g-globin expression, a 20 centiMorgan (cM) genome scan of a C3HeB/F VB transgenics [prime] FVB backcross was performed, followed by high-resolution marker analysis of promising loci. From this analysis we mapped a locus within a 2.2 cM interval of mouse chromosome 1 at a LOD score of 4.2 that contributes 10.4% of variation in g-globin expression level. Combining transgenic modeling of the human b-globin gene cluster with quantitative trait analysis, we have identified and mapped a murine locus that impacts on human g-globin expression in vivo.

  7. Gene structure and expression characteristic of a novel odorant receptor gene cluster in the parasitoid wasp Microplitis mediator (Hymenoptera: Braconidae).

    Science.gov (United States)

    Wang, S-N; Shan, S; Zheng, Y; Peng, Y; Lu, Z-Y; Yang, Y-Q; Li, R-J; Zhang, Y-J; Guo, Y-Y

    2017-08-01

    Odorant receptors (ORs) expressed in the antennae of parasitoid wasps are responsible for detection of various lipophilic airborne molecules. In the present study, 107 novel OR genes were identified from Microplitis mediator antennal transcriptome data. Phylogenetic analysis of the set of OR genes from M. mediator and Microplitis demolitor revealed that M. mediator OR (MmedOR) genes can be classified into different subfamilies, and the majority of MmedORs in each subfamily shared high sequence identities and clear orthologous relationships to M. demolitor ORs. Within a subfamily, six MmedOR genes, MmedOR98, 124, 125, 126, 131 and 155, shared a similar gene structure and were tightly linked in the genome. To evaluate whether the clustered MmedOR genes share common regulatory features, the transcription profile and expression characteristics of the six closely related OR genes were investigated in M. mediator. Rapid amplification of cDNA ends-PCR experiments revealed that the OR genes within the cluster were transcribed as single mRNAs, and a bicistronic mRNA for two adjacent genes (MmedOR124 and MmedOR98) was also detected in female antennae by reverse transcription PCR. In situ hybridization experiments indicated that each OR gene within the cluster was expressed in a different number of cells. Moreover, there was no co-expression of the two highly related OR genes, MmedOR124 and MmedOR98, which appeared to be individually expressed in a distinct population of neurons. Overall, there were distinct expression profiles of closely related MmedOR genes from the same cluster in M. mediator. These data provide a basic understanding of the olfactory coding in parasitoid wasps. © 2017 The Royal Entomological Society.

  8. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines

    International Nuclear Information System (INIS)

    Maneckjee, R.; Minna, J.D.

    1990-01-01

    Using specific radioactively-labeled ligands, the authors find that lung cancer cell lines of diverse histologic types express multiple, high-affinity membrane receptors for μ, δ, and κ opioid agonists and for nicotine and α-bungarotoxin. These receptors are biologically active because cAMP levels decreased in lung cancer cells after opioid and nicotine application. Nicotine at concentrations found in the blood of smokers had no effect on in vitro lung cancer cell growth, whereas μ, δ, and κ opioid agonists at low concentrations inhibited lung cancer growth in vitro. They also found that lung cancer cells expressed various combinations of immunoreactive opioid peptides (β-endorphin, enkephalin, or dynorphin), suggesting the participation of opioids in a negative autocrine loop or tumor-suppressing system. Due to the almost universal exposure of patients with lung cancer to nicotine, they tested whether nicotine affected the response of lung cancer cell growth to opioids and found that nicotine at concentrations of 100-200 nM partially or totally reversed opioid-induced growth inhibition in 9/14 lung cancer cell lines. These in vitro results for lung cancer cells suggest that opioids could function as part of a tumor suppressor system and that nicotine can function to circumvent this system in the pathogenesis of lung cancer

  9. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Maneckjee, R.; Minna, J.D. (National Cancer Institute-Navy Medical Oncology Branch, Bethesda, MD (USA) Uniformed Services Univ. of the Health Sciences, Bethesda, MD (USA))

    1990-05-01

    Using specific radioactively-labeled ligands, the authors find that lung cancer cell lines of diverse histologic types express multiple, high-affinity membrane receptors for {mu}, {delta}, and {kappa} opioid agonists and for nicotine and {alpha}-bungarotoxin. These receptors are biologically active because cAMP levels decreased in lung cancer cells after opioid and nicotine application. Nicotine at concentrations found in the blood of smokers had no effect on in vitro lung cancer cell growth, whereas {mu}, {delta}, and {kappa} opioid agonists at low concentrations inhibited lung cancer growth in vitro. They also found that lung cancer cells expressed various combinations of immunoreactive opioid peptides ({beta}-endorphin, enkephalin, or dynorphin), suggesting the participation of opioids in a negative autocrine loop or tumor-suppressing system. Due to the almost universal exposure of patients with lung cancer to nicotine, they tested whether nicotine affected the response of lung cancer cell growth to opioids and found that nicotine at concentrations of 100-200 nM partially or totally reversed opioid-induced growth inhibition in 9/14 lung cancer cell lines. These in vitro results for lung cancer cells suggest that opioids could function as part of a tumor suppressor system and that nicotine can function to circumvent this system in the pathogenesis of lung cancer.

  10. Evolution of the C-Type Lectin-Like Receptor Genes of the DECTIN-1 Cluster in the NK Gene Complex

    Directory of Open Access Journals (Sweden)

    Susanne Sattler

    2012-01-01

    Full Text Available Pattern recognition receptors are crucial in initiating and shaping innate and adaptive immune responses and often belong to families of structurally and evolutionarily related proteins. The human C-type lectin-like receptors encoded in the DECTIN-1 cluster within the NK gene complex contain prominent receptors with pattern recognition function, such as DECTIN-1 and LOX-1. All members of this cluster share significant homology and are considered to have arisen from subsequent gene duplications. Recent developments in sequencing and the availability of comprehensive sequence data comprising many species showed that the receptors of the DECTIN-1 cluster are not only homologous to each other but also highly conserved between species. Even in Caenorhabditis elegans, genes displaying homology to the mammalian C-type lectin-like receptors have been detected. In this paper, we conduct a comprehensive phylogenetic survey and give an up-to-date overview of the currently available data on the evolutionary emergence of the DECTIN-1 cluster genes.

  11. Non-neural androgen receptors affect sexual differentiation of brain and behaviour.

    Science.gov (United States)

    Monks, D A; Swift-Gallant, A

    2018-02-01

    Although gonadal testosterone is the principal endocrine factor that promotes masculine traits in mammals, the development of a male phenotype requires local production of both androgenic and oestrogenic signals within target tissues. Much of our knowledge concerning androgenic components of testosterone signalling in sexual differentiation comes from studies of androgen receptor (Ar) loss of function mutants. Here, we review these studies of loss of Ar function and of AR overexpression either globally or selectively in the nervous system of mice. Global and neural mutations affect socio-sexual behaviour and the neuroanatomy of these mice in a sexually differentiated manner. Some masculine traits are affected by both global and neural mutation, indicative of neural mediation, whereas other masculine traits are affected only by global mutation, indicative of an obligatory non-neural androgen target. These results support a model in which multiple sites of androgen action coordinate to produce masculine phenotypes. Furthermore, AR overexpression does not always have a phenotype opposite to that of loss of Ar function mutants, indicative of a nonlinear relationship between androgen dose and masculine phenotype in some cases. Potential mechanisms of Ar gene function in non-neural targets in producing masculine phenotypes are discussed. © 2017 British Society for Neuroendocrinology.

  12. The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

    Directory of Open Access Journals (Sweden)

    Daniel Navin Olschewski

    2018-03-01

    Full Text Available Background/Aims: The peptide hormone angiotensin II (ATII plays a prominent role in regulating vasoconstriction and blood pressure. Its primary target is the angiotensin II receptor type 1 (AT1, the stimulation of which induces an increase in cytosolic [Ca2+] and calmodulin activation. Ca2+-bound (activated calmodulin stimulates the activity of the Na+/ H+ exchanger isoform 1 (NHE1; and increased NHE1 activity is known to promote melanoma cell motility. The competitive AT1 receptor inhibitor losartan is often used to lower blood pressure in hypertensive patients. Since AT1 mediates ATII-stimulated NHE1 activity, we set out to investigate whether ATII and losartan have an impact on NHE1-dependent behavior of human melanoma (MV3 cells. Methods: ATII receptor expression was verified by PCR, F-actin was visualized using fluorescently labeled phalloidin, and cytosolic [Ca2+] and pH were determined ratiometrically using Fura-2 and BCECF, respectively. MV3 cell behavior was analyzed using migration, adhesion, invasion and proliferation assays. Results: MV3 cells express both AT1 and the angiotensin II receptor type 2 (AT2. Stimulation of MV3 cells with ATII increased NHE1 activity which could be counteracted by both losartan and the Ca2+/ calmodulin inhibitor ophiobolin-A. ATII stimulation induced a decrease in MV3 cell migration and a more spherical cell morphology accompanied by an increase in the density of F-actin. Independently of the presence of ATII, both NHE1 and migratory activity were reduced when AT1 was blocked by losartan. On the other hand, losartan clearly increased cell adhesion to, and the invasion of, a collagen type I substrate. The AT2 inhibitor PD123319 did not affect NHE1 activity, proliferation and migration, but increased adhesion and invasion. Conclusion: Losartan inhibits NHE1 activity and the migration of human melanoma cells. At the same time, losartan promotes MV3 cell adhesion and invasion. The therapeutic use of AT1

  13. 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.

  14. How does stress affect human being—a molecular dynamic simulation study on cortisol and its glucocorticoid receptor

    Directory of Open Access Journals (Sweden)

    Dan Zhang

    2017-03-01

    Full Text Available Stress can be either positive or negative to human beings. Under stressful conditions, the mental and physical conditions of human can be affected. There exists certain relation between stress and illness. The cortisol and other glucocorticoids bind to the same receptor, which is called glucocorticoid receptor. Some evidences indicated that cortisol molecule binding to its glucocorticoid receptor was necessary for the stress response. Up to now, the structure–function relationships between cortisol molecule and its glucocorticoid receptor have not been deliberated from the atomic-level. In order to get a detailed understanding of the structure–function relationships between the cortisol molecule and glucocorticoids receptor, we have carried out molecular dynamic (MD simulations on glucocorticoid receptor (Apo system and cortisol with its glucocorticoid receptor complex (HCY system. On the basis of molecular dynamic simulations, a couple of key residues were identified, which were crucial for the binding of cortisol molecule. The results of binding free energy calculations are in good agreement with the experiment data. Our research gives clear insights from atomic-level into the structural–functional aspects of cortisol molecule and its glucocorticoid receptor, and also provides valuable information for the design of drug which can treat stress related illnesses.

  15. Functional characterization of bursicon receptor and genome-wide analysis for identification of genes affected by bursicon receptor RNAi

    Science.gov (United States)

    Bai, Hua; Palli, Subba R.

    2010-01-01

    Bursicon is an insect neuropeptide hormone that is secreted from the central nervous system into the hemolymph and initiates cuticle tanning. The receptor for bursicon is encoded by the rickets (rk) gene and belongs to the G protein-coupled receptor (GPCR) superfamily. The bursicon and its receptor regulate cuticle tanning as well as wing expansion after adult eclosion. However, the molecular action of bursicon signaling remains unclear. We utilized RNA interference (RNAi) and microarray to study the function of the bursicon receptor (Tcrk) in the model insect, Tribolium castaneum. The data included here showed that in addition to cuticle tanning and wing expansion reported previously, Tcrk is also required for development and expansion of integumentary structures and adult eclosion. Using custom microarrays, we identified 24 genes that are differentially expressed between Tcrk RNAi and control insects. Knockdown in the expression of one of these genes, TC004091, resulted in the arrest of adult eclosion. Identification of genes that are involved in bursicon receptor mediated biological processes will provide tools for future studies on mechanisms of bursicon action. PMID:20457145

  16. Induced formation and maturation of acetylcholine receptor clusters in a defined 3D bio-artificial muscle.

    Science.gov (United States)

    Wang, Lin; Shansky, Janet; Vandenburgh, Herman

    2013-12-01

    Dysfunction of the neuromuscular junction is involved in a wide range of muscular diseases. The development of neuromuscular junction through which skeletal muscle is innervated requires the functional modulation of acetylcholine receptor (AchR) clustering on myofibers. However, studies on AchR clustering in vitro are mostly done on monolayer muscle cell culture, which lacks a three-dimensional (3D) structure, a prominent limitation of the two-dimensional (2D) system. To enable a better understanding on the structure-function correlation underlying skeletal muscle innervation, a muscle system with a well-defined geometry mimicking the in vivo muscular setting is needed. Here, we report a 3D bio-artificial muscle (BAM) bioengineered from green fluorescent protein-transduced C3H murine myoblasts as a novel in vitro tissue-based model for muscle innervation studies. Our cell biological and molecular analysis showed that this BAM is structurally similar to in vivo muscle tissue and can reach the perinatal differentiation stage, higher than does 2D culture. Effective clustering and morphological maturation of AchRs on BAMs induced by agrin and laminin indicate the functional activity and plasticity of this BAM system toward innervation. Taken together, our results show that the BAM provides a favorable 3D environment that at least partially recapitulates real physiological skeletal muscle with regard to innervation. With a convenience of fabrication and manipulation, this 3D in vitro system offers a novel model for studying mechanisms underlying skeletal muscle innervation and testing therapeutic strategies for relevant nervous and muscular diseases.

  17. Revealing dynamically-organized receptor ion channel clusters in live cells by a correlated electric recording and super-resolution single-molecule imaging approach.

    Science.gov (United States)

    Yadav, Rajeev; Lu, H Peter

    2018-03-28

    The N-methyl-d-aspartate (NMDA) receptor ion-channel is activated by the binding of ligands, along with the application of action potential, important for synaptic transmission and memory functions. Despite substantial knowledge of the structure and function, the gating mechanism of the NMDA receptor ion channel for electric on-off signals is still a topic of debate. We investigate the NMDA receptor partition distribution and the associated channel's open-close electric signal trajectories using a combined approach of correlating single-molecule fluorescence photo-bleaching, single-molecule super-resolution imaging, and single-channel electric patch-clamp recording. Identifying the compositions of NMDA receptors, their spatial organization and distributions over live cell membranes, we observe that NMDA receptors are organized inhomogeneously: nearly half of the receptor proteins are individually dispersed; whereas others exist in heterogeneous clusters of around 50 nm in size as well as co-localized within the diffraction limited imaging area. We demonstrate that inhomogeneous interactions and partitions of the NMDA receptors can be a cause of the heterogeneous gating mechanism of NMDA receptors in living cells. Furthermore, comparing the imaging results with the ion-channel electric current recording, we propose that the clustered NMDA receptors may be responsible for the variation in the current amplitude observed in the on-off two-state ion-channel electric signal trajectories. Our findings shed new light on the fundamental structure-function mechanism of NMDA receptors and present a conceptual advancement of the ion-channel mechanism in living cells.

  18. Interactions between polymorphisms in the aryl hydrocarbon receptor signalling pathway and exposure to persistent organochlorine pollutants affect human semen quality

    DEFF Research Database (Denmark)

    Brokken, L J S; Lundberg, P J; Spanò, M

    2014-01-01

    Persistent organic pollutants (POPs) may affect male reproductive function. Many dioxin-like POPs exert their effects by activation of the aryl hydrocarbon receptor (AHR) signalling pathway. We analysed whether gene-environment interactions between polymorphisms in AHR (R554K) and AHR repressor (...

  19. Naturally occurring variants of human Α9 nicotinic receptor differentially affect bronchial cell proliferation and transformation.

    Directory of Open Access Journals (Sweden)

    Anna Chikova

    Full Text Available Isolation of polyadenilated mRNA from human immortalized bronchial epithelial cell line BEP2D revealed the presence of multiple isoforms of RNA coded by the CHRNA9 gene for α9 nicotinic acetylcholine receptor (nAChR. BEP2D cells were homozygous for the rs10009228 polymorphism encoding for N442S amino acid substitution, and also contained mRNA coding for several truncated isoforms of α9 protein. To elucidate the biologic significance of the naturally occurring variants of α9 nAChR, we compared the biologic effects of overexpression of full-length α9 N442 and S442 proteins, and the truncated α9 variant occurring due to a loss of the exon 4 sequence that causes frame shift and early termination of the translation. These as well as control vector were overexpressed in the BEP2D cells that were used in the assays of proliferation rate, spontaneous vs. tobacco nitrosamine 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK-induced cellular transformation, and tumorigenicity in cell culture and mice. Overexpression of the S442 variant significantly increased cellular proliferation, and spontaneous and NNK-induced transformation. The N442 variant significantly decreased cellular transformation, without affecting proliferation rate. Overexpression of the truncated α9 significantly decreased proliferation and suppressed cellular transformation. These results suggested that α9 nAChR plays important roles in regulation of bronchial cell growth by endogenous acetylcholine and exogenous nicotine, and susceptibility to NNK-induced carcinogenic transformation. The biologic activities of α9 nAChR may be regulated at the splicing level, and genetic polymorphisms in CHRNA9 affecting protein levels, amino acid sequence and RNA splicing may influence the risk for lung cancer.

  20. LRRK2 affects vesicle trafficking, neurotransmitter extracellular level and membrane receptor localization.

    Directory of Open Access Journals (Sweden)

    Rossana Migheli

    Full Text Available The leucine-rich repeat kinase 2 (LRRK2 gene was found to play a role in the pathogenesis of both familial and sporadic Parkinson's disease (PD. LRRK2 encodes a large multi-domain protein that is expressed in different tissues. To date, the physiological and pathological functions of LRRK2 are not clearly defined. In this study we have explored the role of LRRK2 in controlling vesicle trafficking in different cellular or animal models and using various readouts. In neuronal cells, the presence of LRRK2(G2019S pathological mutant determines increased extracellular dopamine levels either under basal conditions or upon nicotine stimulation. Moreover, mutant LRRK2 affects the levels of dopamine receptor D1 on the membrane surface in neuronal cells or animal models. Ultrastructural analysis of PC12-derived cells expressing mutant LRRK2(G2019S shows an altered intracellular vesicle distribution. Taken together, our results point to the key role of LRRK2 to control vesicle trafficking in neuronal cells.

  1. Estrous cycle and food availability affect feeding induced by amygdala 5-HT receptor blockade.

    Science.gov (United States)

    Parker, Graham C; Bishop, Christopher; Coscina, Donald V

    2002-04-01

    We have recently reported that bilateral infusions of the 5-HT receptor antagonist metergoline (MET) into the posterior basolateral amygdala (pBLA) elicit feeding in female rats tested at mid-light cycle. The present study was performed to determine whether (1) testing at two different phases of the estrous cycle, and/or (2) the palatability of the food might modify this effect. Subjects were 18 adult females with bilateral pBLA cannulae. Following familiarization with Froot Loops cereal, a within-subjects design tested all animals for 1- and 2-h food intake under 2 Drug (0.3 nmol MET vs. Vehicle), 2 Estrous Cycle (diestrus vs. estrus) and 2 Food (lab chow vs. Froot Loops) conditions. Rats weighed more at diestrus than at proestrus (Pestrus (Pestrus. A three-way interaction (Pestrus than in diestrus to lab chow but not Froot Loops. These data suggest pBLA MET differentially affects feeding over the estrous cycle depending on the palatability of food available.

  2. N-glycosylation and disulfide bonding affects GPRC6A receptor expression, function, and dimerization

    DEFF Research Database (Denmark)

    Nørskov-Lauritsen, Lenea; Jørgensen, Stine; Bräuner-Osborne, Hans

    2015-01-01

    Investigation of post-translational modifications of receptor proteins is important for our understanding of receptor pharmacology and disease physiology. However, our knowledge about post-translational modifications of class C G protein-coupled receptors and how these modifications regulate expr...... covalently linked dimers through cysteine disulfide linkage in the extracellular amino-terminal domain and here we show that GPRC6A indeed is a homodimer and that a disulfide bridge between the C131 residues is formed....

  3. Cluster analysis of the clinical histories of cattle affected with bovine anaemia associated with Theileria orientalis Ikeda type infection.

    Science.gov (United States)

    Lawrence, K E; Forsyth, S F; Vaatstra, B L; McFadden, Amj; Pulford, D J; Govindaraju, K; Pomroy, W E

    2017-11-01

    AIM To determine the most commonly used words in the clinical histories of animals naturally infected with Theileria orientalis Ikeda type; whether these words differed between cases categorised by age, farm type or haematocrit (HCT), and if there was any clustering of the common words in relation to these categories. METHODS Clinical histories were transcribed for 605 cases of bovine anaemia associated with T. orientalis (TABA), that were submitted to laboratories with blood samples which tested positive for T. orientalis Ikeda type infection by PCR analysis, between October 2012 and November 2014. χ 2 tests were used to determine whether the proportion of submissions for each word was similar across the categories of HCT (normal, moderate anaemia or severe anaemia), farm type (dairy or beef) and age (young or old). Correspondence analysis (CA) was carried out on a contingency table of the frequency of the 28 most commonly used history words, cross-tabulated by age categories (young, old or unknown). Agglomerative hierarchical clustering, using Ward's method, was then performed on the coordinates from the correspondence analysis. RESULTS The six most commonly used history words were jaundice (204/605), lethargic (162/605), pale mucous membranes (161/605), cow (151/605), anaemia (147/605), and off milk (115/605). The proportion of cases with some history words differed between categories of age, farm type and HCT. The cluster analysis indicated that the recorded history words were grouped in two main clusters. The first included the words weight loss, tachycardia, pale mucous membranes, anaemia, lethargic and thin, and was associated with adult (pcluster included the words deaths, ill-thrift, calves, calf and diarrhoea, and was associated with young (pCluster analysis of words recorded in clinical histories submitted with blood samples from cases of TABA indicates that two potentially different disease syndromes were associated with T. orientalis Ikeda type

  4. Does training frequency and supervision affect compliance, performance and muscular health? A cluster randomized controlled trial.

    Science.gov (United States)

    Dalager, Tina; Bredahl, Thomas G V; Pedersen, Mogens T; Boyle, Eleanor; Andersen, Lars L; Sjøgaard, Gisela

    2015-10-01

    The aim was to determine the effect of one weekly hour of specific strength training within working hours, performed with the same total training volume but with different training frequencies and durations, or with different levels of supervision, on compliance, muscle health and performance, behavior and work performance. In total, 573 office workers were cluster-randomized to: 1 WS: one 60-min supervised session/week, 3 WS: three 20-min supervised sessions/week, 9 WS: nine 7-min supervised sessions/week, 3 MS: three 20-min sessions/week with minimal supervision, or REF: a reference group without training. Outcomes were diary-based compliance, total training volume, muscle performance and questionnaire-based health, behavior and work performance. Comparisons were made among the WS training groups and between 3 WS and 3 MS. If no difference, training groups were collapsed (TG) and compared with REF. Results demonstrated similar degrees of compliance, mean(range) of 39(33-44)%, and total training volume, 13.266(11.977-15.096)kg. Musculoskeletal pain in neck and shoulders were reduced with approx. 50% in TG, which was significant compared with REF. Only the training groups improved significantly their muscle strength 8(4-13)% and endurance 27(12-37)%, both being significant compared with REF. No change in workability, productivity or self-rated health was demonstrated. Secondary analysis showed exercise self-efficacy to be a significant predictor of compliance. Regardless of training schedule and supervision, similar degrees of compliance were shown together with reduced musculoskeletal pain and improved muscle performance. These findings provide evidence that a great degree of flexibility is legitimate for companies in planning future implementation of physical exercise programs at the workplace. ClinicalTrials.gov, number NCT01027390. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Affective and cognitive effects of global deletion of alpha3-containing gamma-aminobutyric acid-A receptors.

    Science.gov (United States)

    Fiorelli, Roberto; Rudolph, Uwe; Straub, Carolin J; Feldon, Joram; Yee, Benjamin K

    2008-09-01

    Gamma-aminobutyric acid (GABA)A receptors characterized by the presence of the alpha3 subunit are the major GABAA receptor subtype expressed in brain stem monoaminergic nuclei. These alpha3-GABAA receptors are therefore in a unique position to regulate monoaminergic functions. To characterize the functional properties of alpha3-GABAA receptors, we present a preliminary assessment of the expression of affective and cognitive behaviour in male mice with a targeted deletion of the Gabra3 gene encoding the alpha3 subunit [alpha3 knockout (KO) mice] on a C57BL/6Jx129X1/SvJ F1 hybrid genetic background. The alpha3 KO mice did not exhibit any gross change of anxiety-like behaviour or spontaneous locomotor behaviour. In the Porsolt forced swim test for potential antidepressant activity, alpha3 KO mice exhibited reduced floating and enhanced swimming behaviour relative to wild-type controls. Performance on a two-choice sucrose preference test, however, revealed no evidence for an increase in sucrose preference in the alpha3 KO mice that would have substantiated a potential phenotype for depression-related behaviour. In contrast, a suggestion of an enhanced negative contrast effect was revealed in a one-bottle sucrose consumption test across different sucrose concentrations. These affective phenotypes were accompanied by alterations in the balance between conditioned responding to the discrete conditioned stimulus and to the context, and a suggestion of faster extinction, in the Pavlovian conditioned freezing paradigm. Spatial learning in the water maze reference memory test, however, was largely unchanged in the alpha3 KO mice, except for a trend of preservation during reversal learning. The novel phenotypes following global deletion of the GABAA receptor alpha3 subunit identified here provided relevant insights, in addition to our earlier study, into the potential behavioural relevance of this specific receptor subtypes in the modulation of both affective and cognitive

  6. Cluster-cluster clustering

    International Nuclear Information System (INIS)

    Barnes, J.; Dekel, A.; Efstathiou, G.; Frenk, C.S.; Yale Univ., New Haven, CT; California Univ., Santa Barbara; Cambridge Univ., England; Sussex Univ., Brighton, England)

    1985-01-01

    The cluster correlation function xi sub c(r) is compared with the particle correlation function, xi(r) in cosmological N-body simulations with a wide range of initial conditions. The experiments include scale-free initial conditions, pancake models with a coherence length in the initial density field, and hybrid models. Three N-body techniques and two cluster-finding algorithms are used. In scale-free models with white noise initial conditions, xi sub c and xi are essentially identical. In scale-free models with more power on large scales, it is found that the amplitude of xi sub c increases with cluster richness; in this case the clusters give a biased estimate of the particle correlations. In the pancake and hybrid models (with n = 0 or 1), xi sub c is steeper than xi, but the cluster correlation length exceeds that of the points by less than a factor of 2, independent of cluster richness. Thus the high amplitude of xi sub c found in studies of rich clusters of galaxies is inconsistent with white noise and pancake models and may indicate a primordial fluctuation spectrum with substantial power on large scales. 30 references

  7. Clusters Regarding Key Factors Affecting Changes in Accounting, Finance, Administration and Management Control

    Directory of Open Access Journals (Sweden)

    Rodica Gabriela Blidisel

    2010-01-01

    Full Text Available During the last decade, important changes have occurred in public governance, which has evolved in this time from hierarchical bureaucracy to participatory governance, where the role of citizens in public decision-making process is more direct. There were performed reforms in finance, management administration and finances of public sector. Starting from the factors that influenced during the history the accounting, finances, administration and management control, we want to test the factors that affect the changes of these elements in Romanian environment.

  8. Androgen Receptor Involvement in Rat Amelogenesis: An Additional Way for Endocrine-Disrupting Chemicals to Affect Enamel Synthesis.

    Science.gov (United States)

    Jedeon, Katia; Loiodice, Sophia; Salhi, Khaled; Le Normand, Manon; Houari, Sophia; Chaloyard, Jessica; Berdal, Ariane; Babajko, Sylvie

    2016-11-01

    Endocrine-disrupting chemicals (EDCs) that interfere with the steroid axis can affect amelogenesis, leading to enamel hypomineralization similar to that of molar incisor hypomineralization, a recently described enamel disease. We investigated the sex steroid receptors that may mediate the effects of EDCs during rat amelogenesis. The expression of androgen receptor (AR), estrogen receptor (ER)-α, and progesterone receptor was dependent on the stage of ameloblast differentiation, whereas ERβ remained undetectable. AR was the only receptor selectively expressed in ameloblasts involved in final enamel mineralization. AR nuclear translocation and induction of androgen-responsive element-containing promoter activity upon T treatment, demonstrated ameloblast responsiveness to androgens. T regulated the expression of genes involved in enamel mineralization such as KLK4, amelotin, SLC26A4, and SLC5A8 but not the expression of genes encoding matrix proteins, which determine enamel thickness. Vinclozolin and to a lesser extent bisphenol A, two antiandrogenic EDCs that cause enamel defects, counteracted the actions of T. In conclusion, we show, for the first time, the following: 1) ameloblasts express AR; 2) the androgen signaling pathway is involved in the enamel mineralization process; and 3) EDCs with antiandrogenic effects inhibit AR activity and preferentially affect amelogenesis in male rats. Their action, through the AR pathway, may specifically and irreversibly affect enamel, potentially leading to the use of dental defects as a biomarker of exposure to environmental pollutants. These results are consistent with the steroid hormones affecting ameloblasts, raising the issue of the hormonal influence on amelogenesis and possible sexual dimorphism in enamel quality.

  9. Galectin-3 Induces Clustering of CD147 and Integrin-β1 Transmembrane Glycoprotein Receptors on the RPE Cell Surface

    Science.gov (United States)

    Priglinger, Claudia S.; Szober, Christoph M.; Priglinger, Siegfried G.; Merl, Juliane; Euler, Kerstin N.; Kernt, Marcus; Gondi, Gabor; Behler, Jennifer; Geerlof, Arie; Kampik, Anselm; Ueffing, Marius; Hauck, Stefanie M.

    2013-01-01

    Proliferative vitreoretinopathy (PVR) is a blinding disease frequently occurring after retinal detachment surgery. Adhesion, migration and matrix remodeling of dedifferentiated retinal pigment epithelial (RPE) cells characterize the onset of the disease. Treatment options are still restrained and identification of factors responsible for the abnormal behavior of the RPE cells will facilitate the development of novel therapeutics. Galectin-3, a carbohydrate-binding protein, was previously found to inhibit attachment and spreading of retinal pigment epithelial cells, and thus bares the potential to counteract PVR-associated cellular events. However, the identities of the corresponding cell surface glycoprotein receptor proteins on RPE cells are not known. Here we characterize RPE-specific Gal-3 containing glycoprotein complexes using a proteomic approach. Integrin-β1, integrin-α3 and CD147/EMMPRIN, a transmembrane glycoprotein implicated in regulating matrix metalloproteinase induction, were identified as potential Gal-3 interactors on RPE cell surfaces. In reciprocal immunoprecipitation experiments we confirmed that Gal-3 associated with CD147 and integrin-β1, but not with integrin-α3. Additionally, association of Gal-3 with CD147 and integrin-β1 was observed in co-localization analyses, while integrin-α3 only partially co-localized with Gal-3. Blocking of CD147 and integrin-β1 on RPE cell surfaces inhibited binding of Gal-3, whereas blocking of integrin-α3 failed to do so, suggesting that integrin-α3 is rather an indirect interactor. Importantly, Gal-3 binding promoted pronounced clustering and co-localization of CD147 and integrin-β1, with only partial association of integrin-α3. Finally, we show that RPE derived CD147 and integrin-β1, but not integrin-α3, carry predominantly β-1,6-N-actyl-D-glucosamine-branched glycans, which are high-affinity ligands for Gal-3. We conclude from these data that extracellular Gal-3 triggers clustering of CD147 and

  10. Galectin-3 induces clustering of CD147 and integrin-β1 transmembrane glycoprotein receptors on the RPE cell surface.

    Directory of Open Access Journals (Sweden)

    Claudia S Priglinger

    Full Text Available Proliferative vitreoretinopathy (PVR is a blinding disease frequently occurring after retinal detachment surgery. Adhesion, migration and matrix remodeling of dedifferentiated retinal pigment epithelial (RPE cells characterize the onset of the disease. Treatment options are still restrained and identification of factors responsible for the abnormal behavior of the RPE cells will facilitate the development of novel therapeutics. Galectin-3, a carbohydrate-binding protein, was previously found to inhibit attachment and spreading of retinal pigment epithelial cells, and thus bares the potential to counteract PVR-associated cellular events. However, the identities of the corresponding cell surface glycoprotein receptor proteins on RPE cells are not known. Here we characterize RPE-specific Gal-3 containing glycoprotein complexes using a proteomic approach. Integrin-β1, integrin-α3 and CD147/EMMPRIN, a transmembrane glycoprotein implicated in regulating matrix metalloproteinase induction, were identified as potential Gal-3 interactors on RPE cell surfaces. In reciprocal immunoprecipitation experiments we confirmed that Gal-3 associated with CD147 and integrin-β1, but not with integrin-α3. Additionally, association of Gal-3 with CD147 and integrin-β1 was observed in co-localization analyses, while integrin-α3 only partially co-localized with Gal-3. Blocking of CD147 and integrin-β1 on RPE cell surfaces inhibited binding of Gal-3, whereas blocking of integrin-α3 failed to do so, suggesting that integrin-α3 is rather an indirect interactor. Importantly, Gal-3 binding promoted pronounced clustering and co-localization of CD147 and integrin-β1, with only partial association of integrin-α3. Finally, we show that RPE derived CD147 and integrin-β1, but not integrin-α3, carry predominantly β-1,6-N-actyl-D-glucosamine-branched glycans, which are high-affinity ligands for Gal-3. We conclude from these data that extracellular Gal-3 triggers

  11. Dopamine D1 receptor gene variation modulates opioid dependence risk by affecting transition to addiction.

    Directory of Open Access Journals (Sweden)

    Feng Zhu

    Full Text Available Dopamine D1 receptor (DRD1 modulates opioid reinforcement, reward, and opioid-induced neuroadaptation. We propose that DRD1 polymorphism affects susceptibility to opioid dependence (OD, the efficiency of transition to OD, and opioid-induced pleasure response. We analyzed potential association between seven DRD1 polymorphisms with the following traits: duration of transition from the first use to dependence (DTFUD, subjective pleasure responses to opioid on first use and post-dependence use, and OD risk in 425 Chinese with OD and 514 healthy controls. DTFUD and level of pleasure responses were examined using a semi-structured interview. The DTFUD of opioid addicts ranged from 5 days to 11 years. Most addicts (64.0% reported non-comfortable response upon first opioid use, while after dependence, most addicts (53.0% felt strong opioid-induced pleasure. Survival analysis revealed a correlation of prolonged DTFUD with the minor allele-carrying genotypes of DRD1 rs4532 (hazard ratios (HR = 0.694; p = 0.001 and rs686 (HR = 0.681, p = 0.0003. Binary logistic regression indicated that rs10063995 GT genotype (vs. GG+TT, OR = 0.261 could predict decreased pleasure response to first-time use and the minor alleles of rs686 (OR = 0.535 and rs4532 (OR = 0.537 could predict decreased post-dependence pleasure. Moreover, rs686 minor allele was associated with a decreased risk for rapid transition from initial use to dependence (DTFUD≤30 days; OR = 0.603 or post-dependence euphoria (OR = 0.603 relative to major allele. In conclusion, DRD1 rs686 minor allele decreases the OD risk by prolonging the transition to dependence and attenuating opioid-induced pleasure in Chinese.

  12. Chronic exposure to dopamine agonists affects the integrity of striatal D2 receptors in Parkinson's patients

    Directory of Open Access Journals (Sweden)

    Marios Politis

    2017-01-01

    Full Text Available We aimed to investigate the integrity and clinical relevance of striatal dopamine receptor type-2 (D2R availability in Parkinson's disease (PD patients. We studied 68 PD patients, spanning from early to advanced disease stages, and 12 healthy controls. All participants received one [11C]raclopride PET scan in an OFF medication condition for quantification of striatal D2R availability in vivo. Parametric images of [11C]raclopride non-displaceable binding potential were generated from the dynamic [11C]raclopride scans using implementation of the simplified reference tissue model with cerebellum as the reference tissue. PET data were interrogated for correlations with clinical data related to disease burden and dopaminergic treatment. PD patients showed a mean 16.7% decrease in caudate D2R and a mean 3.5% increase in putaminal D2R availability compared to healthy controls. Lower caudate [11C]raclopride BPND correlated with longer PD duration. PD patients on dopamine agonist treatment had 9.2% reduced D2R availability in the caudate and 12.8% in the putamen compared to PD patients who never received treatment with dopamine agonists. Higher amounts of lifetime dopamine agonist therapy correlated with reduced D2Rs availability in both caudate and putamen. No associations between striatal D2R availability and levodopa treatment and dyskinesias were found. In advancing PD the caudate and putamen D2R availability are differentially affected. Chronic exposure to treatment with dopamine agonists, but no levodopa, suppresses striatal D2R availability, which may have relevance to output signaling to frontal lobes and the occurrence of executive deficits, but not dyskinesias.

  13. Drosophila insulin-producing cells are differentially modulated by serotonin and octopamine receptors and affect social behavior.

    Directory of Open Access Journals (Sweden)

    Jiangnan Luo

    Full Text Available A set of 14 insulin-producing cells (IPCs in the Drosophila brain produces three insulin-like peptides (DILP2, 3 and 5. Activity in IPCs and release of DILPs is nutrient dependent and controlled by multiple factors such as fat body-derived proteins, neurotransmitters, and neuropeptides. Two monoamine receptors, the octopamine receptor OAMB and the serotonin receptor 5-HT1A, are expressed by the IPCs. These receptors may act antagonistically on adenylate cyclase. Here we investigate the action of the two receptors on activity in and output from the IPCs. Knockdown of OAMB by targeted RNAi led to elevated Dilp3 transcript levels in the brain, whereas 5-HT1A knockdown resulted in increases of Dilp2 and 5. OAMB-RNAi in IPCs leads to extended survival of starved flies and increased food intake, whereas 5-HT1A-RNAi produces the opposite phenotypes. However, knockdown of either OAMB or 5-HT1A in IPCs both lead to increased resistance to oxidative stress. In assays of carbohydrate levels we found that 5-HT1A knockdown in IPCs resulted in elevated hemolymph glucose, body glycogen and body trehalose levels, while no effects were seen after OAMB knockdown. We also found that manipulations of the two receptors in IPCs affected male aggressive behavior in different ways and 5-HT1A-RNAi reduced courtship latency. Our observations suggest that activation of 5-HT1A and OAMB signaling in IPCs generates differential effects on Dilp transcription, fly physiology, metabolism and social interactions. However the findings do not support an antagonistic action of the two monoamines and their receptors in this particular system.

  14. Drosophila insulin-producing cells are differentially modulated by serotonin and octopamine receptors and affect social behavior.

    Science.gov (United States)

    Luo, Jiangnan; Lushchak, Oleh V; Goergen, Philip; Williams, Michael J; Nässel, Dick R

    2014-01-01

    A set of 14 insulin-producing cells (IPCs) in the Drosophila brain produces three insulin-like peptides (DILP2, 3 and 5). Activity in IPCs and release of DILPs is nutrient dependent and controlled by multiple factors such as fat body-derived proteins, neurotransmitters, and neuropeptides. Two monoamine receptors, the octopamine receptor OAMB and the serotonin receptor 5-HT1A, are expressed by the IPCs. These receptors may act antagonistically on adenylate cyclase. Here we investigate the action of the two receptors on activity in and output from the IPCs. Knockdown of OAMB by targeted RNAi led to elevated Dilp3 transcript levels in the brain, whereas 5-HT1A knockdown resulted in increases of Dilp2 and 5. OAMB-RNAi in IPCs leads to extended survival of starved flies and increased food intake, whereas 5-HT1A-RNAi produces the opposite phenotypes. However, knockdown of either OAMB or 5-HT1A in IPCs both lead to increased resistance to oxidative stress. In assays of carbohydrate levels we found that 5-HT1A knockdown in IPCs resulted in elevated hemolymph glucose, body glycogen and body trehalose levels, while no effects were seen after OAMB knockdown. We also found that manipulations of the two receptors in IPCs affected male aggressive behavior in different ways and 5-HT1A-RNAi reduced courtship latency. Our observations suggest that activation of 5-HT1A and OAMB signaling in IPCs generates differential effects on Dilp transcription, fly physiology, metabolism and social interactions. However the findings do not support an antagonistic action of the two monoamines and their receptors in this particular system.

  15. Regulatory proteins (inhibitors or activators) affect estimates of Msub(r) of enzymes and receptors by radiation inactivation

    International Nuclear Information System (INIS)

    Potier, M.; Giroux, S.

    1985-01-01

    The radiation-inactivation method allows the determination of the Msub(r) of enzymes and receptors by monitoring the decay of biological activity as a function of absorbed dose. The presence of regulatory or effector proteins (inhibitors or activators) associated with an enzyme or receptor, or released in the preparation after tissue homogenization, may affect the decay of biological activity. How the activity is affected, however, will depend on the type of inhibition (competitive or non-competitive), the inhibitor or activator concentration, the dissociation constant of the enzyme-effector system, and the effector Msub(r) relative to that of the enzyme. Since little is known on how effector proteins influence radiation inactivation of enzymes and receptors, we have considered a theoretical model in an effort to provide a framework for the interpretation of experimentally obtained data. Our model predicts that competitive and non-competitive inhibitors of enzymes could be distinguished by analysing irradiated samples with various substrate concentrations. Inhibitors will decrease whereas activators will increase the apparent target size of enzymes or receptors. (author)

  16. Homoeologous Recombination of the V1r1-V1r2 Gene Cluster of Pheromone Receptors in an Allotetraploid Lineage of Teleosts

    Directory of Open Access Journals (Sweden)

    Lei Zhong

    2017-11-01

    Full Text Available In contrast to other olfactory receptor families that exhibit frequent lineage-specific expansions, the vomeronasal type 1 receptor (V1R family exhibits a canonical six-member repertoire in teleosts. V1r1 and V1r2 are present in no more than one copy in all examined teleosts, including salmons, which are ancient polyploids, implying strict evolutionary constraints. However, recent polyploids have not been examined. Here, we identified a young allotetraploid lineage of weatherfishes and investigated their V1r1-V1r2 cluster. We found a novel pattern that the parental V1r1-V1r2 clusters had recombined in the tetraploid genome and that the recombinant was nearly fixed in the tetraploid population. Subsequent analyses suggested strong selective pressure, for both a new combination of paralogs and homogeneity among gene duplicates, acting on the V1r1-V1r2 pair.

  17. Synthetic Ligands of Cannabinoid Receptors Affect Dauer Formation in the Nematode Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Pedro Reis Rodrigues

    2016-06-01

    Full Text Available Under adverse environmental conditions the nematode Caenorhabditis elegans can enter an alternate developmental stage called the dauer larva. To identify lipophilic signaling molecules that influence this process, we screened a library of bioactive lipids and found that AM251, an antagonist of the human cannabinoid (CB receptor, suppresses dauer entry in daf-2 insulin receptor mutants. AM251 acted synergistically with glucose supplementation indicating that the metabolic status of the animal influenced the activity of this compound. Similarly, loss of function mutations in the energy-sensing AMP-activated kinase subunit, aak-2, enhanced the dauer-suppressing effects of AM251, while constitutive activation of aak-2 in neurons was sufficient to inhibit AM251 activity. Chemical epistasis experiments indicated that AM251 acts via G-protein signaling and requires the TGF-β ligand DAF-7, the insulin peptides DAF-28 and INS-6, and a functional ASI neuron to promote reproductive growth. AM251 also required the presence of the SER-5 serotonin receptor, but in vitro experiments suggest that this may not be via a direct interaction. Interestingly, we found that other antagonists of mammalian CB receptors also suppress dauer entry, while the nonselective CB receptor agonist, O-2545, not only inhibited the activity of AM251, but also was able to promote dauer entry when administered alone. Since worms do not have obvious orthologs of CB receptors, the effects of synthetic CBs on neuroendocrine signaling in C. elegans are likely to be mediated via another, as yet unknown, receptor mechanism. However, we cannot exclude the existence of a noncanonical CB receptor in C. elegans.

  18. Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability

    OpenAIRE

    Beckley, Ethan H.; Scibelli, Angela C.; Finn, Deborah A.

    2010-01-01

    Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone’s GABAA receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role ...

  19. Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability.

    Science.gov (United States)

    Beckley, Ethan H; Scibelli, Angela C; Finn, Deborah A

    2011-07-01

    Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone's GABA(A) receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression. Copyright © 2010 Elsevier Ltd. All rights reserved.

  20. Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability

    Science.gov (United States)

    Beckley, Ethan H.; Scibelli, Angela C.; Finn, Deborah A.

    2010-01-01

    Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone’s GABAA receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression. PMID:21163582

  1. Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder

    DEFF Research Database (Denmark)

    Frokjaer, Vibe G.; Mortensen, Erik L.; Nielsen, Finn Årup

    2008-01-01

    Background: Serotonergic dysfunction has been associated with affective disorders. High trait neuroticism, as measured on personality inventories, is a risk factor for major depression. In this study we investigated whether neuroticism is associated with serotonin 2A receptor binding in brain...... regions of relevance for affective disorders. Methods: Eighty-three healthy volunteers completed the standardized personality questionnaire NEO-PI-R (Revised NEO Personality Inventory) and underwent [F-18]altanserin positron emission tomography imaging for assessment of serotonin 2A receptor binding...... remained significant after correction for multiple comparisons (r = .35, p = .009). Conclusions: In healthy subjects the personality dimension neuroticism and particularly its constituent trait, vulnerability, are positively associated with frontolimbic serotonin 2A binding. Our findings point...

  2. Differential S1P Receptor Profiles on M1- and M2-Polarized Macrophages Affect Macrophage Cytokine Production and Migration.

    Science.gov (United States)

    Müller, Jan; von Bernstorff, Wolfram; Heidecke, Claus-Dieter; Schulze, Tobias

    2017-01-01

    Introduction . Macrophages are key players in complex biological processes. In response to environmental signals, macrophages undergo polarization towards a proinflammatory (M1) or anti-inflammatory (M2) phenotype. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid that acts via 5 G-protein coupled receptors (S1P 1-5 ) in order to influence a broad spectrum of biological processes. This study assesses S1P receptor expression on macrophages before and after M1 and M2 polarization and performs a comparative analysis of S1P signalling in the two activational states of macrophages. Methods . Bone marrow derived macrophages (BMDM) from C57 BL/6 mice were cultured under either M1- or M2-polarizing conditions. S1P-receptor expression was determined by quantitative RT-PCR. Influence of S1P on macrophage activation, migration, phagocytosis, and cytokine secretion was assessed in vitro. Results . All 5 S1P receptor subclasses were expressed in macrophages. Culture under both M1- and M2-polarizing conditions led to significant downregulation of S1P 1 . In contrast, M1-polarized macrophages significantly downregulated S1P 4 . The expression of the remaining three S1P receptors did not change. S1P increased expression of iNOS under M2-polarizing conditions. Furthermore, S1P induced chemotaxis in M1 macrophages and changed cytokine production in M2 macrophages. Phagocytosis was not affected by S1P-signalling. Discussion . The expression of different specific S1P receptor profiles may provide a possibility to selectively influence M1- or M2-polarized macrophages.

  3. Blockade of AT1 receptors by losartan did not affect renin gene expression in kidney medulla

    Czech Academy of Sciences Publication Activity Database

    Tybitanclová, K.; Szabová, L.; Grima, M.; Ingert, C.; Železná, Blanka; Zórad, Š.

    2006-01-01

    Roč. 25, č. 1 (2006), s. 43-51 ISSN 0231-5882 Grant - others:VEGA(SK) 2/5090/25 Institutional research plan: CEZ:AV0Z50520514 Keywords : AT1 receptor * renin-angiotensin system * kidneys Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.771, year: 2006

  4. Factors affecting estrogen receptor status in a multiracial Asian country : An analysis of 3557 cases

    NARCIS (Netherlands)

    Yip, C. H.; Pathy, N. Bhoo; Uiterwaal, C. S.; Taib, N. A.; Tan, G. H.; Mun, K. S.; Choo, W. Y.; Rhodes, A.

    Estrogen receptor (ER) positive rates in breast cancer may be influenced by grade, stage, age and race. This study reviews the ER positive rates over a 15-year period at the University Malaya Medical Centre, Kuala Lumpur, Malaysia. Data on ER status of 3557 patients from 1994 to 2008 was analyzed.

  5. Triiodothyronine affects the alternative splicing of thyroid hormone receptor alpha mRNA

    NARCIS (Netherlands)

    Timmer, D. C.; Bakker, O.; Wiersinga, W. M.

    2003-01-01

    The c-erbAalpha gene encodes two thyroid hormone receptors, TRalpha1 and TRalpha2, that arise from alternative splicing of the TRalpha pre-mRNA. TRalpha2 is not able to bind triiodothyronine (T-3) and acts as a weak antagonist of TRs. It has been suggested that the balance of TRalpha1 to TRalpha2 is

  6. Melanocortin receptor 4 deficiency affects body weight regulation, grooming behavior, and substrate preference in the rat

    NARCIS (Netherlands)

    Mul, J.D.; van Boxtel, R.; Bergen, D.J.; Brans, M.A.; Brakkee, J.H.; Toonen, P.W.; Garner, K.M.; Adan, R.A.; Cuppen, E.

    2012-01-01

    Obesity is caused by an imbalance between energy intake and expenditure and has become a major health-care problem in western society. The central melanocortin system plays a crucial role in the regulation of feeding and energy expenditure, and functional loss of melanocortin receptor 4 (MC4R) is

  7. Analysis of variables affecting unemployment rate and detecting for cluster in West Java, Central Java, and East Java in 2012

    Science.gov (United States)

    Samuel, Putra A.; Widyaningsih, Yekti; Lestari, Dian

    2016-02-01

    The objective of this study is modeling the Unemployment Rate (UR) in West Java, Central Java, and East Java, with rate of disease, infant mortality rate, educational level, population size, proportion of married people, and GDRP as the explanatory variables. Spatial factors are also considered in the modeling since the closer the distance, the higher the correlation. This study uses the secondary data from BPS (Badan Pusat Statistik). The data will be analyzed using Moran I test, to obtain the information about spatial dependence, and using Spatial Autoregressive modeling to obtain the information, which variables are significant affecting UR and how great the influence of the spatial factors. The result is, variables proportion of married people, rate of disease, and population size are related significantly to UR. In all three regions, the Hotspot of unemployed will also be detected districts/cities using Spatial Scan Statistics Method. The results are 22 districts/cities as a regional group with the highest unemployed (Most likely cluster) in the study area; 2 districts/cities as a regional group with the highest unemployed in West Java; 1 district/city as a regional groups with the highest unemployed in Central Java; 15 districts/cities as a regional group with the highest unemployed in East Java.

  8. [INHIBITORS OF MAP-KINASE PATHWAY U0126 AND PD98059 DIFFERENTLY AFFECT ORGANIZATION OF TUBULIN CYTOSKELETON AFTER STIMULATION OF EGF RECEPTOR ENDOCYTOSIS].

    Science.gov (United States)

    Zlobina, M V; Steblyanko, Yu Yu; Shklyaeva, M A; Kharchenko, V V; Salova, A V; Kornilova, E S

    2015-01-01

    To confirm the hypothesis about the involvement of EGF-stimulated MAP-kinase ERK1/2 in the regulation of microtubule (MT) system, the influence of two widely used ERK1/2 inhibitors, U0126 and PD98059, on the organization of tubulin cytoskeleton in interphase HeLa cells during EGF receptor endocytosis has been investigated. We have found that addition of U0126 or PD98059 to not-stimulated with EGF ells for 30 min has no effect on radially organized MT system. However, in the case of U0126 addition before EGF endocytosis stimulation, the number of MT per cell decreased within 15 min after such stimulation and was followed by complete MT depolymerization by 60-90 min. Stimulation of EGF endocytosis in the presence of PD98059 resulted only in insignificant depolymerization of MT and it could be detected mainly from their minus-ends. At the same time, MT regions close to plasma membrane became stabilized, which was proved by increase in tubulin acetylation level. This situation was characteristic for all period of the experiment. It has been also found that the inhibitors affect endocytosis dynamics of EGF-receptor complexes. Quantitative analysis demonstrated that the stimulation of endocytosis in the presence of U0126 generated a greater number of endosomes compared to control cells, and their number did not change significantly during the experiment. All these endosomes were localized peripherally. Effect of PD98059 resulted in the formation of lower number of endosomes that in control, but they demonstrated very slow clusterization despite the presence of some intact MT. Both inhibitors decreased EGFR colocolization with early endosomal marker EEA1, which indicated a delay in endosome fusions and maturation. The inhibitors were also shown to affect differently phospho-ERK 1 and 2 forms: U0126 completely inhibited phospho-ERK1 and 2, white, in the presence of PD98059, the two ERK forms demonstrated sharp transient activation in 15 min after stimulation, but only

  9. Glycosylation at Asn91 of H1N1 haemagglutinin affects binding to glycan receptors.

    Science.gov (United States)

    Jayaraman, Akila; Koh, Xiaoying; Li, Jing; Raman, Rahul; Viswanathan, Karthik; Shriver, Zachary; Sasisekharan, Ram

    2012-06-15

    The glycoprotein HA (haemagglutinin) on the surface of influenza A virus plays a central role in recognition and binding to specific host cell-surface glycan receptors and in fusion of viral membrane to the host nuclear membrane during viral replication. Given the abundance of HA on the viral surface, this protein is also the primary target for host innate and adaptive immune responses. Although addition of glycosylation sites on HA are a part of viral evolution to evade the host immune responses, there are specific glycosylation sites that are conserved during most of the evolution of the virus. In the present study, it was demonstrated that one such conserved glycosylation site at Asn(91) in H1N1 HA critically governs the glycan receptor-binding specificity and hence would potentially impinge on the host adaptation of the virus.

  10. Astrocytic β2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice.

    Directory of Open Access Journals (Sweden)

    Cathy Joanna Jensen

    Full Text Available In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the β2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific β2-adrenergic receptor knock-out mice were generated by crossing homozygous β2-adrenergic receptor floxed mice (Adrb2flox and mice with heterozygous tamoxifen-inducible Cre recombinase-expression driven by the astrocyte specific L-glutamate/L-aspartate transporter promoter (GLAST-CreERT2. Assessments using the modified SHIRPA (SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment test battery, swimming ability test, and accelerating rotarod test, performed at 1, 2 and 4 weeks, 6 and 12 months after tamoxifen (or vehicle administration did not reveal any differences in physical health or motor functions between the knock-out mice and controls. However deficits were found in the cognitive ability of aged, but not young adult mice, reflected in impaired learning in the Morris Water Maze. Similarly, long-term potentiation (LTP was impaired in hippocampal brain slices of aged knock-out mice maintained in low glucose media. Using microdialysis in cerebellar white matter we found no significant differences in extracellular lactate or glucose between the young adult knock-out mice and controls, although trends were detected. Our results suggest that β2-adrenergic receptor expression on astrocytes in mice may be important for maintaining cognitive health at advanced age, but is dispensable for motor function.

  11. Cathelicidin LL-37 Affects Surface and Intracellular Toll-Like Receptor Expression in Tissue Mast Cells

    Directory of Open Access Journals (Sweden)

    Justyna Agier

    2018-01-01

    Full Text Available Undoubtedly, mast cells take part in host defense against microorganisms as they are numerous at the portal of infection, they release many proinflammatory and antimicrobial mediators, and they express pattern recognition receptors, such as TLRs. These receptors play a key role in recognition and binding molecules associated with microorganisms and molecules associated with damage. Cathelicidins exhibit direct antimicrobial activities against a broad spectrum of microbes by perturbing their cell membranes. Accumulating evidence suggests a role for these molecules in supporting cell activation. We examined the impact of human cathelicidin LL-37 on tissue mast cell TLR expression and distribution. Depending on context, we show that LL-37 stimulation resulted in minor to major effects on TLR2, TLR3, TLR4, TLR5, TLR7, and TLR9 expression. Confocal microscopy analysis showed that, upon stimulation, TLRs may translocate from the cell interior to the surface and conversely. FPR2 and EGFR inhibitors reduced the increase in expression of selected receptors. We also established that LL-37 acts as a powerful inducer of CCL3 and ROS generation. These results showed that in response to LL-37, mast cells enhance the capability to detect invading pathogens by modulation of TLR expression in what may be involved FPR2 or EGFR molecules.

  12. Nettle extract (Urtica dioica) affects key receptors and enzymes associated with allergic rhinitis.

    Science.gov (United States)

    Roschek, Bill; Fink, Ryan C; McMichael, Matthew; Alberte, Randall S

    2009-07-01

    A nettle (Urtica dioica) extract shows in vitro inhibition of several key inflammatory events that cause the symptoms of seasonal allergies. These include the antagonist and negative agonist activity against the Histamine-1 (H(1)) receptor and the inhibition of mast cell tryptase preventing degranulation and release of a host of pro-inflammatory mediators that cause the symptoms of hay fevers. The nettle extract also inhibits prostaglandin formation through inhibition of Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), and Hematopoietic Prostaglandin D(2) synthase (HPGDS), central enzymes in pro-inflammatory pathways. The IC(50) value for histamine receptor antagonist activity was 251 (+/-13) microg mL(-1) and for the histamine receptor negative agonist activity was 193 (+/-71) microg mL(-1). The IC(50) values for inhibition of mast cell tryptase was 172 (+/-28) microg mL(-1), for COX-1 was 160 (+/-47) microg mL(-1), for COX-2 was 275 (+/-9) microg mL(-1), and for HPGDS was 295 (+/-51) microg mL(-1). Through the use of DART TOF-MS, which yields exact masses and relative abundances of compounds present in complex mixtures, bioactives have been identified in nettle that contribute to the inhibition of pro-inflammatory pathways related to allergic rhinitis. These results provide for the first time, a mechanistic understanding of the role of nettle extracts in reducing allergic and other inflammatory responses in vitro. Copyright 2009 John Wiley & Sons, Ltd.

  13. Measuring human rights violations in a conflict-affected country: results from a nationwide cluster survey in Central African Republic

    Directory of Open Access Journals (Sweden)

    Roberts Les

    2011-03-01

    Full Text Available Abstract Background Measuring human rights violations is particularly challenging during or after armed conflict. A recent nationwide survey in the Central African Republic produced estimates of rates of grave violations against children and adults affected by armed conflict, using an approach known as the "Neighborhood Method". Methods In June and July, 2009, a random household survey was conducted based on population estimates from the 2003 national census. Clusters were assigned systematically proportional to population size. Respondents in randomly selected households were interviewed regarding incidents of killing, intentional injury, recruitment into armed groups, abduction, sexual abuse and rape between January 1, 2008 and the date of interview, occurring in their homes' and those of their three closest neighbors. Results Sixty of the selected 69 clusters were surveyed. In total, 599 women were interviewed about events in 2,370 households representing 13,669 persons. Estimates of annual rates of each violation occurring per 1000 people in each of two strata are provided for children between the ages of five and 17, adults 18 years of age and older and the entire population five years and older, along with a combined and weighted national rate. The national rates for children age five to 17 were estimated to be 0.98/1000/year (95% CI: 0.18 - 1.78 for recruitment, 2.56/1000/year (95% CI: 1.50 - 3.62 for abduction, 1.13/1000/year (95% CI: 0.33 - 1.93 for intentional injury, 10.72/1000 girls/year (95% CI: 7.40 - 14.04 for rape, and 4.80/1000 girls/year (95% CI: 2.61 - 6.00 for sexual abuse. No reports of any violation against a person under the age of five were recorded and there were no reports of rape or sexual abuse of males. No children were reported to have been killed during the recall period. Rape and abduction were the most frequently reported events. Conclusions The population-based figures greatly augment existing information on

  14. Activation of protein kinase A and clustering of cell surface receptors by N-methyl-N'-nitro-N-nitrosoguanidine are independent of genomic DNA damage

    Energy Technology Data Exchange (ETDEWEB)

    Wang Zheng; Wang Guliang; Yang Jun; Guo Lei; Yu Yingnian

    2003-07-25

    Alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces cellular stress leading to chromosomal aberrations, mutations and cell death. Previous reports from our laboratory have shown that low concentration of MNNG induces untargeted mutation (UTM), which occurs on intact DNA in mammalian cells through changes in gene expression profile. It also causes the activation of cAMP-protein kinase A (PKA) and up-regulation of POL-{beta}, which is demonstrated to play a role in DNA repair system. In order to find out the possible initial signal involved in UTM, we try to investigate whether the activation of PKA-CREB signal pathway is closely related to DNA damage. Our data shows that the treatment of low concentration MNNG (0.2 {mu}M) activates PKA-CREB pathway in a comparable level both in a nuclear and enucleated cell system. And similar to the cell response caused by UV, the clustering of cell surface receptors of epidermal growth factor (EGF) and tumor necrosis factor {alpha} (TNF{alpha}) was also observed in cells exposed to MNNG. It was further demonstrated that the clustering of the surface receptors is independent of the genomic DNA damage, as this phenomenon was also observed in enucleated cells. These observations indicate that the initiation of signal cascades induced by low concentration of MNNG might be associated with its interaction with cell surface receptors and/or direct activation of related signal proteins but not its DNA damaging property.

  15. Increased leptin/leptin receptor pathway affects systemic and airway inflammation in COPD former smokers

    Directory of Open Access Journals (Sweden)

    Bruno A

    2011-05-01

    Full Text Available Andreina Bruno1, Marinella Alessi2, Simona Soresi2, Anna Bonanno1, Loredana Riccobono1, Angela Marina Montalbano1, Giusy Daniela Albano1, Mark Gjomarkaj1, Mirella Profita11Institute of Biomedicine and Molecular Immunology, Italian National Research Council, Palermo, Italy; 2Dipartimento Biomedico di Biomedicina Interna e Specialistica, University Palermo, ItalyBackground: Leptin, a hormone produced mainly by adipose tissue, regulates food intake and energy expenditure. It is involved in inflammatory diseases such as chronic obstructive pulmonary disease (COPD and its deficiency is associated with increased susceptibility to the infection. The leptin receptor is expressed in the lung and in the neutrophils.Methods: We measured the levels of leptin, tumor necrosis factor alpha (TNF-a and soluble form of intercellular adhesion molecule-1 (sICAM-1 in sputum and plasma from 27 smoker and former smoker patients with stable COPD using ELISA methods. Further we analyzed leptin and its receptor expression in sputum cells from 16 COPD patients using immunocytochemistry.Results: In plasma of COPD patients, leptin was inversely correlated with TNF-a and positively correlated with the patient weight, whereas the levels of sICAM-1 were positively correlated with TNF-a. In sputum of COPD patients leptin levels were correlated with forced expiratory volume in 1 second/forced vitality capacity. Additionally, increased levels of sputum leptin and TNF-a were observed in COPD former smokers rather than smokers. Further the expression of leptin receptor in sputum neutrophils was significantly higher in COPD former smokers than in smokers, and the expression of leptin and its receptor was positively correlated in neutrophils of COPD former smokers.Conclusion: Our findings suggest a role of leptin in the local and systemic inflammation of COPD and, taking into account the involvement of neutrophils in this inflammatory disease, describe a novel aspect of the leptin

  16. Affect

    NARCIS (Netherlands)

    Cetinic, M.; Diamanti, J.; Szeman, I.; Blacker, S.; Sully, J.

    2017-01-01

    This chapter historicizes four divergent but historically contemporaneous genres of affect theory – romantic, realist, speculative, and materialist. While critics credited with the turn to affect in the 1990s wrote largely in the wake of poststructuralism from the perspective of gender and queer

  17. Prostate stem cell antigen interacts with nicotinic acetylcholine receptors and is affected in Alzheimer's disease

    DEFF Research Database (Denmark)

    Jensen, Majbrit Myrup; Mikkelsen, Jens D.; Arvaniti, Maria

    2015-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder involving impaired cholinergic neurotransmission and dysregulation of nicotinic acetylcholine receptors (nAChRs). Ly-6/neurotoxin (Lynx) proteins have been shown to modulate cognition and neural plasticity by binding to nAChR subtypes...... are present in the human brain. We further showed that PSCA forms stable complexes with the α4 nAChR subunit and decreases nicotine-induced extracellular-signal regulated kinase phosphorylation in PC12 cells. In addition, we analyzed protein levels of PSCA and Lypd6 in postmortem tissue of medial frontal...

  18. Pulsatile atheroprone shear stress affects the expression of transient receptor potential channels in human endothelial cells

    DEFF Research Database (Denmark)

    Thilo, Florian; Vorderwülbecke, Bernd J; Marki, Alex

    2012-01-01

    in comparison with endothelial cells grown under static conditions. There was a significant association between the expression of TRPC6 and tumor necrosis factor-α mRNA in human vascular tissue. No-flow and atheroprone flow conditions are equally characterized by an increase in the expression of tumor necrosis......The goal of the study was to assess whether pulsatile atheroprone shear stress modulates the expression of transient receptor potential (TRP) channels, TRPC3, TRPC6, TRPM7, and TRPV1 mRNA, in human umbilical vascular endothelial cells. Exposure of cultured vascular endothelial cells to defined...

  19. Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function

    DEFF Research Database (Denmark)

    Egea, Joaquim; Nissen, Ulla Vig; Dufour, Audrey

    2005-01-01

    Signaling by receptor tyrosine kinases (RTKs) is mediated by their intrinsic kinase activity. Typically, kinase-activating mutations result in ligand-independent signaling and gain-of-function phenotypes. Like other RTKs, Ephs require kinase activity to signal, but signaling by Ephs in vitro also...... requires clustering by their membrane bound ephrin ligands. The relative importance of Eph kinase activity and clustering for in vivo functions is unknown. We find that knockin mice expressing a mutant form of EphA4 (EphA4 EE), whose kinase is constitutively activated in the absence of ephrinB ligands......, are deficient in the development of thalamocortical projections and some aspects of central pattern generator rhythmicity. Surprisingly, other functions of EphA4 were regulated normally by EphA4EE, including midline axon guidance, hindlimb locomotion, in vitro growth cone collapse, and phosphorylation...

  20. School-based mental health intervention for children in war-affected Burundi: a cluster randomized trial.

    Science.gov (United States)

    Tol, Wietse A; Komproe, Ivan H; Jordans, Mark J D; Ndayisaba, Aline; Ntamutumba, Prudence; Sipsma, Heather; Smallegange, Eva S; Macy, Robert D; de Jong, Joop T V M

    2014-04-01

    Armed conflicts are associated with a wide range of impacts on the mental health of children and adolescents. We evaluated the effectiveness of a school-based intervention aimed at reducing symptoms of posttraumatic stress disorder, depression, and anxiety (treatment aim); and improving a sense of hope and functioning (preventive aim). We conducted a cluster randomized trial with 329 children in war-affected Burundi (aged 8 to 17 (mean 12.29 years, standard deviation 1.61); 48% girls). One group of children (n = 153) participated in a 15-session school-based intervention implemented by para-professionals, and the remaining 176 children formed a waitlist control condition. Outcomes were measured before, one week after, and three months after the intervention. No main effects of the intervention were identified. However, longitudinal growth curve analyses showed six favorable and two unfavorable differences in trajectories between study conditions in interaction with several moderators. Children in the intervention condition living in larger households showed decreases on depressive symptoms and function impairment, and those living with both parents showed decreases on posttraumatic stress disorder and depressive symptoms. The groups of children in the waitlist condition showed increases in depressive symptoms. In addition, younger children and those with low levels of exposure to traumatic events in the intervention condition showed improvements on hope. Children in the waitlist condition who lived on their original or newly bought land showed improvements in hope and function impairment, whereas children in the intervention condition showed deterioration on these outcomes. Given inconsistent effects across studies, findings do not support this school-based intervention as a treatment for posttraumatic stress disorder and depressive symptoms in conflict-affected children. The intervention appears to have more consistent preventive benefits, but these effects are

  1. The biology of NK cells and their receptors affects clinical outcomes after hematopoietic cell transplantation (HCT).

    Science.gov (United States)

    Foley, Bree; Felices, Martin; Cichocki, Frank; Cooley, Sarah; Verneris, Michael R; Miller, Jeffrey S

    2014-03-01

    Natural killer (NK) cells were first identified for their capacity to reject bone marrow allografts in lethally irradiated mice without prior sensitization. Subsequently, human NK cells were detected and defined by their non-major histocompatibility complex (MHC)-restricted cytotoxicity toward transformed or virally infected target cells. Karre et al. later proposed 'the missing self hypothesis' to explain the mechanism by which self-tolerant cells could kill targets that had lost self MHC class I. Subsequently, the receptors that recognize MHC class I to mediate tolerance in the host were identified on NK cells. These class I-recognizing receptors contribute to the acquisition of function by a dynamic process known as NK cell education or licensing. In the past, NK cells were assumed to be short lived, but more recently NK cells have been shown to mediate immunologic memory to secondary exposures to cytomegalovirus infection. Because of their ability to lyse tumors with aberrant MHC class I expression and to produce cytokines and chemokines upon activation, NK cells may be primed by many stimuli, including viruses and inflammation, to contribute to a graft-versus-tumor effect. In addition, interactions with other immune cells support the therapeutic potential of NK cells to eradicate tumor and to enhance outcomes after hematopoietic cell transplantation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. TRAIL death receptor 4 signaling via lysosome fusion and membrane raft clustering in coronary arterial endothelial cells: evidence from ASM knockout mice.

    Science.gov (United States)

    Li, Xiang; Han, Wei-Qing; Boini, Krishna M; Xia, Min; Zhang, Yang; Li, Pin-Lan

    2013-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 4 (DR4), have been implicated in the development of endothelial dysfunction and atherosclerosis. However, the signaling mechanism mediating DR4 activation leading to endothelial injury remains unclear. We recently demonstrated that ceramide production via hydrolysis of membrane sphingomyelin by acid sphingomyelinase (ASM) results in membrane raft (MR) clustering and the formation of important redox signaling platforms, which play a crucial role in amplifying redox signaling in endothelial cells leading to endothelial dysfunction. The present study aims to investigate whether TRAIL triggers MR clustering via lysosome fusion and ASM activation, thereby conducting transmembrane redox signaling and changing endothelial function. Using confocal microscopy, we found that TRAIL induced MR clustering and co-localized with DR4 in coronary arterial endothelial cells (CAECs) isolated from wild-type (Smpd1 (+/+)) mice. Furthermore, TRAIL triggered ASM translocation, ceramide production, and NADPH oxidase aggregation in MR clusters in Smpd1 ( +/+ ) CAECs, whereas these observations were not found in Smpd1 (-/-) CAECs. Moreover, ASM deficiency reduced TRAIL-induced O(2) (-[Symbol: see text]) production in CAECs and abolished TRAIL-induced impairment on endothelium-dependent vasodilation in small resistance arteries. By measuring fluorescence resonance energy transfer, we found that Lamp-1 (lysosome membrane marker protein) and ganglioside G(M1) (MR marker) were trafficking together in Smpd1 (+/+) CAECs, which was absent in Smpd1 (-/-) CAECs. Consistently, fluorescence imaging of living cells with specific lysosome probes demonstrated that TRAIL-induced lysosome fusion with membrane was also absent in Smpd1 (-/-) CAECs. Taken together, these results suggest that ASM is essential for TRAIL-induced lysosomal trafficking, membrane fusion and formation of MR redox signaling platforms

  3. Genomewide Analysis of Aryl Hydrocarbon Receptor Binding Targets Reveals an Extensive Array of Gene Clusters that Control Morphogenetic and Developmental Programs

    Science.gov (United States)

    Sartor, Maureen A.; Schnekenburger, Michael; Marlowe, Jennifer L.; Reichard, John F.; Wang, Ying; Fan, Yunxia; Ma, Ci; Karyala, Saikumar; Halbleib, Danielle; Liu, Xiangdong; Medvedovic, Mario; Puga, Alvaro

    2009-01-01

    Background The vertebrate aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates cellular responses to environmental polycyclic and halogenated compounds. The naive receptor is believed to reside in an inactive cytosolic complex that translocates to the nucleus and induces transcription of xenobiotic detoxification genes after activation by ligand. Objectives We conducted an integrative genomewide analysis of AHR gene targets in mouse hepatoma cells and determined whether AHR regulatory functions may take place in the absence of an exogenous ligand. Methods The network of AHR-binding targets in the mouse genome was mapped through a multipronged approach involving chromatin immunoprecipitation/chip and global gene expression signatures. The findings were integrated into a prior functional knowledge base from Gene Ontology, interaction networks, Kyoto Encyclopedia of Genes and Genomes pathways, sequence motif analysis, and literature molecular concepts. Results We found the naive receptor in unstimulated cells bound to an extensive array of gene clusters with functions in regulation of gene expression, differentiation, and pattern specification, connecting multiple morphogenetic and developmental programs. Activation by the ligand displaced the receptor from some of these targets toward sites in the promoters of xenobiotic metabolism genes. Conclusions The vertebrate AHR appears to possess unsuspected regulatory functions that may be potential targets of environmental injury. PMID:19654925

  4. Association between the GABA(A) receptor alpha5 subunit gene locus (GABRA5) and bipolar affective disorder.

    Science.gov (United States)

    Papadimitriou, G N; Dikeos, D G; Karadima, G; Avramopoulos, D; Daskalopoulou, E G; Vassilopoulos, D; Stefanis, C N

    1998-02-07

    Genetic factors seem to play an important role in the pathogenesis of affective disorder. The candidate gene strategies are being used, among others, to identify the genes conferring vulnerability to the disease. The genes coding for the receptors of gamma-aminobutyric acid (GABA) have been proposed as candidates for affective disorder, since the GABA neurotransmitter system has been implicated in the pathogenesis of the illness. We examined the possible genetic association between the GABA(A) receptor alpha5 subunit gene locus (GABRA5) on chromosome 15 and affective disorder, in 48 bipolar patients (BP), 40 unipolar patients (UP), and 50 healthy individuals, age- and sex-matched to the patients. All patients and controls were unrelated Greeks. Diagnoses were made after direct interviews according to the DSM-IV and ICD-10 criteria. For the genotyping, a dinucleotide (CA) repeat marker was used. The polymerase chain reaction (PCR) products found were nine alleles with lengths between 272 and 290 base pairs (bp). The distribution of allelic frequencies of the GABRA5 locus differed significantly between BP patients and controls with the 282-bp allele found to be associated with BP affective disorder, while no such difference was observed between the groups of UP patients and controls nor between the two patient groups. The presence or absence of the 282-bp allele in the genotype of BP patients was not shown to influence the age of onset and the overall clinical severity, but was found to be associated with a preponderance of manic over depressive episodes in the course of the illness.

  5. Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse

    Science.gov (United States)

    Pellegrino, Rosa Maria; Boda, Enrica; Montarolo, Francesca; Boero, Martina; Mezzanotte, Mariarosa; Saglio, Giuseppe; Buffo, Annalisa; Roetto, Antonella

    2016-01-01

    The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc response. Moreover, Tfr2-KO mice presented a selective overactivation of neurons in the limbic circuit and the emergence of an anxious-like behaviour. Furthermore, microglial cells showed a particular sensitivity to iron perturbation. We conclude that Tfr2 is a key regulator of brain iron homeostasis and propose a role for Tfr2 alpha in the regulation of anxiety circuits. PMID:27477597

  6. Ratio of dopamine synthesis capacity to D2 receptor availability in ventral striatum correlates with central processing of affective stimuli

    International Nuclear Information System (INIS)

    Kienast, Thorsten; Rapp, Michael; Siessmeier, Thomas; Buchholz, Hans G.; Schreckenberger, Mathias; Wrase, Jana; Heinz, Andreas; Braus, Dieter F.; Smolka, Michael N.; Mann, Karl; Roesch, Frank; Cumming, Paul; Gruender, Gerhard; Bartenstein, Peter

    2008-01-01

    Dopaminergic neurotransmission in the ventral striatum may interact with limbic processing of affective stimuli, whereas dorsal striatal dopaminergic neurotransmission can affect habitual processing of emotionally salient stimuli in the pre-frontal cortex. We investigated the dopaminergic neurotransmission in the ventral and dorsal striatum with respect to central processing of affective stimuli in healthy subjects. Subjects were investigated with positron emission tomography and [ 18 F]DOPA for measurements of dopamine synthesis capacity and [ 18 F]DMFP for estimation of dopamine D2 receptor binding potential. Functional magnetic resonance imaging was used to assess the blood-oxygen-level-dependent (BOLD) response to affective pictures, which was correlated with the ratio of [ 18 F]DOPA net influx constant K in app /[ 18 F]DMFP-binding potential (BP N D) in the ventral and dorsal striatum. The magnitude of the ratio in the ventral striatum was positively correlated with BOLD signal increases elicited by negative versus neutral pictures in the right medial frontal gyrus (BA10), right inferior parietal lobe and left post-central gyrus. In the dorsal striatum, the ratio was positively correlated with BOLD signal activation elicited by negative versus neutral stimuli in the left post-central gyrus. The BOLD signal elicited by positive versus neutral stimuli in the superior parietal gyrus was positively correlated with the dorsal and ventral striatal ratio. The correlations of the ratio in the ventral and dorsal striatum with processing of affective stimuli in the named cortical regions support the hypothesis that dopamine transmission in functional divisions of the striatum modulates processing of affective stimuli in specific cortical areas. (orig.)

  7. Ratio of dopamine synthesis capacity to D2 receptor availability in ventral striatum correlates with central processing of affective stimuli

    Energy Technology Data Exchange (ETDEWEB)

    Kienast, Thorsten; Rapp, Michael [Charite Campus Mitte, Department of Psychiatry and Psychotherapy of the Charite University Medical Center, Berlin (Germany); Siessmeier, Thomas; Buchholz, Hans G.; Schreckenberger, Mathias [University of Mainz, Department of Nuclear Medicine, Mainz (Germany); Wrase, Jana; Heinz, Andreas [Charite Campus Mitte, Department of Psychiatry and Psychotherapy of the Charite University Medical Center, Berlin (Germany); Central Institute of Mental Health, Mannheim (Germany); Braus, Dieter F. [University of Hamburg, Neuroimage Nord, Department of Psychiatry, Hamburg (Germany); Smolka, Michael N.; Mann, Karl [Central Institute of Mental Health, Mannheim (Germany); Roesch, Frank [University of Mainz, Institute of Nuclear Chemistry, Mainz (Germany); Cumming, Paul [PET Center and Center for Functionally Integrative Neuroscience, Aarhus (Denmark); Gruender, Gerhard [Aachen University Medical Center, Department of Psychiatry of the RWTH, Mainz (Germany); Bartenstein, Peter [Ludwig-Maximilians-University, Department of Nuclear Medicine, Munich (Germany)

    2008-06-15

    Dopaminergic neurotransmission in the ventral striatum may interact with limbic processing of affective stimuli, whereas dorsal striatal dopaminergic neurotransmission can affect habitual processing of emotionally salient stimuli in the pre-frontal cortex. We investigated the dopaminergic neurotransmission in the ventral and dorsal striatum with respect to central processing of affective stimuli in healthy subjects. Subjects were investigated with positron emission tomography and [{sup 18}F]DOPA for measurements of dopamine synthesis capacity and [{sup 18}F]DMFP for estimation of dopamine D2 receptor binding potential. Functional magnetic resonance imaging was used to assess the blood-oxygen-level-dependent (BOLD) response to affective pictures, which was correlated with the ratio of [{sup 18}F]DOPA net influx constant K{sub in}{sup app} /[{sup 18}F]DMFP-binding potential (BP{sub N}D) in the ventral and dorsal striatum. The magnitude of the ratio in the ventral striatum was positively correlated with BOLD signal increases elicited by negative versus neutral pictures in the right medial frontal gyrus (BA10), right inferior parietal lobe and left post-central gyrus. In the dorsal striatum, the ratio was positively correlated with BOLD signal activation elicited by negative versus neutral stimuli in the left post-central gyrus. The BOLD signal elicited by positive versus neutral stimuli in the superior parietal gyrus was positively correlated with the dorsal and ventral striatal ratio. The correlations of the ratio in the ventral and dorsal striatum with processing of affective stimuli in the named cortical regions support the hypothesis that dopamine transmission in functional divisions of the striatum modulates processing of affective stimuli in specific cortical areas. (orig.)

  8. Nuclear orphan receptor TLX affects gene expression, proliferation and cell apoptosis in beta cells

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Xiaoli; Xiong, Xiaokan; Dai, Zhe; Deng, Haohua; Sun, Li; Hu, Xuemei; Zhou, Feng; Xu, Yancheng, E-mail: oxyccc@163.com

    2015-12-04

    Nuclear orphan receptor TLX is an essential regulator of the growth of neural stem cells. However, its exact function in pancreatic islet cells is still unknown. In the present study, gene expression profiling analysis revealed that overexpression of TLX in beta cell line MIN6 causes suppression of 176 genes and upregulation of 49 genes, including a cadre of cell cycle, cell proliferation and cell death control genes, such as Btg2, Ddit3 and Gadd45a. We next examined the effects of TLX overexpression on proliferation, apoptosis and insulin secretion in MIN6 cells. Proliferation analysis using EdU assay showed that overexpression of TLX increased percentage of EdU-positive cells. Cell cycle and apoptosis analysis revealed that overexpression of TLX in MIN6 cells resulted in higher percentage of cells exiting G1 into S-phase, and a 58.8% decrease of cell apoptosis induced by 0.5 mM palmitate. Moreover, TLX overexpression did not cause impairment of insulin secretion. Together, we conclude that TLX is among factors capable of controlling beta cell proliferation and survival, which may serve as a target for the development of novel therapies for diabetes. - Highlights: • TLX overexpression in MIN6 cell causes significant expression changes of 225 genes. • TLX overexpression promotes MIN6 cell proliferation and decreases cell apoptosis. • TLX overexpression does not cause impairment of insulin secretion.

  9. Nuclear orphan receptor TLX affects gene expression, proliferation and cell apoptosis in beta cells

    International Nuclear Information System (INIS)

    Shi, Xiaoli; Xiong, Xiaokan; Dai, Zhe; Deng, Haohua; Sun, Li; Hu, Xuemei; Zhou, Feng; Xu, Yancheng

    2015-01-01

    Nuclear orphan receptor TLX is an essential regulator of the growth of neural stem cells. However, its exact function in pancreatic islet cells is still unknown. In the present study, gene expression profiling analysis revealed that overexpression of TLX in beta cell line MIN6 causes suppression of 176 genes and upregulation of 49 genes, including a cadre of cell cycle, cell proliferation and cell death control genes, such as Btg2, Ddit3 and Gadd45a. We next examined the effects of TLX overexpression on proliferation, apoptosis and insulin secretion in MIN6 cells. Proliferation analysis using EdU assay showed that overexpression of TLX increased percentage of EdU-positive cells. Cell cycle and apoptosis analysis revealed that overexpression of TLX in MIN6 cells resulted in higher percentage of cells exiting G1 into S-phase, and a 58.8% decrease of cell apoptosis induced by 0.5 mM palmitate. Moreover, TLX overexpression did not cause impairment of insulin secretion. Together, we conclude that TLX is among factors capable of controlling beta cell proliferation and survival, which may serve as a target for the development of novel therapies for diabetes. - Highlights: • TLX overexpression in MIN6 cell causes significant expression changes of 225 genes. • TLX overexpression promotes MIN6 cell proliferation and decreases cell apoptosis. • TLX overexpression does not cause impairment of insulin secretion.

  10. Nuclear orphan receptor TLX affects gene expression, proliferation and cell apoptosis in beta cells.

    Science.gov (United States)

    Shi, Xiaoli; Xiong, Xiaokan; Dai, Zhe; Deng, Haohua; Sun, Li; Hu, Xuemei; Zhou, Feng; Xu, Yancheng

    Nuclear orphan receptor TLX is an essential regulator of the growth of neural stem cells. However, its exact function in pancreatic islet cells is still unknown. In the present study, gene expression profiling analysis revealed that overexpression of TLX in beta cell line MIN6 causes suppression of 176 genes and upregulation of 49 genes, including a cadre of cell cycle, cell proliferation and cell death control genes, such as Btg2, Ddit3 and Gadd45a. We next examined the effects of TLX overexpression on proliferation, apoptosis and insulin secretion in MIN6 cells. Proliferation analysis using EdU assay showed that overexpression of TLX increased percentage of EdU-positive cells. Cell cycle and apoptosis analysis revealed that overexpression of TLX in MIN6 cells resulted in higher percentage of cells exiting G1 into S-phase, and a 58.8% decrease of cell apoptosis induced by 0.5 mM palmitate. Moreover, TLX overexpression did not cause impairment of insulin secretion. Together, we conclude that TLX is among factors capable of controlling beta cell proliferation and survival, which may serve as a target for the development of novel therapies for diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Does signaling of estrogen-related receptors affect structure and function of bank vole Leydig cells?

    Science.gov (United States)

    Pawlicki, P; Milon, A; Zarzycka, M; Galas, J; Tworzydlo, W; Kaminska, A; Pardyak, L; Lesniak, K; Pacwa, A; Bilinska, B; Gorowska-Wojtowicz, E; Kotula-Balak, M

    2017-06-01

    To get a deeper insight into the function of estrogen-related receptors (ERRs) and dissect underlying mechanism in Leydig cells, ERRs (type α, β and γ) were blocked or activated in testes of adult bank voles (Myodes glareolus) which show seasonal changes in the intratesticular sex hormones level. Both actively reproducing animals (long day conditions; LD) and those with regression of the reproductive system (short day conditions; SD) received intraperitoneal injections of selective ERRα antagonist 3-[4-(2,4-Bis-trifluoromethylbenzyloxy)-3-methoxyphenyl]-2-cyano-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)acrylamide (XCT 790) or selective ERRβ/ERRγ agonist N-(4-(Diethylaminobenzylidenyl)-N'-(4-hydroxybenzoyl)-hydrazine (DY131) (50 μ/kg bw; six doses every other day). Markedly more, XCT 790 (P endogenous estrogen level in treated males. Notably, immunolocalization of ERRs and above proteins, exclusively in Leydig cells, indicated their involvement in Leydig cell function control based on interactions with endogenous estrogen level and/or estrogen signaling via ERRs. Treatment with XCT 790 or DY131 significantly decreased (P endogenous estrogen status in the testis. Further understanding of mechanism(s) by which individual types of ERRs can control Leydig cell function is relevant for predicting and preventing steroidogenic and spermatogenic disorders.

  12. Revealing transboundary and local air pollutant sources affecting Metro Manila through receptor modeling studies

    International Nuclear Information System (INIS)

    Pabroa, Preciosa Corazon B.; Bautista VII, Angel T.; Santos, Flora L.; Racho, Joseph Michael D.

    2011-01-01

    Ambient fine particulate matter (PM 2 .5) levels at the Metro Manila air sampling stations of the Philippine Nuclear Research Research Institute were found to be above the WHO guideline value of 10 μg m 3 indicating, in general, very poor air quality in the area. The elemental components of the fine particulate matter were obtained using the energy-dispersive x-ray fluorescence spectrometry. Positive matrix factorization, a receptor modelling tool, was used to identify and apportion air pollution sources. Location of probable transboundary air pollutants were evaluated using HYSPLIT (Hybrid Single Particle Lagrangian Integrated Trajectory Model) while location of probable local air pollutant sources were determined using the conditional probability function (CPF). Air pollutant sources can either be natural or anthropogenic. This study has shown natural air pollutant sources such as volcanic eruptions from Bulusan volcano in 2006 and from Anatahan volcano in 2005 to have impacted on the region. Fine soils was shown to have originated from China's Mu US Desert some time in 2004. Smoke in the fine fraction in 2006 show indications of coming from forest fires in Sumatra and Borneo. Fine particulate Pb in Valenzuela was shown to be coming from the surrounding area. Many more significant air pollution impacts can be evaluated with the identification of probable air pollutant sources with the use of elemental fingerprints and locating these sources with the use of HYSPLIT and CPF. (author)

  13. Killer immunoglobulin-like receptor (KIR and HLA genotypes affect the outcome of allogeneic kidney transplantation.

    Directory of Open Access Journals (Sweden)

    Izabela Nowak

    Full Text Available BACKGROUND: Recipient NK cells may detect the lack of recipient's (i.e., self HLA antigens on donor renal tissue by means of their killer cell immunoglobulin-like receptors (KIRs. KIR genes are differently distributed in individuals, possibly contributing to differences in response to allogeneic graft. METHODOLOGY/PRINCIPAL FINDINGS: We compared frequencies of 10 KIR genes by PCR-SSP in 93 kidney graft recipients rejecting allogeneic renal transplants with those in 190 recipients accepting grafts and 690 healthy control individuals. HLA matching results were drawn from medical records. We observed associations of both a full-length KIR2DS4 gene and its variant with 22-bp deletion with kidney graft rejection. This effect was modulated by the HLA-B,-DR matching, particularly in recipients who did not have glomerulonephritis but had both forms of KIR2DS4 gene. In contrast, in recipients with glomerulonephritis, HLA compatibility seemed to be much less important for graft rejection than the presence of KIR2DS4 gene. Simultaneous presence of both KIR2DS4 variants strongly increased the probability of rejection. Interestingly, KIR2DS5 seemed to protect the graft in the presence of KIR2DS4fl but in the absence of KIR2DS4del. CONCLUSIONS/SIGNIFICANCE: Our results suggest a protective role of KIR2DS5 in graft rejection and an association of KIR2DS4 with kidney rejection, particularly in recipients with glomerulonephritis.

  14. 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”.

  15. Agonists and partial agonists of rhodopsin: retinal polyene methylation affects receptor activation.

    Science.gov (United States)

    Vogel, Reiner; Lüdeke, Steffen; Siebert, Friedrich; Sakmar, Thomas P; Hirshfeld, Amiram; Sheves, Mordechai

    2006-02-14

    Using Fourier transform infrared (FTIR) difference spectroscopy, we have studied the impact of sites and extent of methylation of the retinal polyene with respect to position and thermodynamic parameters of the conformational equilibrium between the Meta I and Meta II photoproducts of rhodopsin. Deletion of methyl groups to form 9-demethyl and 13-demethyl analogues, as well as addition of a methyl group at C10 or C12, shifted the Meta I/Meta II equilibrium toward Meta I, such that the retinal analogues behaved like partial agonists. This equilibrium shift resulted from an apparent reduction of the entropy gain of the transition of up to 65%, which was only partially offset by a concomitant reduction of the enthalpy increase. The analogues produced Meta II photoproducts with relatively small alterations, while their Meta I states were significantly altered, which accounted for the aberrant transitions to Meta II. Addition of a methyl group at C14 influenced the thermodynamic parameters but had little impact on the position of the Meta I/Meta II equilibrium. Neutralization of the residue 134 in the E134Q opsin mutant increased the Meta II content of the 13-demethyl analogue, but not of the 9-demethyl analogue, indicating a severe impairment of the allosteric coupling between the conserved cytoplasmic ERY motif involved in proton uptake and the Schiff base/Glu 113 microdomain in the 9-demethyl analogue. The 9-methyl group appears therefore essential for the correct positioning of retinal to link protonation of the cytoplasmic motif with protonation of Glu 113 during receptor activation.

  16. Assessment of chitosan-affected metabolic response by peroxisome proliferator-activated receptor bioluminescent imaging-guided transcriptomic analysis.

    Directory of Open Access Journals (Sweden)

    Chia-Hung Kao

    Full Text Available Chitosan has been widely used in food industry as a weight-loss aid and a cholesterol-lowering agent. Previous studies have shown that chitosan affects metabolic responses and contributes to anti-diabetic, hypocholesteremic, and blood glucose-lowering effects; however, the in vivo targeting sites and mechanisms of chitosan remain to be clarified. In this study, we constructed transgenic mice, which carried the luciferase genes driven by peroxisome proliferator-activated receptor (PPAR, a key regulator of fatty acid and glucose metabolism. Bioluminescent imaging of PPAR transgenic mice was applied to report the organs that chitosan acted on, and gene expression profiles of chitosan-targeted organs were further analyzed to elucidate the mechanisms of chitosan. Bioluminescent imaging showed that constitutive PPAR activities were detected in brain and gastrointestinal tract. Administration of chitosan significantly activated the PPAR activities in brain and stomach. Microarray analysis of brain and stomach showed that several pathways involved in lipid and glucose metabolism were regulated by chitosan. Moreover, the expression levels of metabolism-associated genes like apolipoprotein B (apoB and ghrelin genes were down-regulated by chitosan. In conclusion, these findings suggested the feasibility of PPAR bioluminescent imaging-guided transcriptomic analysis on the evaluation of chitosan-affected metabolic responses in vivo. Moreover, we newly identified that downregulated expression of apoB and ghrelin genes were novel mechanisms for chitosan-affected metabolic responses in vivo.

  17. Vineyard floor management and cluster thinning inconsistently affect ‘Pinot noir’ crop load, berry composition, and wine quality

    Science.gov (United States)

    A 3-year field study was developed to determine relationships between crop load metrics and berry composition for ‘Pinot noir’ in a cool-climate through the manipulation of vegetative growth and fruit yield using competitive cover cropping and cluster thinning, respectively. To alter vine vigor, per...

  18. Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors

    International Nuclear Information System (INIS)

    Bodei, L.; Kidd, M.; Modlin, I.M.; Severi, S.; Nicolini, S.; Paganelli, G.; Drozdov, I.; Kwekkeboom, D.J.; Krenning, E.P.; Baum, R.P.

    2016-01-01

    Peptide receptor radionuclide therapy (PRRT) is an effective method for treating neuroendocrine tumors (NETs). It is limited, however, in the prediction of individual tumor response and the precise and early identification of changes in tumor size. Currently, response prediction is based on somatostatin receptor expression and efficacy by morphological imaging and/or chromogranin A (CgA) measurement. The aim of this study was to assess the accuracy of circulating NET transcripts as a measure of PRRT efficacy, and moreover to identify prognostic gene clusters in pretreatment blood that could be interpolated with relevant clinical features in order to define a biological index for the tumor and a predictive quotient for PRRT efficacy. NET patients (n = 54), M: F 37:17, median age 66, bronchial: n = 13, GEP-NET: n = 35, CUP: n = 6 were treated with 177 Lu-based-PRRT (cumulative activity: 6.5-27.8 GBq, median 18.5). At baseline: 47/54 low-grade (G1/G2; bronchial typical/atypical), 31/49 18 FDG positive and 39/54 progressive. Disease status was assessed by RECIST1.1. Transcripts were measured by real-time quantitative reverse transcription PCR (qRT-PCR) and multianalyte algorithmic analysis (NETest); CgA by enzyme-linked immunosorbent assay (ELISA). Gene cluster (GC) derivations: regulatory network, protein:protein interactome analyses. Statistical analyses: chi-square, non-parametric measurements, multiple regression, receiver operating characteristic and Kaplan-Meier survival. The disease control rate was 72 %. Median PFS was not achieved (follow-up: 1-33 months, median: 16). Only grading was associated with response (p < 0.01). At baseline, 94 % of patients were NETest-positive, while CgA was elevated in 59 %. NETest accurately (89 %, χ 2 = 27.4; p = 1.2 x 10 -7 ) correlated with treatment response, while CgA was 24 % accurate. Gene cluster expression (growth-factor signalome and metabolome) had an AUC of 0.74 ± 0.08 (z-statistic = 2.92, p < 0.004) for predicting

  19. Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors

    Energy Technology Data Exchange (ETDEWEB)

    Bodei, L. [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Kidd, M. [Wren Laboratories, Branford, CT (United States); Modlin, I.M. [LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Yale School of Medicine, New Haven, CT (United States); Severi, S.; Nicolini, S.; Paganelli, G. [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine and Radiometabolic Units, Meldola (Italy); Drozdov, I. [Bering Limited, London (United Kingdom); Kwekkeboom, D.J.; Krenning, E.P. [LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Erasmus Medical Center, Nuclear Medicine Department, Rotterdam (Netherlands); Baum, R.P. [LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Zentralklinik Bad Berka, Theranostics Center for Molecular Radiotherapy and Imaging, Bad Berka (Germany)

    2016-05-15

    Peptide receptor radionuclide therapy (PRRT) is an effective method for treating neuroendocrine tumors (NETs). It is limited, however, in the prediction of individual tumor response and the precise and early identification of changes in tumor size. Currently, response prediction is based on somatostatin receptor expression and efficacy by morphological imaging and/or chromogranin A (CgA) measurement. The aim of this study was to assess the accuracy of circulating NET transcripts as a measure of PRRT efficacy, and moreover to identify prognostic gene clusters in pretreatment blood that could be interpolated with relevant clinical features in order to define a biological index for the tumor and a predictive quotient for PRRT efficacy. NET patients (n = 54), M: F 37:17, median age 66, bronchial: n = 13, GEP-NET: n = 35, CUP: n = 6 were treated with {sup 177}Lu-based-PRRT (cumulative activity: 6.5-27.8 GBq, median 18.5). At baseline: 47/54 low-grade (G1/G2; bronchial typical/atypical), 31/49 {sup 18}FDG positive and 39/54 progressive. Disease status was assessed by RECIST1.1. Transcripts were measured by real-time quantitative reverse transcription PCR (qRT-PCR) and multianalyte algorithmic analysis (NETest); CgA by enzyme-linked immunosorbent assay (ELISA). Gene cluster (GC) derivations: regulatory network, protein:protein interactome analyses. Statistical analyses: chi-square, non-parametric measurements, multiple regression, receiver operating characteristic and Kaplan-Meier survival. The disease control rate was 72 %. Median PFS was not achieved (follow-up: 1-33 months, median: 16). Only grading was associated with response (p < 0.01). At baseline, 94 % of patients were NETest-positive, while CgA was elevated in 59 %. NETest accurately (89 %, χ{sup 2} = 27.4; p = 1.2 x 10{sup -7}) correlated with treatment response, while CgA was 24 % accurate. Gene cluster expression (growth-factor signalome and metabolome) had an AUC of 0.74 ± 0.08 (z-statistic = 2.92, p < 0

  20. Macrophage ABCA2 deletion modulates intracellular cholesterol deposition, affects macrophage apoptosis, and decreases early atherosclerosis in LDL receptor knockout mice.

    Science.gov (United States)

    Calpe-Berdiel, Laura; Zhao, Ying; de Graauw, Marjo; Ye, Dan; van Santbrink, Peter J; Mommaas, A Mieke; Foks, Amanda; Bot, Martine; Meurs, Illiana; Kuiper, Johan; Mack, Jody T; Van Eck, Miranda; Tew, Kenneth D; van Berkel, Theo J C

    2012-08-01

    The ABCA2 transporter shares high structural homology to ABCA1, which is crucial for the removal of excess cholesterol from macrophages and, by extension, in atherosclerosis. It has been suggested that ABCA2 sequesters cholesterol inside the lysosomes, however, little is known of the macrophage-specific role of ABCA2 in regulating lipid homeostasis in vivo and in modulating susceptibility to atherosclerosis. Chimeras with dysfunctional macrophage ABCA2 were generated by transplantation of bone marrow from ABCA2 knockout (KO) mice into irradiated LDL receptor (LDLr) KO mice. Interestingly, lack of ABCA2 in macrophages resulted in a diminished lesion size in the aortic root (-24.5%) and descending thoracic aorta (-36.6%) associated with a 3-fold increase in apoptotic cells, as measured by both caspase 3 and TUNEL. Upon oxidized LDL exposure, macrophages from wildtype (WT) transplanted animals developed filipin-positive droplets in lysosomal-like compartments, corresponding to free cholesterol (FC) accumulation. In contrast, ABCA2-deficient macrophages displayed an abnormal diffuse distribution of FC over peripheral regions. The accumulation of neutral sterols in lipid droplets was increased in ABCA2-deficient macrophages, but primarily in cytoplasmic clusters and not in lysosomes. Importantly, apoptosis of oxLDL loaded macrophages lacking ABCA2 was increased 2.7-fold, probably as a consequence of the broad cellular distribution of FC. Lack of functional ABCA2 generates abnormalities in intracellular lipid distribution/trafficking in macrophages consistent with its lysosomal sequestering role, leading to an increased susceptibility to apoptosis in response to oxidized lipids and reduced atherosclerotic lesion development. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  1. Skeletal muscle expression of p43, a truncated thyroid hormone receptor α, affects lipid composition and metabolism.

    Science.gov (United States)

    Casas, François; Fouret, Gilles; Lecomte, Jérome; Cortade, Fabienne; Pessemesse, Laurence; Blanchet, Emilie; Wrutniak-Cabello, Chantal; Coudray, Charles; Feillet-Coudray, Christine

    2018-02-01

    Thyroid hormone is a major regulator of metabolism and mitochondrial function. Thyroid hormone also affects reactions in almost all pathways of lipids metabolism and as such is considered as the main hormonal regulator of lipid biogenesis. The aim of this study was to explore the possible involvement of p43, a 43 Kda truncated form of the nuclear thyroid hormone receptor TRα1 which stimulates mitochondrial activity. Therefore, using mouse models overexpressing p43 in skeletal muscle (p43-Tg) or lacking p43 (p43-/-), we have investigated the lipid composition in quadriceps muscle and in mitochondria. Here, we reported in the quadriceps muscle of p43-/- mice, a fall in triglycerides, an inhibition of monounsaturated fatty acids (MUFA) synthesis, an increase in elongase index and an decrease in desaturase index. However, in mitochondria from p43-/- mice, fatty acid profile was barely modified. In the quadriceps muscle of p43-Tg mice, MUFA content was decreased whereas the unsaturation index was increased. In addition, in quadriceps mitochondria of p43-Tg mice, we found an increase of linoleic acid level and unsaturation index. Last, we showed that cardiolipin content, a key phospholipid for mitochondrial function, remained unchanged both in quadriceps muscle and in its mitochondria whatever the mice genotype. In conclusion, this study shows that muscle lipid content and fatty acid profile are strongly affected in skeletal muscle by p43 levels. We also demonstrate that regulation of cardiolipin biosynthesis by the thyroid hormone does not imply p43.

  2. The mir-279/996 cluster represses receptor tyrosine kinase signaling to determine cell fates in the Drosophila eye.

    Science.gov (United States)

    Duan, Hong; de Navas, Luis F; Hu, Fuqu; Sun, Kailiang; Mavromatakis, Yannis E; Viets, Kayla; Zhou, Cyrus; Kavaler, Joshua; Johnston, Robert J; Tomlinson, Andrew; Lai, Eric C

    2018-04-09

    Photoreceptors in the crystalline Drosophila eye are recruited by receptor tyrosine kinase (RTK)/Ras signaling mediated by Epidermal growth factor receptor (EGFR) and the Sevenless (Sev) receptor. Analyses of an allelic deletion series of the mir-279/996 locus, along with a panel of modified genomic rescue transgenes, show that Drosophila eye patterning depends on both miRNAs. Transcriptional reporter and activity sensor transgenes reveal expression and function of miR-279/996 in non-neural cells of the developing eye. Moreover, mir-279/996 mutants exhibit substantial numbers of ectopic photoreceptors, particularly of R7, and cone cell loss. These miRNAs restrict RTK signaling in the eye, since mir-279/996 nulls are dominantly suppressed by positive components of the EGFR pathway and enhanced by heterozygosity for an EGFR repressor. miR-279/996 limit photoreceptor recruitment by targeting multiple positive RTK/Ras signaling components that promote photoreceptor/R7 specification. Strikingly, deletion of mir-279/996 sufficiently derepresses RTK/Ras signaling so as to rescue a population of R7 cells in R7-specific RTK null mutants boss and sev , which otherwise completely lack this cell fate. Altogether, we reveal a rare setting of developmental cell specification that involves substantial miRNA control. © 2018. Published by The Company of Biologists Ltd.

  3. Cluster headache

    OpenAIRE

    Leroux, Elizabeth; Ducros, Anne

    2008-01-01

    Abstract Cluster headache (CH) is a primary headache disease characterized by recurrent short-lasting attacks (15 to 180 minutes) of excruciating unilateral periorbital pain accompanied by ipsilateral autonomic signs (lacrimation, nasal congestion, ptosis, miosis, lid edema, redness of the eye). It affects young adults, predominantly males. Prevalence is estimated at 0.5–1.0/1,000. CH has a circannual and circadian periodicity, attacks being clustered (hence the name) in bouts that can occur ...

  4. GABA-A receptor beta3 and alpha5 subunit gene cluster on chromosome 15q11-q13 and bipolar disorder: a genetic association study.

    Science.gov (United States)

    Papadimitriou, G N; Dikeos, D G; Karadima, G; Avramopoulos, D; Daskalopoulou, E G; Stefanis, C N

    2001-05-08

    There is accumulated evidence that the genes coding for the receptor of gamma aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the CNS, may be involved in the pathogenesis of affective disorders. In a previous study, we have found a genetic association between the GABA-A receptor alpha5 subunit gene locus (GABRA5) on chromosome 15q11-of 13 and bipolar affective disorder. The aim of the present study was to examine the same subjects to see if there exists a genetic association between bipolar affective disorder and the GABA receptor beta3 subunit gene (GABRB3), which is located within 100 kb from GABRA5. The sample consisted of 48 bipolar patients compared to 44 controls (blood donors). All subjects were Greek, unrelated, and personally interviewed. Diagnosis was based on DSM-IV and ICD-10 criteria. The marker used was a dinucleotide (CA) repeat polymorphism with 12 alleles 179 to 201 bp long; genotyping was successful in all patients and 43 controls. The distribution of GABRB3 genotypes among the controls did not deviate significantly from the Hardy-Weinberg equilibrium. No differences in allelic frequencies between bipolar patients and controls were found for GABRB3, while this locus and GABRA5 did not seem to be in significant linkage disequilibrium. In conclusion, the GABRB3 CA-repeat polymorphism we investigated does not present the observed association between bipolar affective illness and GABRA5. This could be due to higher mutation rate in the GABRB3 CA-repeat polymorphism, but it might also signify that GABRA5 is the gene actually associated with the disease. Copyright 2001 Wiley-Liss, Inc.

  5. Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity

    KAUST Repository

    Orlando, Marta; Ravasenga, Tiziana; Petrini, Enrica Maria; Falqui, Andrea; Marotta, Roberto; Barberis, Andrea

    2017-01-01

    Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABAA Receptors (GABAARs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABAAR clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABAAR clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.

  6. Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity

    KAUST Repository

    Orlando, Marta

    2017-10-17

    Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABAA Receptors (GABAARs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABAAR clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABAAR clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.

  7. Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity.

    Science.gov (United States)

    Orlando, Marta; Ravasenga, Tiziana; Petrini, Enrica Maria; Falqui, Andrea; Marotta, Roberto; Barberis, Andrea

    2017-10-23

    Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABA A Receptors (GABA A Rs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABA A R clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABA A R clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.

  8. 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.

  9. Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3.

    Science.gov (United States)

    Grieco, Steven F; Velmeshev, Dmitry; Magistri, Marco; Eldar-Finkelman, Hagit; Faghihi, Mohammad A; Jope, Richard S; Beurel, Eleonore

    2017-09-01

    We examined mechanisms that contribute to the rapid antidepressant effect of ketamine in mice that is dependent on glycogen synthase kinase-3 (GSK3) inhibition. We measured serotonergic (5HT)-2C-receptor (5HTR2C) cluster microRNA (miRNA) levels in mouse hippocampus after administering an antidepressant dose of ketamine (10 mg/kg) in wild-type and GSK3 knockin mice, after GSK3 inhibition with L803-mts, and in learned helpless mice. Ketamine up-regulated cluster miRNAs 448-3p, 764-5p, 1264-3p, 1298-5p and 1912-3p (2- to 11-fold). This up-regulation was abolished in GSK3 knockin mice that express mutant constitutively active GSK3. The GSK3 specific inhibitor L803-mts was antidepressant in the learned helplessness and novelty suppressed feeding depression-like behaviours and up-regulated the 5HTR2C miRNA cluster in mouse hippocampus. After administration of the learned helplessness paradigm mice were divided into cohorts that were resilient (non-depressed) or were susceptible (depressed) to learned helplessness. The resilient, but not depressed, mice displayed increased hippocampal levels of miRNAs 448-3p and 1264-3p. Administration of an antagonist to miRNA 448-3p diminished the antidepressant effect of ketamine in the learned helplessness paradigm, indicating that up-regulation of miRNA 448-3p provides an antidepressant action. These findings identify a new outcome of GSK3 inhibition by ketamine that may contribute to antidepressant effects.

  10. HIV-1 Nef induces proinflammatory state in macrophages through its acidic cluster domain: involvement of TNF alpha receptor associated factor 2.

    Directory of Open Access Journals (Sweden)

    Giorgio Mangino

    Full Text Available BACKGROUND: HIV-1 Nef is a virulence factor that plays multiple roles during HIV replication. Recently, it has been described that Nef intersects the CD40 signalling in macrophages, leading to modification in the pattern of secreted factors that appear able to recruit, activate and render T lymphocytes susceptible to HIV infection. The engagement of CD40 by CD40L induces the activation of different signalling cascades that require the recruitment of specific tumor necrosis factor receptor-associated factors (i.e. TRAFs. We hypothesized that TRAFs might be involved in the rapid activation of NF-κB, MAPKs and IRF-3 that were previously described in Nef-treated macrophages to induce the synthesis and secretion of proinflammatory cytokines, chemokines and IFNβ to activate STAT1, -2 and -3. METHODOLOGY/PRINCIPAL FINDINGS: Searching for possible TRAF binding sites on Nef, we found a TRAF2 consensus binding site in the AQEEEE sequence encompassing the conserved four-glutamate acidic cluster. Here we show that all the signalling effects we observed in Nef treated macrophages depend on the integrity of the acidic cluster. In addition, Nef was able to interact in vitro with TRAF2, but not TRAF6, and this interaction involved the acidic cluster. Finally silencing experiments in THP-1 monocytic cells indicate that both TRAF2 and, surprisingly, TRAF6 are required for the Nef-induced tyrosine phosphorylation of STAT1 and STAT2. CONCLUSIONS: Results reported here revealed TRAF2 as a new possible cellular interactor of Nef and highlighted that in monocytes/macrophages this viral protein is able to manipulate both the TRAF/NF-κB and TRAF/IRF-3 signalling axes, thereby inducing the synthesis of proinflammatory cytokines and chemokines as well as IFNβ.

  11. Neural androgen receptors affect the number of surviving new neurones in the adult dentate gyrus of male mice.

    Science.gov (United States)

    Swift-Gallant, A; Duarte-Guterman, P; Hamson, D K; Ibrahim, M; Monks, D A; Galea, L A M

    2018-04-01

    Adult hippocampal neurogenesis occurs in many mammalian species. In rats, the survival of new neurones within the hippocampus is modulated by the action of androgen via the androgen receptor (AR); however, it is not known whether this holds true in mice. Furthermore, the evidence is mixed regarding whether androgens act in neural tissue or via peripheral non-neural targets to promote new neurone survival in the hippocampus. We evaluated whether the action of androgen via AR underlies the survival of new neurones in mice, and investigated whether increasing AR selectively in neural tissue would increase new neurone survival in the hippocampus. We used the cre-loxP system to overexpress AR only in neural tissues (Nestin-AR). These males were compared with wild-type males, as well as control males with 1 of the 2 mutations required for overexpression. Mice were gonadectomised and injected with the DNA synthesis marker, bromodeoxyuridine (BrdU) and for 37 days (following BrdU injection), mice were treated with oil or dihydrotestosterone (DHT). Using immunohistochemistry, proliferation (Ki67) and survival (BrdU) of new neurones were both evaluated in the dorsal and ventral dentate gyrus. Dihydrotestosterone treatment increased the survival of new neurones in the entire hippocampus in wild-type mice and control mice that only have 1 of 2 necessary mutations for transgenic expression. However, DHT treatment did not increase the survival of new neurones in mice that overexpressed AR in neural tissue. Cell proliferation (Ki67) and cell death (pyknotic cells) were not affected by DHT treatment in wild-type or transgenic males. These results suggest that androgens act via neural AR to affect hippocampal neurogenesis by promoting cell survival; however, the relationship between androgen dose and new neurone survival is nonlinear. © 2018 British Society for Neuroendocrinology.

  12. Lymphotropic Virions Affect Chemokine Receptor-Mediated Neural Signaling and Apoptosis: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

    Science.gov (United States)

    Zheng, Jialin; Ghorpade, Anuja; Niemann, Douglas; Cotter, Robin L.; Thylin, Michael R.; Epstein, Leon; Swartz, Jennifer M.; Shepard, Robin B.; Liu, Xiaojuan; Nukuna, Adeline; Gendelman, Howard E.

    1999-01-01

    Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated neuronal apoptosis was confirmed in pure populations of rat cerebellar granule neurons and was blocked by HA1004, an inhibitor of calcium/calmodulin-dependent protein kinase II, protein kinase A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduction and apoptosis. This process occurs, in part, through CXCR4 and is independent of CD4 binding. T-tropic viruses that traffic in and out of the brain during progressive HIV-1 disease may play an important role in HAD neuropathogenesis. PMID:10482576

  13. Cluster headache

    Directory of Open Access Journals (Sweden)

    Ducros Anne

    2008-07-01

    Full Text Available Abstract Cluster headache (CH is a primary headache disease characterized by recurrent short-lasting attacks (15 to 180 minutes of excruciating unilateral periorbital pain accompanied by ipsilateral autonomic signs (lacrimation, nasal congestion, ptosis, miosis, lid edema, redness of the eye. It affects young adults, predominantly males. Prevalence is estimated at 0.5–1.0/1,000. CH has a circannual and circadian periodicity, attacks being clustered (hence the name in bouts that can occur during specific months of the year. Alcohol is the only dietary trigger of CH, strong odors (mainly solvents and cigarette smoke and napping may also trigger CH attacks. During bouts, attacks may happen at precise hours, especially during the night. During the attacks, patients tend to be restless. CH may be episodic or chronic, depending on the presence of remission periods. CH is associated with trigeminovascular activation and neuroendocrine and vegetative disturbances, however, the precise cautive mechanisms remain unknown. Involvement of the hypothalamus (a structure regulating endocrine function and sleep-wake rhythms has been confirmed, explaining, at least in part, the cyclic aspects of CH. The disease is familial in about 10% of cases. Genetic factors play a role in CH susceptibility, and a causative role has been suggested for the hypocretin receptor gene. Diagnosis is clinical. Differential diagnoses include other primary headache diseases such as migraine, paroxysmal hemicrania and SUNCT syndrome. At present, there is no curative treatment. There are efficient treatments to shorten the painful attacks (acute treatments and to reduce the number of daily attacks (prophylactic treatments. Acute treatment is based on subcutaneous administration of sumatriptan and high-flow oxygen. Verapamil, lithium, methysergide, prednisone, greater occipital nerve blocks and topiramate may be used for prophylaxis. In refractory cases, deep-brain stimulation of the

  14. The Gustatory Signaling Pathway and Bitter Taste Receptors Affect the Development of Obesity and Adipocyte Metabolism in Mice.

    Directory of Open Access Journals (Sweden)

    Bert Avau

    Full Text Available Intestinal chemosensory signaling pathways involving the gustatory G-protein, gustducin, and bitter taste receptors (TAS2R have been implicated in gut hormone release. Alterations in gut hormone profiles may contribute to the success of bariatric surgery. This study investigated the involvement of the gustatory signaling pathway in the development of diet-induced obesity and the therapeutic potential of targeting TAS2Rs to induce body weight loss. α-gustducin-deficient (α-gust-/- mice became less obese than wild type (WT mice when fed a high-fat diet (HFD. White adipose tissue (WAT mass was lower in α-gust-/- mice due to increased heat production as a result of increases in brown adipose tissue (BAT thermogenic activity, involving increased protein expression of uncoupling protein 1. Intra-gastric treatment of obese WT and α-gust-/- mice with the bitter agonists denatonium benzoate (DB or quinine (Q during 4 weeks resulted in an α-gustducin-dependent decrease in body weight gain associated with a decrease in food intake (DB, but not involving major changes in gut peptide release. Both WAT and 3T3-F442A pre-adipocytes express TAS2Rs. Treatment of pre-adipocytes with DB or Q decreased differentiation into mature adipocytes. In conclusion, interfering with the gustatory signaling pathway protects against the development of HFD-induced obesity presumably through promoting BAT activity. Intra-gastric bitter treatment inhibits weight gain, possibly by directly affecting adipocyte metabolism.

  15. Evaluation of a Classroom-Based Psychosocial Intervention in Conflict-Affected Nepal: A Cluster Randomized Controlled Trial

    Science.gov (United States)

    Jordans, Mark J. D.; Komproe, Ivan H.; Tol, Wietse A.; Kohrt, Brandon A.; Luitel, Nagendra P.; Macy, Robert D.; de Jong, Joop T. V. M.

    2010-01-01

    Background: In situations of ongoing violence, childhood psychosocial and mental health problems require care. However, resources and evidence for adequate interventions are scarce for children in low- and middle-income countries. This study evaluated a school-based psychosocial intervention in conflict-affected, rural Nepal. Methods: A cluster…

  16. Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s)

    DEFF Research Database (Denmark)

    Jorgensen, Rasmus; Kubale, Valentina; Vrecl, Milka

    2007-01-01

    The glucagon-like peptide (GLP)-1 receptor is a promising target for the treatment of type 2 diabetes and obesity, and there is great interest in characterizing the pharmacology of the GLP-1 receptor and its ligands. In the present report, we have applied bioluminescence resonance energy transfer...

  17. Clustering of near clusters versus cluster compactness

    International Nuclear Information System (INIS)

    Yu Gao; Yipeng Jing

    1989-01-01

    The clustering properties of near Zwicky clusters are studied by using the two-point angular correlation function. The angular correlation functions for compact and medium compact clusters, for open clusters, and for all near Zwicky clusters are estimated. The results show much stronger clustering for compact and medium compact clusters than for open clusters, and that open clusters have nearly the same clustering strength as galaxies. A detailed study of the compactness-dependence of correlation function strength is worth investigating. (author)

  18. Clustering Dycom

    KAUST Repository

    Minku, Leandro L.

    2017-10-06

    Background: Software Effort Estimation (SEE) can be formulated as an online learning problem, where new projects are completed over time and may become available for training. In this scenario, a Cross-Company (CC) SEE approach called Dycom can drastically reduce the number of Within-Company (WC) projects needed for training, saving the high cost of collecting such training projects. However, Dycom relies on splitting CC projects into different subsets in order to create its CC models. Such splitting can have a significant impact on Dycom\\'s predictive performance. Aims: This paper investigates whether clustering methods can be used to help finding good CC splits for Dycom. Method: Dycom is extended to use clustering methods for creating the CC subsets. Three different clustering methods are investigated, namely Hierarchical Clustering, K-Means, and Expectation-Maximisation. Clustering Dycom is compared against the original Dycom with CC subsets of different sizes, based on four SEE databases. A baseline WC model is also included in the analysis. Results: Clustering Dycom with K-Means can potentially help to split the CC projects, managing to achieve similar or better predictive performance than Dycom. However, K-Means still requires the number of CC subsets to be pre-defined, and a poor choice can negatively affect predictive performance. EM enables Dycom to automatically set the number of CC subsets while still maintaining or improving predictive performance with respect to the baseline WC model. Clustering Dycom with Hierarchical Clustering did not offer significant advantage in terms of predictive performance. Conclusion: Clustering methods can be an effective way to automatically generate Dycom\\'s CC subsets.

  19. Practice context affects efforts to improve diabetes care for primary care patients: a pragmatic cluster randomized trial.

    Science.gov (United States)

    Dickinson, L Miriam; Dickinson, W Perry; Nutting, Paul A; Fisher, Lawrence; Harbrecht, Marjie; Crabtree, Benjamin F; Glasgow, Russell E; West, David R

    2015-04-01

    Efforts to improve primary care diabetes management have assessed strategies across heterogeneous groups of patients and practices. However, there is substantial variability in how well practices implement interventions and achieve desired outcomes. To examine practice contextual features that moderate intervention effectiveness. Secondary analysis of data from a cluster randomized trial of three approaches for implementing the Chronic Care Model to improve diabetes care. Forty small to mid-sized primary care practices participated, with 522 clinician and staff member surveys. Outcomes were assessed for 822 established patients with a diagnosis of type 2 diabetes who had at least one visit to the practice in the 18 months following enrollment. The primary outcome was a composite measure of diabetes process of care, ascertained by chart audit, regarding nine quality measures from the American Diabetes Association Physician Recognition Program: HgA1c, foot exam, blood pressure, dilated eye exam, cholesterol, nephropathy screen, flu shot, nutrition counseling, and self-management support. Data from practices included structural and demographic characteristics and Practice Culture Assessment survey subscales (Change Culture, Work Culture, Chaos). Across the three implementation approaches, demographic/structural characteristics (rural vs. urban + .70(p = .006), +2.44(p Culture (high vs. low: -.86(p = .048), +1.71(p = .005), +.34(p = .22)), Work Culture (high vs. low: -.67(p = .18), +2.41(p Culture (high vs. low: -.24(p = .006), -.20(p = .0771), -.44(p = .0019) and Work Culture (high vs. low: +.56(p = .3160), -1.0(p = .008), -.25 (p = .0216) were associated with trajectories of change in diabetes process of care, either directly or differentially by study arm. This study supports the need for broader use of methodological approaches to better examine contextual effects on implementation and effectiveness of quality improvement interventions in primary care settings.

  20. Acetylcholine receptor (AChR) clustering is regulated both by glycogen synthase kinase 3β (GSK3β)-dependent phosphorylation and the level of CLIP-associated protein 2 (CLASP2) mediating the capture of microtubule plus-ends.

    Science.gov (United States)

    Basu, Sreya; Sladecek, Stefan; Pemble, Hayley; Wittmann, Torsten; Slotman, Johan A; van Cappellen, Wiggert; Brenner, Hans-Rudolf; Galjart, Niels

    2014-10-31

    The postsynaptic apparatus of the neuromuscular junction (NMJ) traps and anchors acetylcholine receptors (AChRs) at high density at the synapse. We have previously shown that microtubule (MT) capture by CLASP2, a MT plus-end-tracking protein (+TIP), increases the size and receptor density of AChR clusters at the NMJ through the delivery of AChRs and that this is regulated by a pathway involving neuronal agrin and several postsynaptic kinases, including GSK3. Phosphorylation by GSK3 has been shown to cause CLASP2 dissociation from MT ends, and nine potential phosphorylation sites for GSK3 have been mapped on CLASP2. How CLASP2 phosphorylation regulates MT capture at the NMJ and how this controls the size of AChR clusters are not yet understood. To examine this, we used myotubes cultured on agrin patches that induce AChR clustering in a two-dimensional manner. We show that expression of a CLASP2 mutant, in which the nine GSK3 target serines are mutated to alanine (CLASP2-9XS/9XA) and are resistant to GSK3β-dependent phosphorylation, promotes MT capture at clusters and increases AChR cluster size, compared with myotubes that express similar levels of wild type CLASP2 or that are noninfected. Conversely, myotubes expressing a phosphomimetic form of CLASP2 (CLASP2-8XS/D) show enrichment of immobile mutant CLASP2 in clusters, but MT capture and AChR cluster size are reduced. Taken together, our data suggest that both GSK3β-dependent phosphorylation and the level of CLASP2 play a role in the maintenance of AChR cluster size through the regulated capture and release of MT plus-ends. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors

    DEFF Research Database (Denmark)

    Ronn, Jonas; Jensen, Elisa P; Wewer Albrechtsen, Nicolai J

    2017-01-01

    to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP-1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP-1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect......Glucagon-like peptide-1 (GLP-1) is an incretin hormone increasing postprandial insulin release. GLP-1 also induces diuresis and natriuresis in humans and rodents. The GLP-1 receptor is extensively expressed in the renal vascular tree in normotensive rats where acute GLP-1 treatment leads...... in the kidney from SHR. However, acute intrarenal infusion of GLP-1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP-1 in SHR are caused either by extrarenal GLP-1 receptors activating other mechanisms (e...

  2. Members of Bitter Taste Receptor Cluster Tas2r143/Tas2r135/Tas2r126 Are Expressed in the Epithelium of Murine Airways and Other Non-gustatory Tissues

    Directory of Open Access Journals (Sweden)

    Shuya Liu

    2017-10-01

    Full Text Available The mouse bitter taste receptors Tas2r143, Tas2r135, and Tas2r126 are encoded by genes that cluster on chromosome 6 and have been suggested to be expressed under common regulatory elements. Previous studies indicated that the Tas2r143/Tas2r135/Tas2r126 cluster is expressed in the heart, but other organs had not been systematically analyzed. In order to investigate the expression of this bitter taste receptor gene cluster in non-gustatory tissues, we generated a BAC (bacterial artificial chromosome based transgenic mouse line, expressing CreERT2 under the control of the Tas2r143 promoter. After crossing this line with a mouse line expressing EGFP after Cre-mediated recombination, we were able to validate the Tas2r143-CreERT2 transgenic mouse line and monitor the expression of Tas2r143. EGFP-positive cells, indicating expression of members of the cluster, were found in about 47% of taste buds, and could also be found in several other organs. A population of EGFP-positive cells was identified in thymic epithelial cells, in the lamina propria of the intestine and in vascular smooth muscle cells of cardiac blood vessels. EGFP-positive cells were also identified in the epithelium of organs readily exposed to pathogens including lower airways, the gastrointestinal tract, urethra, vagina, and cervix. With respect to the function of cells expressing this bitter taste receptor cluster, RNA-seq analysis in EGFP-positive cells isolated from the epithelium of trachea and stomach showed expression of genes related to innate immunity. These data further support the concept that bitter taste receptors serve functions outside the gustatory system.

  3. Long-Range Regulatory Polymorphisms Affecting a GABA Receptor Constitute a Quantitative Trait Locus (QTL) for Social Behavior in Caenorhabditis elegans

    Science.gov (United States)

    Bendesky, Andres; Pitts, Jason; Rockman, Matthew V.; Chen, William C.; Tan, Man-Wah; Kruglyak, Leonid; Bargmann, Cornelia I.

    2012-01-01

    Aggregation is a social behavior that varies between and within species, providing a model to study the genetic basis of behavioral diversity. In the nematode Caenorhabditis elegans, aggregation is regulated by environmental context and by two neuromodulatory pathways, one dependent on the neuropeptide receptor NPR-1 and one dependent on the TGF-β family protein DAF-7. To gain further insight into the genetic regulation of aggregation, we characterize natural variation underlying behavioral differences between two wild-type C. elegans strains, N2 and CB4856. Using quantitative genetic techniques, including a survey of chromosome substitution strains and QTL analysis of recombinant inbred lines, we identify three new QTLs affecting aggregation in addition to the two known N2 mutations in npr-1 and glb-5. Fine-mapping with near-isogenic lines localized one QTL, accounting for 5%–8% of the behavioral variance between N2 and CB4856, 3′ to the transcript of the GABA neurotransmitter receptor gene exp-1. Quantitative complementation tests demonstrated that this QTL affects exp-1, identifying exp-1 and GABA signaling as new regulators of aggregation. exp-1 interacts genetically with the daf-7 TGF-β pathway, which integrates food availability and population density, and exp-1 mutations affect the level of daf-7 expression. Our results add to growing evidence that genetic variation affecting neurotransmitter receptor genes is a source of natural behavioral variation. PMID:23284308

  4. Long-range regulatory polymorphisms affecting a GABA receptor constitute a quantitative trait locus (QTL for social behavior in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Andres Bendesky

    Full Text Available Aggregation is a social behavior that varies between and within species, providing a model to study the genetic basis of behavioral diversity. In the nematode Caenorhabditis elegans, aggregation is regulated by environmental context and by two neuromodulatory pathways, one dependent on the neuropeptide receptor NPR-1 and one dependent on the TGF-β family protein DAF-7. To gain further insight into the genetic regulation of aggregation, we characterize natural variation underlying behavioral differences between two wild-type C. elegans strains, N2 and CB4856. Using quantitative genetic techniques, including a survey of chromosome substitution strains and QTL analysis of recombinant inbred lines, we identify three new QTLs affecting aggregation in addition to the two known N2 mutations in npr-1 and glb-5. Fine-mapping with near-isogenic lines localized one QTL, accounting for 5%-8% of the behavioral variance between N2 and CB4856, 3' to the transcript of the GABA neurotransmitter receptor gene exp-1. Quantitative complementation tests demonstrated that this QTL affects exp-1, identifying exp-1 and GABA signaling as new regulators of aggregation. exp-1 interacts genetically with the daf-7 TGF-β pathway, which integrates food availability and population density, and exp-1 mutations affect the level of daf-7 expression. Our results add to growing evidence that genetic variation affecting neurotransmitter receptor genes is a source of natural behavioral variation.

  5. Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors.

    Science.gov (United States)

    Ronn, Jonas; Jensen, Elisa P; Wewer Albrechtsen, Nicolai J; Holst, Jens Juul; Sorensen, Charlotte M

    2017-12-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone increasing postprandial insulin release. GLP-1 also induces diuresis and natriuresis in humans and rodents. The GLP-1 receptor is extensively expressed in the renal vascular tree in normotensive rats where acute GLP-1 treatment leads to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP-1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP-1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect of acute intrarenal infusion of GLP-1. We hypothesized that GLP-1 would increase diuresis and natriuresis and reduce MAP in SHR. Immunohistochemical staining and in situ hybridization for the GLP-1 receptor were used to localize GLP-1 receptors in the kidney. Sevoflurane-anesthetized normotensive Sprague-Dawley rats and SHR received a 20 min intrarenal infusion of GLP-1 and changes in MAP, RBF, heart rate, dieresis, and natriuresis were measured. The vasodilatory effect of GLP-1 was assessed in isolated interlobar arteries from normo- and hypertensive rats. We found no expression of GLP-1 receptors in the kidney from SHR. However, acute intrarenal infusion of GLP-1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP-1 in SHR are caused either by extrarenal GLP-1 receptors activating other mechanisms (e.g., insulin) to induce the renal changes observed or possibly by an alternative renal GLP-1 receptor. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  6. Uteroplacental insufficiency down regulates insulin receptor and affects expression of key enzymes of long-chain fatty acid (LCFA metabolism in skeletal muscle at birth

    Directory of Open Access Journals (Sweden)

    Puglianiello Antonella

    2008-05-01

    Full Text Available Abstract Background Epidemiological studies have revealed a relationship between early growth restriction and the subsequent development of insulin resistance and type 2 diabetes. Ligation of the uterine arteries in rats mimics uteroplacental insufficiency and serves as a model of intrauterine growth restriction (IUGR and subsequent developmental programming of impaired glucose tolerance, hyperinsulinemia and adiposity in the offspring. The objective of this study was to investigate the effects of uterine artery ligation on the skeletal muscle expression of insulin receptor and key enzymes of LCFA metabolism. Methods Bilateral uterine artery ligation was performed on day 19 of gestation in Sprague-Dawley pregnant rats. Muscle of the posterior limb was dissected at birth and processed by real-time RT-PCR to analyze the expression of insulin receptor, ACCα, ACCβ (acetyl-CoA carboxylase alpha and beta subunits, ACS (acyl-CoA synthase, AMPK (AMP-activated protein kinase, alpha2 catalytic subunit, CPT1B (carnitine palmitoyltransferase-1 beta subunit, MCD (malonyl-CoA decarboxylase in 14 sham and 8 IUGR pups. Muscle tissue was treated with lysis buffer and Western immunoblotting was performed to assay the protein content of insulin receptor and ACC. Results A significant down regulation of insulin receptor protein (p Conclusion Our data suggest that uteroplacental insufficiency may affect skeletal muscle metabolism down regulating insulin receptor and reducing the expression of key enzymes involved in LCFA formation and oxidation.

  7. Label-free sensitive luminescence biosensor for immunoglobulin G based on Ag6Au6 ethisterone cluster-estrogen receptor α aggregation and graphene.

    Science.gov (United States)

    Chen, Nannan; Guo, Wenjing; Lin, Zhixiang; Wei, Qiaohua; Chen, Guonan

    2018-08-01

    A specific and label-free "on-off-on" luminescence biosensor based on a novel heterometallic cluster [Ag 6 Au 6 (ethisterone) 12 ]-estrogen receptor α (Ag 6 Au 6 Eth-ERα) aggregation utilizing graphene oxide (GO) as a quencher to lead a small background signal was firstly constructed to detect immunoglobulin G (IgG) with a simple process and high selectivity. The efficient photoluminescent (PL) Ag 6 Au 6 Eth-ERα aggregation is strongly quenched by GO. In the presence of IgG, the PL of this system will be restored, and perceivable by human eyes under UV lamp excitation (365 nm). The quenching mechanism of GO on Ag 6 Au 6 Eth-ERα and enhancement mechanism of IgG on Ag 6 Au 6 Eth-ERα-GO were investigated in detail. Under the optimum conditions, the biosensor for high sensitive IgG detection expressed a wider linear range of 0.0078-10 ng/mL and a lower detection limit of 0.65 pg/mL with good stability and repeatability, which provided a new approach for label-free IgG detection. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Affective temperaments are associated with specific clusters of symptoms and psychopathology: a cross-sectional study on bipolar disorder inpatients in acute manic, mixed, or depressive relapse.

    Science.gov (United States)

    Iasevoli, Felice; Valchera, Alessandro; Di Giovambattista, Emanuela; Marconi, Massimo; Rapagnani, Maria Paola; De Berardis, Domenico; Martinotti, Giovanni; Fornaro, Michele; Mazza, Monica; Tomasetti, Carmine; Buonaguro, Elisabetta F; Di Giannantonio, Massimo; Perugi, Giulio; de Bartolomeis, Andrea

    2013-11-01

    The aim of this study was to assess whether different affective temperaments could be related to a specific mood disorder diagnosis and/or to different therapeutic choices in inpatients admitted for an acute relapse of their primary mood disorder. Hundred and twenty-nine inpatients were consecutively assessed by means of the Structured and Clinical Interview for axis-I disorders/Patient edition and by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego auto-questionnaire, Young Mania Rating Scale, Hamilton Scale for Depression and for Anxiety, Brief Psychiatry Rating Scale, Clinical Global impression, Drug Attitude Inventory, Barratt Impulsiveness Scale, Toronto Alexithymia Scale, and Symptoms Checklist-90 items version, along with records of clinical and demographic data. The following prevalence rates for axis-I mood diagnoses were detected: bipolar disorder type I (BD-I, 28%), type II (31%), type not otherwise specified (BD-NOS, 33%), major depressive disorder (4%), and schizoaffective disorder (4%). Mean scores on the hyperthymic temperament scale were significantly higher in BD-I and BD-NOS, and in mixed and manic acute states. Hyperthymic temperament was significantly more frequent in BD-I and BD-NOS patients, whereas depressive temperament in BD-II ones. Hyperthymic and irritable temperaments were found more frequently in mixed episodes, while patients with depressive and mixed episodes more frequently exhibited anxious and depressive temperaments. Affective temperaments were associated with specific symptom and psychopathology clusters, with an orthogonal subdivision between hyperthymic temperament and anxious/cyclothymic/depressive/irritable temperaments. Therapeutic choices were often poorly differentiated among temperaments and mood states. Cross-sectional design; sample size. Although replication studies are needed, current results suggest that temperament-specific clusters of symptoms severity and psychopathology domains could be

  9. Cocaine self-administration differentially affects allosteric A2A-D2 receptor-receptor interactions in the striatum. Relevance for cocaine use disorder.

    Science.gov (United States)

    Pintsuk, Julia; Borroto-Escuela, Dasiel O; Pomierny, Bartosz; Wydra, Karolina; Zaniewska, Magdalena; Filip, Malgorzata; Fuxe, Kjell

    2016-05-01

    In the current study behavioral and biochemical experiments were performed to study changes in the allosteric A2AR-D2R interactions in the ventral and dorsal striatum after cocaine self-administration versus corresponding yoked saline control. By using ex vivo [(3)H]-raclopride/quinpirole competition experiments, the effects of the A2AR agonist CGS 21680 (100 nM) on the KiH and KiL values of the D2-like receptor (D2-likeR) were determined. One major result was a significant reduction in the D2-likeR agonist high affinity state observed with CGS 21680 after cocaine self-administration in the ventral striatum compared with the yoked saline group. The results therefore support the hypothesis that A2AR agonists can at least in part counteract the motivational actions of cocaine. This action is mediated via the D2-likeR by targeting the A2AR protomer of A2AR-D2-like R heteroreceptor complexes in the ventral striatum, which leads to the reduction of D2-likeR protomer recognition through the allosteric receptor-receptor interaction. In contrast, in the dorsal striatum the CGS 21680-induced antagonistic modulation in the D2-likeR agonist high affinity state was abolished after cocaine self-administration versus the yoked saline group probably due to a local dysfunction/disruption of the A2AR-D2-like R heteroreceptor complexes. Such a change in the dorsal striatum in cocaine self-administration can contribute to the development of either locomotor sensitization, habit-forming learning and/or the compulsive drug seeking by enhanced D2-likeR protomer signaling. Potential differences in the composition and stoichiometry of the A2AR-D2R heteroreceptor complexes, including differential recruitment of sigma 1 receptor, in the ventral and dorsal striatum may explain the differential regional changes observed in the A2A-D2-likeR interactions after cocaine self-administration. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. High fructose-mediated attenuation of insulin receptor signaling does not affect PDGF-induced proliferative signaling in vascular smooth muscle cells.

    Science.gov (United States)

    Osman, Islam; Poulose, Ninu; Ganapathy, Vadivel; Segar, Lakshman

    2016-11-15

    Insulin resistance is associated with accelerated atherosclerosis. Although high fructose is known to induce insulin resistance, it remains unclear as to how fructose regulates insulin receptor signaling and proliferative phenotype in vascular smooth muscle cells (VSMCs), which play a major role in atherosclerosis. Using human aortic VSMCs, we investigated the effects of high fructose treatment on insulin receptor substrate-1 (IRS-1) serine phosphorylation, insulin versus platelet-derived growth factor (PDGF)-induced phosphorylation of Akt, S6 ribosomal protein, and extracellular signal-regulated kinase (ERK), and cell cycle proteins. In comparison with PDGF (a potent mitogen), neither fructose nor insulin enhanced VSMC proliferation and cyclin D1 expression. d-[ 14 C(U)]fructose uptake studies revealed a progressive increase in fructose uptake in a time-dependent manner. Concentration-dependent studies with high fructose (5-25mM) showed marked increases in IRS-1 serine phosphorylation, a key adapter protein in insulin receptor signaling. Accordingly, high fructose treatment led to significant diminutions in insulin-induced phosphorylation of downstream signaling components including Akt and S6. In addition, high fructose significantly diminished insulin-induced ERK phosphorylation. Nevertheless, high fructose did not affect PDGF-induced key proliferative signaling events including phosphorylation of Akt, S6, and ERK and expression of cyclin D1 protein. Together, high fructose dysregulates IRS-1 phosphorylation state and proximal insulin receptor signaling in VSMCs, but does not affect PDGF-induced proliferative signaling. These findings suggest that systemic insulin resistance rather than VSMC-specific dysregulation of insulin receptor signaling by high fructose may play a major role in enhancing atherosclerosis and neointimal hyperplasia. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Disturbances of ligand potency and enhanced degradation of the human glycine receptor at affected positions G160 and T162 originally identified in patients suffering from hyperekplexia

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    Sinem eAtak

    2015-12-01

    Full Text Available Ligand-binding of Cys-loop receptors is determined by N-terminal extracellular loop structures from the plus as well as from the minus side of two adjacent subunits in the pentameric receptor complex. An aromatic residue in loop B of the glycine receptor (GlyR undergoes direct interaction with the incoming ligand via cation-π interactions. Recently we showed that mutated residues in loop B identified from human patients suffering from hyperekplexia disturb ligand-binding. Here, we exchanged the affected human residues by amino acids found in related members of the Cys-loop receptor family to determine the effects of side chain volume for ion channel properties. GlyR variants were characterized in vitro following transfection into cell lines in order to analyze protein expression, trafficking, degradation and ion channel function. GlyR α1 G160 mutations significantly decrease glycine potency arguing for a positional effect on neighboring aromatic residues and consequently glycine-binding within the ligand-binding pocket. Disturbed glycinergic inhibition due to T162 α1 mutations is an additive effect of affected biogenesis and structural changes within the ligand-binding site. Protein trafficking from the ER towards ER-Golgi intermediate compartment, the secretory Golgi pathways and finally the cell surface is largely diminished, but still sufficient to deliver ion channels that are functional at least at high glycine concentrations. The majority of T162 mutant protein accumulates in the ER and is conducted to ER-associated proteasomal degradation. Hence, G160 is an important determinant during glycine binding. In contrast, T162 assigns primarily receptor biogenesis whereas exchanges in functionality are secondary effects thereof.

  12. Quantitation of Fc receptors and surface immunoglobulin is affected by cell isolation procedures using plasmagel and ficoll-hypaque.

    Science.gov (United States)

    Alexander, E L; Titus, J A; Segal, D M

    1978-01-01

    When mononuclear leukocytes are isolated directly from whole human blood using Ficoll-Hypaque or Plasmagel, cytophilic immunoglobulin is detected on cell surfaces. Upon incubation at 37 degrees C, this cell-associated immunoglobulin is shed slowly into the medium. However, when cells are prewashed in phosphate-buffered saline prior to isolation, they appear to be free of cytophilic immunoglobulin. Compared to prewashed cells, populations retaining cytophilic immunoglobulin on their surfaces demonstrate a decreased binding of soluble immune complexes and radiolabelled trimeric rabbit IgG. The data suggest that Ficoll-Hypaque and Plasmagel cause serum IgG to bind with abnormally high affinity to human mononuclear leukocytes, probably via Fc receptors. This artifact of preparation can lead to erroneous estimates of the numbers of cells bearing Fc receptors or intrinsic membrane immunoglobulin within a given population of cells and to an inaccurate assessment of the average number of Fc receptors per cell.

  13. Raphe serotonin neuron-specific oxytocin receptor knockout reduces aggression without affecting anxiety-like behavior in male mice only.

    Science.gov (United States)

    Pagani, J H; Williams Avram, S K; Cui, Z; Song, J; Mezey, É; Senerth, J M; Baumann, M H; Young, W S

    2015-02-01

    Serotonin and oxytocin influence aggressive and anxiety-like behaviors, though it is unclear how the two may interact. That the oxytocin receptor is expressed in the serotonergic raphe nuclei suggests a mechanism by which the two neurotransmitters may cooperatively influence behavior. We hypothesized that oxytocin acts on raphe neurons to influence serotonergically mediated anxiety-like, aggressive and parental care behaviors. We eliminated expression of the oxytocin receptor in raphe neurons by crossing mice expressing Cre recombinase under control of the serotonin transporter promoter (Slc6a4) with our conditional oxytocin receptor knockout line. The knockout mice generated by this cross are normal across a range of behavioral measures: there are no effects for either sex on locomotion in an open-field, olfactory habituation/dishabituation or, surprisingly, anxiety-like behaviors in the elevated O and plus mazes. There was a profound deficit in male aggression: only one of 11 raphe oxytocin receptor knockouts showed any aggressive behavior, compared to 8 of 11 wildtypes. In contrast, female knockouts displayed no deficits in maternal behavior or aggression. Our results show that oxytocin, via its effects on raphe neurons, is a key regulator of resident-intruder aggression in males but not maternal aggression. Furthermore, this reduction in male aggression is quite different from the effects reported previously after forebrain or total elimination of oxytocin receptors. Finally, we conclude that when constitutively eliminated, oxytocin receptors expressed by serotonin cells do not contribute to baseline anxiety-like behaviors or maternal care. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  14. GnRH-agonist implantation of prepubertal male cats affects their reproductive performance and testicular LH receptor and FSH receptor expression.

    Science.gov (United States)

    Mehl, N S; Khalid, M; Srisuwatanasagul, S; Swangchan-Uthai, T; Sirivaidyapong, S

    2016-03-15

    This study was conducted to investigate the effect of GnRH-agonist implantation in prepubertal tomcats on sexual behavior, reproductive performance, and expression of testicular LH receptor (LHR) and FSH receptor (FSHR) and also to compare the testicular characteristics, LHR and FSHR expression between prepubertal and adult tomcats. In experiment 1, 3-month-old tomcats (n = 6/group) were either treated with or left without 4.7 mg deslorelin implants. Semen collection and evaluation were performed just before castration at 48 weeks after treatment; removed testes were analyzed for mRNA and protein expression of LHR and FSHR. We were able to collect semen from six non-treated cats, whereas in treated cats, semen was uncollectable. The results revealed that sexual behavior was absent in the implanted cats throughout the study period. Testicular volume was found to decrease from 30 weeks after treatment onward in the implanted cats compared to the controls (P score, seminiferous tubule diameter, and LHR protein expression were found lower in the implanted cats (P reproductive function without any adverse effects for at least 48 weeks in male cats. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Zolpidem, a clinical hypnotic that affects electronic transfer, alters synaptic activity through potential GABA receptors in the nervous system without significant free radical generation.

    Science.gov (United States)

    Kovacic, Peter; Somanathan, Ratnasamy

    2009-01-01

    Zolpidem (trade name Ambien) has attracted much interest as a sleep-inducing agent and also in research. Attention has been centered mainly on receptor binding and electrochemistry in the central nervous system which are briefly addressed herein. A novel integrated approach to mode of action is presented. The pathways to be discussed involve basicity, reduction potential, electrostatics, cell signaling, GABA receptor binding, electron transfer (ET), pharmacodynamics, structure activity relationships (SAR) and side effects. The highly conjugated pyridinium salt formed by protonation of the amidine moiety is proposed to be the active form acting as an ET agent. Extrapolation of reduction potentials for related compounds supports the premise that zolpidem may act as an ET species in vivo. From recent literature reports, electrostatics is believed to play a significant role in drug action. The pyridinium cation displays molecular electrostatic potential which may well play a role energetically or as a bridging mechanism. An SAR analysis points to analogy with other physiologically active xenobiotics, namely benzodiazepines and paraquat in the conjugated iminium category. Inactivity of metabolites indicates that the parent is the active form of zolpidem. Absence of reactive oxygen species and oxidative stress is in line with minor side effects. In contrast, generally, the prior literature contains essentially no discussion of these fundamental biochemical relationships. Pharmacodynamics may play an important role. Concerning behavior at the blood-brain barrier, useful insight can be gained from investigations of the related cationic anesthetics that are structurally related to acetyl choline. Evidently, the neutral form of the drug penetrates the neuronal membrane, with the salt form operating at the receptor. The pathways of zolpidem have several clinical implications since the agent affects sedation, electroencephalographic activity, oxidative metabolites and

  16. Community engagement and integrated health and polio immunisation campaigns in conflict-affected areas of Pakistan: a cluster randomised controlled trial.

    Science.gov (United States)

    Habib, Muhammad Atif; Soofi, Sajid; Cousens, Simon; Anwar, Saeed; Haque, Najib Ul; Ahmed, Imran; Ali, Noshad; Tahir, Rehman; Bhutta, Zulfiqar A

    2017-06-01

    Pakistan faces huge challenges in eradicating polio due to widespread poliovirus transmission and security challenges. Innovative interventions are urgently needed to strengthen community buy-in, to increase the coverage of oral polio vaccine (OPV) and other routine immunisations, and to enhance immunity through the introduction of inactivated polio vaccine (IPV) in combination with OPV. We aimed to evaluate the acceptability and effect on immunisation coverage of an integrated strategy for community engagement and maternal and child health immunisation campaigns in insecure and conflict-affected polio-endemic districts of Pakistan. We did a community-based three-arm cluster randomised trial in healthy children aged 1 month to 5 years that resided within the study sites in three districts of Pakistan at high risk of polio. Clusters were randomly assigned by a computer algorithm using restricted randomisation in blocks of 20 by an external statistician (1:1:1) to receive routine polio programme activities (control, arm A), additional interventions with community outreach and mobilisation using an enhanced communication package and provision of short-term preventive maternal and child health services and routine immunisation (health camps), including OPV (arm B), or all interventions of arm B with additional provision of IPV delivered at the maternal and child health camps (arm C). An independent team conducted surveys at baseline, endline, and after each round of supplementary immunisation activity for acceptability and effect. The primary outcome measures for the study were coverage of OPV, IPV, and routine extended programme on immunisation vaccines and changes in the proportion of unvaccinated and fully vaccinated children. This trial is registered with ClinicalTrials.gov, number NCT01908114. Between June 4, 2013, and May 31, 2014, 387 clusters were randomised (131 to arm A, 127 to arm B, and 129 to arm C). At baseline, 28 760 children younger than 5 years were

  17. Toll-Like Receptors 2 and 3 Agonists Differentially Affect Oligodendrocyte Survival, Differentiation, and Myelin Membrane Formation

    NARCIS (Netherlands)

    Bsibsi, Malika; Nomden, Anita; van Noort, Johannes M.; Baron, Wia

    Toll-like receptors (TLRs) play a key role in controlling innate immune responses to a wide variety of pathogen-associated molecules as well as endogenous signals. In addition, TLR expression within nonimmune cells has been recognized as as modulator of cell behavior. In this study we have addressed

  18. Cdx2 Polymorphism Affects the Activities of Vitamin D Receptor in Human Breast Cancer Cell Lines and Human Breast Carcinomas

    Science.gov (United States)

    Di Benedetto, Anna; Korita, Etleva; Goeman, Frauke; Sacconi, Andrea; Biagioni, Francesca; Blandino, Giovanni; Strano, Sabrina; Muti, Paola; Mottolese, Marcella; Falvo, Elisabetta

    2015-01-01

    Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). It regulates the action of hormone responsive genes and is involved in cell cycle regulation, differentiation and apoptosis. VDR is a critical component of the vitamin D pathway and different common single nucleotide polymorphisms have been identified. Cdx2 VDR polymorphism can play an important role in breast cancer, modulating the activity of VDR. The objective of this study is to assess the relationship between the Cdx2 VDR polymorphism and the activities of VDR in human breast cancer cell lines and carcinomas breast patients. Cdx2 VDR polymorphism and antiproliferative effects of vitamin D treatment were investigated in a panel of estrogen receptor-positive (MCF7 and T-47D) and estrogen receptor-negative (MDA-MB-231, SUM 159PT, SK-BR-3, BT549, MDA-MB-468, HCC1143, BT20 and HCC1954) human breast cancer cell lines. Furthermore, the potential relationship among Cdx2 VDR polymorphism and a number of biomarkers used in clinical management of breast cancer was assessed in an ad hoc set of breast cancer cases. Vitamin D treatment efficacy was found to be strongly dependent on the Cdx2 VDR status in ER-negative breast cancer cell lines tested. In our series of breast cancer cases, the results indicated that patients with variant homozygote AA were associated with bio-pathological characteristics typical of more aggressive tumours, such as ER negative, HER2 positive and G3. Our results may suggest a potential effect of Cdx2 VDR polymorphism on the efficacy of vitamin D treatment in aggressive breast cancer cells (estrogen receptor negative). These results suggest that Cdx2 polymorphism may be a potential biomarker for vitamin D treatment in breast cancer, independently of the VDR receptor expression. PMID:25849303

  19. Cdx2 polymorphism affects the activities of vitamin D receptor in human breast cancer cell lines and human breast carcinomas.

    Directory of Open Access Journals (Sweden)

    Claudio Pulito

    Full Text Available Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR. It regulates the action of hormone responsive genes and is involved in cell cycle regulation, differentiation and apoptosis. VDR is a critical component of the vitamin D pathway and different common single nucleotide polymorphisms have been identified. Cdx2 VDR polymorphism can play an important role in breast cancer, modulating the activity of VDR. The objective of this study is to assess the relationship between the Cdx2 VDR polymorphism and the activities of VDR in human breast cancer cell lines and carcinomas breast patients. Cdx2 VDR polymorphism and antiproliferative effects of vitamin D treatment were investigated in a panel of estrogen receptor-positive (MCF7 and T-47D and estrogen receptor-negative (MDA-MB-231, SUM 159PT, SK-BR-3, BT549, MDA-MB-468, HCC1143, BT20 and HCC1954 human breast cancer cell lines. Furthermore, the potential relationship among Cdx2 VDR polymorphism and a number of biomarkers used in clinical management of breast cancer was assessed in an ad hoc set of breast cancer cases. Vitamin D treatment efficacy was found to be strongly dependent on the Cdx2 VDR status in ER-negative breast cancer cell lines tested. In our series of breast cancer cases, the results indicated that patients with variant homozygote AA were associated with bio-pathological characteristics typical of more aggressive tumours, such as ER negative, HER2 positive and G3. Our results may suggest a potential effect of Cdx2 VDR polymorphism on the efficacy of vitamin D treatment in aggressive breast cancer cells (estrogen receptor negative. These results suggest that Cdx2 polymorphism may be a potential biomarker for vitamin D treatment in breast cancer, independently of the VDR receptor expression.

  20. Source-receptor relationships for PM2.5 during typical pollution episodes in the Pearl River Delta city cluster, China

    Science.gov (United States)

    Fan, Q.; Liu, Y.; Hong, Y.; Wang, X.; Chan, P.; Chen, X.; Lai, A.; Wang, M.; Chen, X.

    2017-12-01

    Located in the Southern China monsoon region, pollution days in Pearl River Delta (PRD) were classified into "Western type", "Central type" or "Eastern type", with a relative percentage of 67%, 24% and 9%, respectively. Using this classification system, three typical pollution events were selected for numerical simulations using the WRF-Chem model. The source sensitivity method for anthropogenic emissions of PM2.5 and its precursors was applied to identify the source-receptor relationships for PM2.5 among 9 cities in PRD. For "Western type" case, the PRD region was under control of a high-pressure system with easterly prevailing winds. The PM2.5 concentrations in the western PRD region were higher than those in the eastern region, with emissions from cities in the eastern PRD region having higher contributions. Within the PRD's urban cluster, PM2.5 in Huizhou, Dongguan and Shenzhen was mainly derived from local emissions, whereas the PM2.5 in the other cities was primarily derived from external transport. For "Eastern type" case, the PRD was influenced by Typhoon Soulik with westerly prevailing winds. Emissions from cities in the western PRD region had the highest impacts on the overall PM2.5 concentration. PM2.5 in Jiangmen and Foshan was primarily derived from local emissions. Regarding "Central type" case, the PRD region was under control of a uniform pressure field with low wind speed. PM2.5 concentrations of each city were primarily caused by local emissions. Overall, wind flows played a significant role in the transport and spatial distribution of PM2.5 across the PRD region. Ideally, local governments would be wise to establish joint prevention and control measures to reduce regional atmospheric pollution, especially for "Western type" pollution.

  1. Pre-Slaughter Stress Affects Ryanodine Receptor Protein Gene Expression and the Water-Holding Capacity in Fillets of the Nile Tilapia.

    Directory of Open Access Journals (Sweden)

    Elenice S R Goes

    Full Text Available Current study evaluated the effect of pre-slaughter stress on serum cortisol levels, pH, colorimetry, water-holding capacity (WHC and gene expression of ryanodine receptors (RyR1 and RyR3 in the Nile tilapia. A 3x4 factorial scheme experiment was conducted comprising three densities (100, 200, 400 kg/m³ with four transportation times (60, 120, 180, and 240 minutes.Transportation times alone reduced cortisol levels up to 180 minutes, followed by increased WHC and mRNA expression, RyR1 and RyR3 (200 kg/m³ density. No effect of density x transportation time interacted on the evaluated parameters. Results provided the first evidence that pre-slaughter stress affected ryanodine gene expression receptors and, consequently, the water-holding capacity in tilapia fillets.

  2. Silencing of Tumor Necrosis Factor Receptor 1 by siRNA in EC109 Cells Affects Cell Proliferation and Apoptosis

    Directory of Open Access Journals (Sweden)

    Ma Changhui

    2009-01-01

    Full Text Available Tumor necrosis factor receptor 1 (TNFR1 is a membrane receptor able to bind TNF-α or TNF-β. TNFR1 can suppress apoptosis by activating the NF-κB or JNK/SAPK signal transduction pathway, or it can induce apoptosis through a series of caspase cascade reactions; the particular effect may depend on the cell line. In the present study, we first showed that TNFR1 is expressed at both the gene and protein levels in the esophageal carcinoma cell line EC109. Then, by applying a specific siRNA, we silenced the expression of TNFR1; this resulted in a significant time-dependent promotion of cell proliferation and downregulation of the apoptotic rate. These results suggest that TNFR1 is strongly expressed in the EC109 cell line and that it may play an apoptosis-mediating role, which may be suppressed by highly activated NF-κB.

  3. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity

    Energy Technology Data Exchange (ETDEWEB)

    Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie, E-mail: ebj@mil.au.dk

    2013-10-15

    The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [{sup 3}H]{sub 2}O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks

  4. Phosphorylation of the Transient Receptor Potential Ankyrin 1 by Cyclin-dependent Kinase 5 affects Chemo-nociception

    OpenAIRE

    Hall, Bradford E.; Prochazkova, Michaela; Sapio, Matthew R.; Minetos, Paul; Kurochkina, Natalya; Binukumar, B. K.; Amin, Niranjana D.; Terse, Anita; Joseph, John; Raithel, Stephen J.; Mannes, Andrew J.; Pant, Harish C.; Chung, Man-Kyo; Iadarola, Michael J.; Kulkarni, Ashok B.

    2018-01-01

    Cyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase that is upregulated during inflammation, and can subsequently modulate sensitivity to nociceptive stimuli. We conducted an in silico screen for Cdk5 phosphorylation sites within proteins whose expression was enriched in nociceptors and identified the chemo-responsive ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) as a possible Cdk5 substrate. Immunoprecipitated full length TRPA1 was shown to be phosphorylated by Cdk5 and th...

  5. Do healthy school meals affect illness, allergies and school attendance in 8- to 11-year-old children? A cluster-randomised controlled study.

    Science.gov (United States)

    Laursen, R P; Lauritzen, L; Ritz, C; Dyssegaard, C B; Astrup, A; Michaelsen, K F; Damsgaard, C T

    2015-05-01

    A nutritionally adequate diet in childhood is important for health and resistance of allergies and infections. This study explored the effects of school meals rich in fish, vegetables and fibre on school attendance, asthma, allergies and illness in 797 Danish 8- to 11-year-old children. No comparable studies conducted in high-income settings have been identified. The OPUS School Meal Study was a cluster-randomised cross-over trial. Children from third and fourth grades at nine Danish schools received school meals or usual packed lunch (control) for two 3-month periods. Occurrence and duration of illnesses, asthma and allergies during the last 14 days were recorded by parental questionnaires at baseline and after each 3-month period. Self-reported well-being was assessed by visual analogue scales. The school meals did not affect school attendance, parent-reported occurrence or duration of asthma and allergies or self-reported well-being. The most common symptoms of illness were stomach pain (24%), headache (28%) and cold (24%). A slightly higher number of children experienced headaches in the school meal (27%) compared with the control period (22%) (P=0.02). However, subgroup analyses showed that this effect was only seen in children eating school meals in the classroom (P=0.007), and not in common dining areas (P=0.2). No effect was found on other symptoms of illness. Provision of nutritionally balanced school meals did not affect school attendance, asthma, allergies, illness or well-being in 8- to 11-year-old children. The slight increase in occurrence of headaches seems to be related to the physical eating environment.

  6. The efficacy of a group Cognitive Behavioural Therapy for war-affected young migrants living in Australia: A cluster randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Chew Sia Ooi

    2016-10-01

    Full Text Available BackgroundPreventative and treatment programmes for people at risk of developing psychological problems after exposure to war trauma have mushroomed in the last decade. However, there is still much contention about evidence-based and culturally sensitive interventions for children. The aim of this study was to examine the efficacy of the Teaching Recovery Techniques in improving the emotional and behavioural outcomes of war-affected children resettled in Australia. Methods and findings A cluster randomised controlled trial with pretest, posttest, and 3-month follow-up design was employed. A total of 82 participants (aged 10 to 17 years were randomised by school into the 8-week intervention (n = 45 or the waiting list (WL control condition (n = 37. Study outcomes included symptoms of posttraumatic stress disorder, depression, internalising and externalising problems, as well as psychosocial functioning. A medium intervention effect was found for depression symptoms. Participants in the intervention condition experienced a greater symptom reduction than participants in the WL control condition, F(1,155 = 5.20, p = .024, partial ƞ2 = 0.07. This improvement was maintained at the 3-month follow-up, F(2,122 = 7.24, p = .001, partial ƞ2 = 0.20. ConclusionsThese findings suggest the potential benefit of the school and group-based intervention on depression symptoms but not on other outcomes, when compared to a waiting list control group.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12611000948998

  7. NMDA and mGluR1 receptor subtypes as major players affecting depotentiation in the hippocampal CA1-region

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    Amira Latif-Hernandez

    2014-03-01

    Full Text Available Neurons have the ability to modify their structure and function which ultimately serves for learning (Abraham and Bear, 1996. Dendritic events provide a major contribution to such modifications. For example, natural and artificial patterns of afferent activation have been shown to induce persistent forms of synaptic plasticity, such as long-term potentiation (LTP and long-term depression (LTD at distinct dendritic synapses. LTP and LTD are both assumed to occur during the physiological processes of learning and memory formation and to sustain the latter (Abraham, 2008. In recent years, there has been a burgeoning interest in the understanding of metaplasticity, which refers to the plasticity of synaptic plasticity (Abraham and Bear, 1996. In particular, depotentiation (DP is the mechanism by which synapses that have recently undergone LTP can reverse their synaptic strengthening in response to low frequency stimulation (LFS; Abraham, 2008. Typically, DP is thought to prevent the saturation of synaptic potentiation by resetting synapses into a more efficient state to store new information. The detailed mechanisms that underlie DP still remain unclear. Bortolotto et al. (1994 first identified metabotropic glutamate receptors (mGluRs as being involved in DP. Experimental evidence indicates that both subtypes of group I mGluRs (mGluR1 and mGluR5 have distinct functions in synaptic plasticity in the hippocampal CA1 region (Gladding et al., 2008. However, their role in DP was not addressed yet in detail and appear to be distinct from those involved in NMDAR-dependent DP (Zho et al., 2002. Therefore, we investigated the precise mechanisms responsible for NMDAR and mGluR-dependent DP by combining electrophysiological recordings in vitro and pharmacological approach. Transverse hippocampal slices (400 µm thick were prepared from the right hippocampus with a tissue chopper and placed into a submerged-type chamber, where they were continuously perfused

  8. Role of the placental Vitamin D receptor in modulating feto-placental growth in Fetal growth restriction and Preeclampsia-affected pregnancies.

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    Padma eMurthi

    2016-02-01

    Full Text Available Fetal growth restriction (FGR is a common pregnancy complication that affects up to 5% of pregnancies worldwide. Recent studies demonstrate that Vitamin D deficiency is implicated in reduced fetal growth, which may be rescued by supplementation of Vitamin D. Despite this, the pathway(s by which Vitamin D modulate fetal growth remains to be investigated. Our own studies demonstrate that the Vitamin D receptor (VDR is significantly decreased in placentae from human pregnancies complicated by FGR and contributes to abnormal placental trophoblast apoptosis and differentiation and regulation of cell-cycle genes in vitro. Thus, Vitamin D signalling is important for normal placental function and fetal growth. This review discusses the association of Vitamin D with fetal growth, the function of Vitamin D and its receptor in pregnancy, as well as the functional significance of a placental source of Vitamin D in FGR. Additionally, we propose that for Vitamin D to be clinically effective to prevent and manage FGR, the molecular mechanisms of Vitamin D and its receptor in modulating fetal growth requires further investigation.

  9. Polymorphic variants of neurotransmitter receptor genes may affect sexual function in aging males: data from the HALS study.

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    Jóźków, Paweł; Słowińska-Lisowska, Małgorzata; Łaczmański, Łukasz; Mędraś, Marek

    2013-01-01

    Human behavior is influenced by a number of brain neurotransmitters. Central dopamine, serotonin and melanocortin systems have special importance for male sexual function. We searched for associations between male aging symptoms and polymorphic sites of serotonin (5-HTR1B), melanocortin (MC4R) and dopamine (DRD2, DRD4) receptors. In a population-based sample, genotyping of 5-HTR1B (polymorphism: G861C), MC4R (polymorphisms: C-2745T, Val103Ile), DRD2 (polymorphism: C313T) and DRD4 (polymorphism: 48-bp VNTR) was performed in 387 healthy men. The Aging Males' Symptoms (AMS) scale was used to evaluate specific ailments of aging men. We analyzed answers to questions from the AMS scale. Five points of the questionnaire addressed sexual symptoms of the aging male: feeling of passing one's peak, decrease in beard growth, decrease in ability/frequency to perform sexually, decrease in the number of morning erections, and decrease in sexual desire/libido (lacking pleasure in sex, lacking desire for sexual intercourse). Relations between reported symptoms and variants of the polymorphic sites of the studied genes were assessed. After adjusting for confounding factors (education, arterial hypertension, physical activity, weight, waist circumference) an association between the sexual dimension of AMS and genetic variants of 5-HTR1B G861C (p = 0.04) was observed. Variability of neurotransmitter receptor genes may be associated with sexual symptoms of aging in men. Copyright © 2013 S. Karger AG, Basel.

  10. Mesenchymal stem cells cannot affect mRNA expression of toll-like receptors in different tissues during sepsis.

    Science.gov (United States)

    Pedrazza, Leonardo; Pereira, Talita Carneiro Brandão; Abujamra, Ana Lucia; Nunes, Fernanda Bordignon; Bogo, Maurício Reis; de Oliveira, Jarbas Rodrigues

    2017-07-01

    Experimental animal models and human clinical studies support a crucial role for TLRs in infectious diseases. The aim of this study was to test the ability of MSCs, which have immunomodulatory effects, of altering the mRNA expression of toll-like receptors during a experimental model of sepsis in different tissues. Three experimental groups (male C57BL/6 mice) were formed for the test: control group, untreated septic group and septic group treated with MSCs (1 × 10 6 cells/animal). Lungs, cortex, kidney, liver and colon tissue were dissected after 12 h of sepsis induction and TLR2/3/4/9 mRNA were evaluated by RT-qPCR. We observed a decrease of TLR2 and 9 mRNA expression in the liver of the sepsis group, while TLR3 was decreased in the lung and liver. No change was found between the sepsis group and the sepsis + MSC group. In this model of experimental sepsis the MSCs were unable to modify the mRNA expression of the different toll-like receptors evaluated.

  11. Low-density lipoprotein receptor genetic polymorphism in chronic hepatitis C virus Egyptian patients affects treatment response.

    Science.gov (United States)

    Naga, Mazen; Amin, Mona; Algendy, Dina; Elbadry, Ahmed; Fawzi, May; Foda, Ayman; Esmat, Serag; Sabry, Dina; Rashed, Laila; Gabal, Samia; Kamal, Manal

    2015-10-21

    To correlate a genetic polymorphism of the low-density lipoprotein (LDL) receptor with antiviral responses in Egyptian chronic hepatitis C virus (HCV) patients. Our study included 657 HCV-infected patients with genotype 4 who received interferon-based combination therapy. Patients were divided into two groups based on their response to therapy: 356 were responders, and 301 were non-responders. Patients were compared to 160 healthy controls. All patients and controls underwent a thorough physical examination, measurement of body mass index (BMI) and the following laboratory tests: serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total bilirubin, direct bilirubin, prothrombin time, prothrombin concentration, INR, complete blood count, serum creatinine, fasting blood sugar, HCV antibody, and hepatitis B surface antigen. All HCV patients were further subjected to the following laboratory tests: HCV-RNA using quantitative polymerase chain reaction (PCR), antinuclear antibodies, thyroid-stimulating hormone, an LDL receptor (LDLR) genotype study of LDLR exon8c.1171G>A and exon10c.1413G>A using real-time PCR-based assays, abdominal ultrasonography, ultrasonographic-guided liver biopsy, and histopathological examination of liver biopsies. Correlations of LDL receptor polymorphisms with HAI, METAVIR score, presence of steatosis, and BMI were performed in all cases. There were no statistically significant differences in response rates between the different types of interferon used or LDLR exon10c.1413G>A. However, there was a significant difference in the frequency of the LDL receptor exon8c.1171G>A genotype between cases (AA: 25.9%, GA: 22.2%, GG: 51.9%) and controls (AA: 3.8%, GA: 53.1% and GG: 43.1%) (P A polymorphism between responders (AA: 3.6%, GA: 15.2%, GG: 81.2%) and non-responders (AA: 52.2%, GA: 30.6%, GG: 17.2%) (P A predominated in cases and controls over the A allele, and a statistically significant association with

  12. Palmitoylation as a Functional Regulator of Neurotransmitter Receptors

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    Vladimir S. Naumenko

    2018-01-01

    Full Text Available The majority of neuronal proteins involved in cellular signaling undergo different posttranslational modifications significantly affecting their functions. One of these modifications is a covalent attachment of a 16-C palmitic acid to one or more cysteine residues (S-palmitoylation within the target protein. Palmitoylation is a reversible modification, and repeated cycles of palmitoylation/depalmitoylation might be critically involved in the regulation of multiple signaling processes. Palmitoylation also represents a common posttranslational modification of the neurotransmitter receptors, including G protein-coupled receptors (GPCRs and ligand-gated ion channels (LICs. From the functional point of view, palmitoylation affects a wide span of neurotransmitter receptors activities including their trafficking, sorting, stability, residence lifetime at the cell surface, endocytosis, recycling, and synaptic clustering. This review summarizes the current knowledge on the palmitoylation of neurotransmitter receptors and its role in the regulation of receptors functions as well as in the control of different kinds of physiological and pathological behavior.

  13. Chemokine-like receptor 1 deficiency does not affect the development of insulin resistance and nonalcoholic fatty liver disease in mice.

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    Nanda Gruben

    Full Text Available The adipokine chemerin and its receptor, chemokine-like receptor 1 (Cmklr1, are associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD, which covers a broad spectrum of liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH. It is possible that chemerin and/or Cmklr1 exert their effects on these disorders through inflammation, but so far the data have been controversial. To gain further insight into this matter, we studied the effect of whole-body Cmklr1 deficiency on insulin resistance and NAFLD. In view of the primary role of macrophages in hepatic inflammation, we also transplanted bone marrow from Cmklr1 knock-out (Cmklr1-/- mice and wild type (WT mice into low-density lipoprotein receptor knock-out (Ldlr-/- mice, a mouse model for NASH. All mice were fed a high fat, high cholesterol diet containing 21% fat from milk butter and 0.2% cholesterol for 12 weeks. Insulin resistance was assessed by an oral glucose tolerance test, an insulin tolerance test, and by measurement of plasma glucose and insulin levels. Liver pathology was determined by measuring hepatic inflammation, fibrosis, lipid accumulation and the NAFLD activity score (NAS. Whole-body Cmklr1 deficiency did not affect body weight gain or food intake. In addition, we observed no differences between WT and Cmklr1-/- mice for hepatic inflammatory and fibrotic gene expression, immune cell infiltration, lipid accumulation or NAS. In line with this, we detected no differences in insulin resistance. In concordance with whole-body Cmklr1 deficiency, the absence of Cmklr1 in bone marrow-derived cells in Ldlr-/- mice did not affect their insulin resistance or liver pathology. Our results indicate that Cmklr1 is not involved in the pathogenesis of insulin resistance or NAFLD. Thus, we recommend that the associations reported between Cmklr1 and insulin resistance or NAFLD should be interpreted with caution.

  14. Acute exposure to high-peak-power pulsed microwaves affecting the histamine H3 receptor expression in rat hippocampus

    International Nuclear Information System (INIS)

    Yu Xiaodong; Li Bo; Li Dehua; He Qiyi; Yu Zhengping

    2006-01-01

    In the Morris Water test, high-peak-power pulsed microwave (MW)-exposed rats displayed some learning and memory behavior dysfunctions, and their escape time and swimming distance to the submerged platform were longer than those of the sham-exposed rats. to understand the molecular mechanism involved, the reverse transcription-polymerase chain reation (RT-PCR) and the Western-blotting technique were used for investigating the mRNA and protein expression patterns of the histamine H 3 receptor (H 3 R) in rat hippocampus. High-peak-power pulsed microwave-exposure did not remarkably lead to the change in expression of H 3 R mRNA in rat hippocampi; however, it promoted the up-regulatory expression of the H 3 R protein, which was possibly triggered through the mitogen-activated protein kinase (MAPK) pathways. Therefore, further investigation of the molecular mechanism of the MW effects on the learning and memory behaviors is required. (authors)

  15. Perfluoroalkylated substances (PFAS) affect neither estrogen and androgen receptor activity nor steroidogenesis in human cells in vitro.

    Science.gov (United States)

    Behr, Anne-Cathrin; Lichtenstein, Dajana; Braeuning, Albert; Lampen, Alfonso; Buhrke, Thorsten

    2018-07-01

    The perfluoroalkylated substances (PFAS) perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are used for the fabrication of water- and dirt-repellent surfaces. The use of PFOS and PFOA was restricted due to their reprotoxic properties and their environmental persistence. Therefore, industry switches to alternative PFAS, however, in contrast to PFOA and PFOS only few toxicological data are available for their substitutes. The molecular mechanism(s) underlying reproductive toxicity of PFOA and PFOS are largely unknown. Here, the endocrine properties of PFOA, PFOS, and of six substitutes including perfluorohexanesulfonic acid (PFHxS), perfluorobutanesulfonic acid (PFBS), perfluorohexanoic acid (PFHxA), perfluorobutanoic acid (PFBA), ammonium perfluoro(2-methyl-3-oxahexanoate) (PMOH), and 3H-perfluoro-3-[(3-methoxypropoxy) propanoic acid] (PMPP) were examined in vitro by using human cell lines such as MCF-7, H295R, LNCaP and MDA-kb2. PFOA, PFOS and PMOH enhanced 17β-estradiol-stimulated estrogen receptor β activity, and PFOS, PMOH, PFHxA and PFBA enhanced dihydrotestosterone-stimulated androgen receptor activity. In the H295R steroidogenesis assay, PFOA and PFOS slightly enhanced estrone secretion, and progesterone secretion was marginally increased by PFOA. All these effects were only observed at concentrations above 10 μM, and none of the PFAS displayed any effect on any of the molecular endocrine endpoints at concentrations of 10 μM or below. Thus, as the blood serum concentrations of the different PFAS in the general Western population are in the range of 10 nM or below, the results suggest that PFAS might not exert endocrine effects in humans at exposure-relevant concentrations according to the molecular endpoints examined in this study. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Acute exposure to high-peak-power pulsed microwaves affecting the histamine H3 receptor expression in rat hippocampus

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In the Morris Water Maze test, high-peak-power pulsed microwave (MW)-exposed rats displayed some learning and memory behavior dysfunctions, and their escape time and swimming distance to the submerged platform were longer than those of the sham-exposed rats. To understand the molecular mechanism involved, the reverse transcription-polymerase chain reaction (RT-PCR) and the Western-blotting technique were used for investigating the mRNA and protein expression patterns of the histamine H3 receptor (H3R) in rat hippocampus. High-peak-power pulsed microwave-exposure did not remarkably lead to the change in expression of H3R mRNA in rat hippocampi;however, it promoted the up-regulatory expression of the H3R protein, which was possibly triggered through the mitogen-activated protein kinase (MAPK) pathways. Therefore, further investigation of the molecular mechanism of the MW effects on the learning and memory behaviors is required.

  17. Local activation of uterine Toll-like receptor 2 and 2/6 decreases embryo implantation and affects uterine receptivity in mice.

    Science.gov (United States)

    Sanchez-Lopez, Javier Arturo; Caballero, Ignacio; Montazeri, Mehrnaz; Maslehat, Nasim; Elliott, Sarah; Fernandez-Gonzalez, Raul; Calle, Alexandra; Gutierrez-Adan, Alfonso; Fazeli, Alireza

    2014-04-01

    Embryo implantation is a complex interaction between maternal endometrium and embryonic structures. Failure to implant is highly recurrent and impossible to diagnose. Inflammation and infections in the female reproductive tract are common causes of infertility, embryo loss, and preterm labor. The current work describes how the activation of endometrial Toll-like receptor (TLR) 2 and 2/6 reduces embryo implantation chances. We developed a morphometric index to evaluate the effects of the TLR 2/6 activation along the uterine horn (UH). TLR 2/6 ligation reduced the endometrial myometrial and glandular indexes and increased the luminal index. Furthermore, TLR 2/6 activation increased the proinflammatory cytokines such as interleukin (IL)-1beta and monocyte chemotactic protein (MCP)-1 in UH lavages in the preimplantation day and IL-1 receptor antagonist in the implantation day. The engagement of TLR 2/6 with its ligand in the UH during embryo transfer severely affected the rate of embryonic implantation (45.00% ± 6.49% vs. 16.69% ± 5.01%, P embryo implantation process was verified using an in vitro model of human embryo implantation where trophoblast spheroids failed to adhere to a monolayer of TLR 2- and TLR 2/6-activated endometrial cells. The inhibition of TLR receptors 2 and 6 in the presence of their specific ligands restored the ability of the spheroids to bind to the endometrial cells. In conclusion, the activation of the innate immune system in the uterus at the time of implantation interfered with the endometrial receptivity and reduced the chances of implantation success.

  18. Risk for self-reported anorexia or bulimia nervosa based on drive for thinness and negative affect clusters/dimensions during adolescence: A three-year prospective study of the TChAD cohort.

    Science.gov (United States)

    Peñas-Lledó, Eva; Bulik, Cynthia M; Lichtenstein, Paul; Larsson, Henrik; Baker, Jessica H

    2015-09-01

    This study explored the cross-sectional and predictive effect of drive for thinness and/or negative affect scores on the development of self-reported anorexia nervosa (AN) and bulimia nervosa (BN). K-means were used to cluster the Eating Disorder Inventory-Drive for Thinness (DT) and Child Behavior Checklist Anxious/Depressed (A/D) scores from 615 unrelated female twins at age 16-17. Logistic regressions were used to assess the effect of these clusters on self-reported eating disorder diagnosis at ages 16-17 (n = 565) and 19-20 (n = 451). DT and A/D scores were grouped into four clusters: Mild (scores lower than 90th percentile on both scales), DT (higher scores only on DT), A/D (higher scores only on A/D), and DT-A/D (higher scores on both the DT and A/D scales). DT and DT-A/D clusters at age 16-17 were associated cross-sectionally with AN and both cross-sectionally and longitudinally with BN. The DT-A/D cluster had the highest prevalence of AN at follow-up compared with all other clusters. Similarly, an interaction was observed between DT and A/D that predicted risk for AN. Having elevated DT and A/D scores may increase risk for eating disorder symptomatology above and beyond a high score on either alone. Findings suggest that cluster modeling based on DT and A/D may be useful to inform novel and useful intervention strategies for AN and BN in adolescents. © 2015 Wiley Periodicals, Inc.

  19. Adult exposure to tributyltin affects hypothalamic neuropeptide Y, Y1 receptor distribution, and circulating leptin in mice.

    Science.gov (United States)

    Bo, E; Farinetti, A; Marraudino, M; Sterchele, D; Eva, C; Gotti, S; Panzica, G

    2016-07-01

    Tributyltin (TBT), a pesticide used in antifouling paints, is toxic for aquatic invertebrates. In vertebrates, TBT may act in obesogen- inducing adipogenetic gene transcription for adipocyte differentiation. In a previous study, we demonstrated that acute administration of TBT induces c-fos expression in the arcuate nucleus. Therefore, in this study, we tested the hypothesis that adult exposure to TBT may alter a part of the nervous pathways controlling animal food intake. In particular, we investigated the expression of neuropeptide Y (NPY) immunoreactivity. This neuropeptide forms neural circuits dedicated to food assumption and its action is mediated by Y1 receptors that are widely expressed in the hypothalamic nuclei responsible for the regulation of food intake and energy homeostasis. To this purpose, TBT was orally administered at a dose of 0.025 mg/kg/day/body weight to adult animals [male and female C57BL/6 (Y1-LacZ transgenic mice] for 4 weeks. No differences were found in body weight and fat deposition, but we observed a significant increase in feed efficiency in TBT-treated male mice and a significant decrease in circulating leptin in both sexes. Computerized quantitative analysis of NPY immunoreactivity and Y1-related β-galactosidase activity demonstrated a statistically significant reduction in NPY and Y1 transgene expression in the hypothalamic circuit controlling food intake of treated male mice in comparison with controls. In conclusion, the present results indicate that adult exposure to TBT is profoundly interfering with the nervous circuits involved in the stimulation of food intake. © 2016 American Society of Andrology and European Academy of Andrology.

  20. Selective ablation of the androgen receptor in mouse sertoli cells affects sertoli cell maturation, barrier formation and cytoskeletal development.

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    Ariane Willems

    2010-11-01

    Full Text Available The observation that mice with a selective ablation of the androgen receptor (AR in Sertoli cells (SC (SCARKO mice display a complete block in meiosis supports the contention that SC play a pivotal role in the control of germ cell development by androgens. To delineate the physiological and molecular mechanism responsible for this control, we compared tubular development in pubertal SCARKO mice and littermate controls. Particular attention was paid to differences in SC maturation, SC barrier formation and cytoskeletal organization and to the molecular mediators potentially involved. Functional analysis of SC barrier development by hypertonic perfusion and lanthanum permeation techniques and immunohistochemical analysis of junction formation showed that SCARKO mice still attempt to produce a barrier separating basal and adluminal compartment but that barrier formation is delayed and defective. Defective barrier formation was accompanied by disturbances in SC nuclear maturation (immature shape, absence of prominent, tripartite nucleoli and SC polarization (aberrant positioning of SC nuclei and cytoskeletal elements such as vimentin. Quantitative RT-PCR was used to study the transcript levels of genes potentially related to the described phenomena between day 8 and 35. Differences in the expression of SC genes known to play a role in junction formation could be shown from day 8 for Cldn11, from day 15 for Cldn3 and Espn, from day 20 for Cdh2 and Jam3 and from day 35 for ZO-1. Marked differences were also noted in the transcript levels of several genes that are also related to cell adhesion and cytoskeletal dynamics but that have not yet been studied in SC (Actn3, Ank3, Anxa9, Scin, Emb, Mpzl2. It is concluded that absence of a functional AR in SC impedes the remodeling of testicular tubules expected at the onset of spermatogenesis and interferes with the creation of the specific environment needed for germ cell development.

  1. c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks.

    Science.gov (United States)

    Barfeld, Stefan J; Urbanucci, Alfonso; Itkonen, Harri M; Fazli, Ladan; Hicks, Jessica L; Thiede, Bernd; Rennie, Paul S; Yegnasubramanian, Srinivasan; DeMarzo, Angelo M; Mills, Ian G

    2017-04-01

    Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  2. c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks

    Directory of Open Access Journals (Sweden)

    Stefan J. Barfeld

    2017-04-01

    Full Text Available Prostate cancer (PCa is the most common non-cutaneous cancer in men. The androgen receptor (AR, a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen, and Glycine N-Methyltransferase (GNMT, in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa.

  3. Ovarian cycle-linked plasticity of δ-GABAA receptor subunits in hippocampal interneurons affects γ oscillations in vivo

    Directory of Open Access Journals (Sweden)

    Albert Miklos Barth

    2014-08-01

    Full Text Available GABAA receptors containing δ subunits (δ-GABAARs are GABA-gated ion channels with extra- and perisynaptic localization, strong sensitivity to neurosteroids (NS, and a high degree of plasticity. In selective brain regions they are expressed on specific principal cells and interneurons (INs, and generate a tonic conductance that controls neuronal excitability and oscillations. Plasticity of δ-GABAARs in principal cells has been described during states of altered NS synthesis including acute stress, puberty, ovarian cycle, pregnancy and the postpartum period, with direct consequences on neuronal excitability and network dynamics. The defining network events implicated in cognitive function, memory formation and encoding are γ oscillations (30-120 Hz, a well-timed loop of excitation and inhibition between principal cells and PV-expressing INs (PV+INs. The δ-GABAARs of INs can modify γ oscillations, and a lower expression of δ-GABAARs on INs during pregnancy alters γ frequency recorded in vitro. The ovarian cycle is another physiological event with large fluctuations in NS levels and δ-GABAARs. Stages of the cycle are paralleled by swings in memory performance, cognitive function, and mood in both humans and rodents. Here we show δ-GABAARs changes during the mouse ovarian cycle in hippocampal cell types, with enhanced expression during diestrus in principal cells and specific INs. The plasticity of δ-GABAARs on PV-INs decreases the magnitude of γ oscillations continuously recorded in area CA1 throughout several days in vivo during diestrus and increases it during estrus. Such recurring changes in γ magnitude were not observed in non-cycling wild-type (WT females, cycling females lacking δ-GABAARs only on PV-INs (PV-Gabrd-/-, and in male mice during a time course equivalent to the ovarian cycle. Our findings may explain the impaired memory and cognitive performance experienced by women with premenstrual syndrome (PMS or premenstrual

  4. Activation of the aryl hydrocarbon receptor affects activation and function of human monocyte-derived dendritic cells.

    Science.gov (United States)

    Wang, C; Ye, Z; Kijlstra, A; Zhou, Y; Yang, P

    2014-08-01

    Aryl hydrocarbon receptor (AhR) is well known for mediating the toxic effects of dioxin-containing pollutants, but has also been shown to be involved in the natural regulation of the immune response. In this study, we investigated the effect of AhR activation by its endogenous ligands 6-formylindolo[3,2-b]carbazole (FICZ) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) on the differentiation, maturation and function of monocyte-derived DCs in Behçet's disease (BD) patients. In this study, we showed that AhR activation by FICZ and ITE down-regulated the expression of co-stimulatory molecules including human leucocyte antigen D-related (HLA-DR), CD80 and CD86, while it had no effect on the expression of CD83 and CD40 on DCs derived from BD patients and normal controls. Lipopolysaccharide (LPS)-treated dendritic cells (DCs) from active BD patients showed a higher level of interleukin (IL)-1β, IL-6, IL-23 and tumour necrosis factor (TNF)-α production. FICZ or ITE significantly inhibited the production of IL-1β, IL-6, IL-23 and TNF-α, but induced IL-10 production by DCs derived from active BD patients and normal controls. FICZ or ITE-treated DCs significantly inhibited the T helper type 17 (Th17) and Th1 cell response. Activation of AhR either by FICZ or ITE inhibits DC differentiation, maturation and function. Further studies are needed to investigate whether manipulation of the AhR pathway may be used to treat BD or other autoimmune diseases. © 2014 British Society for Immunology.

  5. Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats.

    Science.gov (United States)

    Chan, Jiangping; Guan, Xin; Ni, Yiling; Luo, Lilu; Yang, Liqiang; Zhang, Pengyue; Zhang, Jichuan; Chen, Yanmei

    2017-03-15

    The Lateral Habenula (LHb) plays an important role in emotion and cognition. Recent experiments suggest that LHb has functional interaction with the hippocampus and plays an important role in spatial learning. LHb is reciprocally connected with midbrain monoaminergic brain areas such as the ventral tegmental area (VTA). However, the role of dopamine type 1 receptor (D1R) in LHb in learning and memory is not clear yet. In the present study, D1R agonist or antagonist were administered bilaterally into the LHb in rats. We found that both D1R agonist and antagonist impaired the acquisition of contextual fear memory in rats. D1R agonist or antagonist also impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses in freely moving rats and attenuated learning induced phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at Ser831 and Ser845 in hippocampus. Taken together, our results suggested that dysfunction of D1R in LHb affected the function of hippocampus. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. The Conserved Arginine Cluster in the Insert of the Third Cytoplasmic Loop of the Long Form of the D2 Dopamine Receptor (D2L-R Acts as an Intracellular Retention Signal

    Directory of Open Access Journals (Sweden)

    Valentina Kubale

    2016-07-01

    Full Text Available This study examined whether the conserved arginine cluster present within the 29-amino acid insert of the long form of the D2 dopamine receptor (D2L-R confers its predominant intracellular localization. We hypothesized that the conserved arginine cluster (RRR located within the insert could act as an RXR-type endoplasmic reticulum (ER retention signal. Arginine residues (R within the cluster at positions 267, 268, and 269 were charge-reserved to glutamic acids (E, either individually or in clusters, thus generating single, double, and triple D2L-R mutants. Through analyses of cellular localization by confocal microscopy and enzyme-linked immunosorbent assay (ELISA, radioligand binding assay, bioluminescence resonance energy transfer (BRET2 β-arrestin 2 (βarr2 recruitment assay, and cAMP signaling, it was revealed that charge reversal of the R residues at all three positions within the motif impaired their colocalization with ER marker calnexin and led to significantly improved cell surface expression. Additionally, these data demonstrate that an R to glutamic acid (E substitution at position 2 within the RXR motif is not functionally permissible. Furthermore, all generated D2L-R mutants preserved their functional integrity regarding ligand binding, agonist-induced βarr2 recruitment and Gαi-mediated signaling. In summary, our results show that the conserved arginine cluster within the 29-amino acid insert of third cytoplasmic loop (IC3 of the D2L-R appears to be the ER retention signal.

  7. Memantine, an antagonist of the NMDA glutamate receptor, affects cell proliferation, differentiation and the intracellular cycle and induces apoptosis in Trypanosoma cruzi.

    Directory of Open Access Journals (Sweden)

    Flávia Silva Damasceno

    2014-02-01

    Full Text Available Chagas' disease is caused by the protozoan parasite Trypanosoma cruzi and affects approximately 10 million people in endemic areas of Mexico and Central and South America. Currently available chemotherapies are limited to two compounds: Nifurtimox and Benznidazole. Both drugs reduce the symptoms of the disease and mortality among infected individuals when used during the acute phase, but their efficacy during the chronic phase (during which the majority of cases are diagnosed remains controversial. Moreover, these drugs have several side effects. The aim of this study was to evaluate the effect of Memantine, an antagonist of the glutamate receptor in the CNS of mammals, on the life cycle of T. cruzi. Memantine exhibited a trypanocidal effect, inhibiting the proliferation of epimastigotes (IC50 172.6 µM. Furthermore, this compound interfered with metacyclogenesis (approximately 30% reduction and affected the energy metabolism of the parasite. In addition, Memantine triggered mechanisms that led to the apoptosis-like cell death of epimastigotes, with extracellular exposure of phosphatidylserine, increased production of reactive oxygen species, decreased ATP levels, increased intracellular Ca(2+ and morphological changes. Moreover, Memantine interfered with the intracellular cycle of the parasite, specifically the amastigote stage (IC50 31 µM. Interestingly, the stages of the parasite life cycle that require more energy (epimastigote and amastigote were more affected as were the processes of differentiation and cell invasion.

  8. The Role of Hippocampal Estradiol Receptor-α in a Perimenopausal Affective Disorders-Like Rat Model and Attenuating of Anxiety by Electroacupuncture

    Directory of Open Access Journals (Sweden)

    Xun Wang

    2016-01-01

    Full Text Available Hormone replacement therapy is the principal treatment for perimenopausal affective disorders which can cause severe side effects. The present study compared the effects of electroacupuncture (EA and estradiol treatment on perimenopausal affective disorders at the behavioral and cellular levels. In this randomized experimental in vivo study, adult female rats were divided into intact, ovariectomy, chronic unpredictable stress (CUS, and ovariectomy and CUS combination groups. After week 6, all groups were subdivided to three subgroups of control, EA, and estradiol treatment. The behavioral parameters in the open field and the elevated plus maze tests were assessed before and after treatments. Alterations of serum steroid hormones and changes of estradiol receptor-α (ER-α immunofluorescence neurons in the hippocampus sections were evaluated. EA treatment caused more antianxiety effects than estradiol treatment in CUS group (P<0.05. Notably, estradiol and EA treatments had better significant behavioral effects when the models were not estrogen-deficient. Importantly, within each group, compared to the control group, the numbers of ER-α-positive neurons were significantly larger in EA subgroups. Therefore, EA had antianxiety effects on perimenopausal affective disorders caused by CUS but not by estrogen deficiency and upregulation of hippocampus ER-α neurons may contribute to its mechanism of action.

  9. Cluster headache

    Science.gov (United States)

    Histamine headache; Headache - histamine; Migrainous neuralgia; Headache - cluster; Horton's headache; Vascular headache - cluster ... Doctors do not know exactly what causes cluster headaches. They ... (chemical in the body released during an allergic response) or ...

  10. High-mobility group (HMG) protein HMG-1 and TATA-binding protein-associated factor TAF(II)30 affect estrogen receptor-mediated transcriptional activation.

    Science.gov (United States)

    Verrier, C S; Roodi, N; Yee, C J; Bailey, L R; Jensen, R A; Bustin, M; Parl, F F

    1997-07-01

    The estrogen receptor (ER) belongs to a family of ligand-inducible nuclear receptors that exert their effects by binding to cis-acting DNA elements in the regulatory region of target genes. The detailed mechanisms by which ER interacts with the estrogen response element (ERE) and affects transcription still remain to be elucidated. To study the ER-ERE interaction and transcription initiation, we employed purified recombinant ER expressed in both the baculovirus-Sf9 and his-tagged bacterial systems. The effect of high-mobility group (HMG) protein HMG-1 and purified recombinant TATA-binding protein-associated factor TAF(II)30 on ER-ERE binding and transcription initiation were assessed by electrophoretic mobility shift assay and in vitro transcription from an ERE-containing template (pERE2LovTATA), respectively. We find that purified, recombinant ER fails to bind to ERE in spite of high ligand-binding activity and electrophoretic and immunological properties identical to ER in MCF-7 breast cancer cells. HMG-1 interacts with ER and promotes ER-ERE binding in a concentration- and time-dependent manner. The effectiveness of HMG-1 to stimulate ER-ERE binding in the electrophoretic mobility shift assay depends on the sequence flanking the ERE consensus as well as the position of the latter in the oligonucleotide. We find that TAF(II)30 has no effect on ER-ERE binding either alone or in combination with ER and HMG-1. Although HMG-1 promotes ER-ERE binding, it fails to stimulate transcription initiation either in the presence or absence of hormone. In contrast, TAF(II)30, while not affecting ER-ERE binding, stimulates transcription initiation 20-fold in the presence of HMG-1. These results indicate that HMG-1 and TAF(II)30 act in sequence, the former acting to promote ER-ERE binding followed by the latter to stimulate transcription initiation.

  11. NMR spectral mapping of Lipid A molecular patterns affected by interaction with the innate immune receptor CD14

    International Nuclear Information System (INIS)

    Albright, Seth; Agrawal, Prashansa; Jain, Nitin U.

    2009-01-01

    Soluble CD14 (sCD14) is a serum glycoprotein that binds to the Lipid A moiety of lipopolysaccharides (LPS) with high affinity as part of the innate immune response to bacterial endotoxins. In order to investigate structural interactions of Lipid A with sCD14, we have prepared an isotopically labeled form of a fully active and chemically defined endotoxin, Kdo 2 -Lipid A, which allowed us to carry out detailed NMR spectral mapping of this agonist ligand bound to sCD14 and identify for the first time structural regions that are strongly affected during complex formation with sCD14. These map to two adjacent areas comprising the lower portions of the sugar headgroup and upper half of the acyl chains I, III, and V, which are spatially proximal to the 1- and 4'-phosphate ends. Additionally, we have detected for the first time, presence of differential dynamic behavior for the affected resonances, suggesting a likely role for dynamics in the mechanism of Lipid A pattern recognition by sCD14.

  12. Pharmacological interference with metabotropic glutamate receptor subtype 7 but not subtype 5 differentially affects within- and between-session extinction of Pavlovian conditioned fear.

    Science.gov (United States)

    Toth, Iulia; Dietz, Monika; Peterlik, Daniel; Huber, Sabine E; Fendt, Markus; Neumann, Inga D; Flor, Peter J; Slattery, David A

    2012-03-01

    Fear extinction is defined as the attenuation of a conditioned-fear memory by re-exposing animals to the conditioned stimulus without the aversive stimulus. This process is known to be effectively enhanced via administration of D-cycloserine (DCS), a partial NMDA-receptor agonist. However, other glutamatergic mechanisms, such as interference with metabotropic glutamate receptor (mGluR) subtypes 5 and 7 in the extinction of aversive memories are insufficiently understood. Using the allosteric mGluR5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), and DCS for comparison, we aimed to study how pharmacological blockade of mGluR5 and activation of mGluR7 influenced within- and between-session conditioned-fear extinction training and extinction retention in rats. We show that when injected before extinction training, mGluR7 activation with AMN082 enhanced freezing and thereby attenuated within-session fear extinction, whereas both DCS and the mGluR5 receptor antagonist MPEP had no effect on this process. However, these differential drug effects were not long lasting, as no difference in extinction retention were observed 24 h later. Therefore, we assessed whether the compounds affect 24 h consolidation of extinction training following incomplete extinction training (between-session extinction). Similar to DCS, AMN082- but not MPEP-treated rats showed facilitated extinction retention, as exhibited by decreased freezing. Finally, using fluoxetine, we provide evidence that the effect of AMN082 on between-session extinction retention is most likely not via increasing 5-HT transmission. These findings demonstrate that mGluR7 activation differentially modulates conditioned-fear extinction, in dependence on the protocol employed, and suggests drugs with AMN082-like mechanisms as potential add-on drugs following exposure-based psychotherapy for fear-related human

  13. Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Lynch, Caitlin; Pan, Yongmei; Li, Linhao [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States); Heyward, Scott; Moeller, Timothy [Bioreclamation In Vitro Technologies, Baltimore, MD 21227 (United States); Swaan, Peter W. [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States); Wang, Hongbing, E-mail: hwang@rx.umaryland.edu [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States)

    2014-08-15

    Objective: Accumulating evidence suggests that activation of mouse constitutive androstane receptor (mCAR) alleviates type 2 diabetes and obesity by inhibiting hepatic gluconeogenesis, lipogenesis, and fatty acid synthesis. However, the role of human (h) CAR in energy metabolism is largely unknown. The present study aims to investigate the effects of selective hCAR activators on hepatic energy metabolism in human primary hepatocytes (HPH). Methods: Ligand-based structure–activity models were used for virtual screening of the Specs database ( (www.specs.net)) followed by biological validation in cell-based luciferase assays. The effects of two novel hCAR activators (UM104 and UM145) on hepatic energy metabolism were evaluated in HPH. Results: Real-time PCR and Western blotting analyses reveal that activation of hCAR by UM104 and UM145 significantly repressed the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two pivotal gluconeogenic enzymes, while exerting negligible effects on the expression of genes associated with lipogenesis and fatty acid synthesis. Functional experiments show that UM104 and UM145 markedly inhibit hepatic synthesis of glucose but not triglycerides in HPH. In contrast, activation of mCAR by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a selective mCAR activator, repressed the expression of genes associated with gluconeogenesis, lipogenesis, and fatty acid synthesis in mouse primary hepatocytes, which were consistent with previous observations in mouse model in vivo. Conclusion: Our findings uncover an important species difference between hCAR and mCAR in hepatic energy metabolism, where hCAR selectively inhibits gluconeogenesis without suppressing fatty acid synthesis. Implications: Such species selectivity should be considered when exploring CAR as a potential therapeutic target for metabolic disorders. - Highlights: • Novel hCAR activators were identified by computational and biological approaches. • The role

  14. Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes

    International Nuclear Information System (INIS)

    Lynch, Caitlin; Pan, Yongmei; Li, Linhao; Heyward, Scott; Moeller, Timothy; Swaan, Peter W.; Wang, Hongbing

    2014-01-01

    Objective: Accumulating evidence suggests that activation of mouse constitutive androstane receptor (mCAR) alleviates type 2 diabetes and obesity by inhibiting hepatic gluconeogenesis, lipogenesis, and fatty acid synthesis. However, the role of human (h) CAR in energy metabolism is largely unknown. The present study aims to investigate the effects of selective hCAR activators on hepatic energy metabolism in human primary hepatocytes (HPH). Methods: Ligand-based structure–activity models were used for virtual screening of the Specs database ( (www.specs.net)) followed by biological validation in cell-based luciferase assays. The effects of two novel hCAR activators (UM104 and UM145) on hepatic energy metabolism were evaluated in HPH. Results: Real-time PCR and Western blotting analyses reveal that activation of hCAR by UM104 and UM145 significantly repressed the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two pivotal gluconeogenic enzymes, while exerting negligible effects on the expression of genes associated with lipogenesis and fatty acid synthesis. Functional experiments show that UM104 and UM145 markedly inhibit hepatic synthesis of glucose but not triglycerides in HPH. In contrast, activation of mCAR by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a selective mCAR activator, repressed the expression of genes associated with gluconeogenesis, lipogenesis, and fatty acid synthesis in mouse primary hepatocytes, which were consistent with previous observations in mouse model in vivo. Conclusion: Our findings uncover an important species difference between hCAR and mCAR in hepatic energy metabolism, where hCAR selectively inhibits gluconeogenesis without suppressing fatty acid synthesis. Implications: Such species selectivity should be considered when exploring CAR as a potential therapeutic target for metabolic disorders. - Highlights: • Novel hCAR activators were identified by computational and biological approaches. • The role

  15. TISSUE INHIBITOR OF METALLOPROTEINASE 1, MATRIX METALLOPROTEINASE 9, ALPHA-1 ANTITRYPSIN, METALLOTHIONEIN AND UROKINASE TYPE PLASMINOGEN ACTIVATOR RECEPTOR IN SKIN BIOPSIES FROM PATIENTS AFFECTED BY AUTOIMMUNE BLISTERING DISEASES

    Directory of Open Access Journals (Sweden)

    Ana Maria Abreu Velez

    2013-07-01

    Full Text Available Introduction: Proteinases and proteinase inhibitors have been described to play a role in autoimmune skin blistering diseases. We studied skin lesional biopsies from patients affected by several autoimmune skin blistering diseases for proteinases and proteinase inhibitors. Methods: We utilized immunohistochemistry to evaluate biopsies for alpha-1-antitrypsin, human matrix metalloproteinase 9 (MMP9, human tissue inhibitor of metalloproteinases 1 (TIMP-1, metallothionein and urokinase type plasminogen activator receptor (uPAR. We tested 30 patients affected by endemic pemphigus, 30 controls from the endemic area, and 15 normal controls. We also tested 30 biopsies from patients with bullous pemphigoid (BP, 20 with pemphigus vulgaris (PV, 8 with pemphigus foliaceus, and 14 with dermatitis herpetiformis (DH. Results: Contrary to findings in the current literature, most autoimmune skin blistering disease biopsies were negative for uPAR and MMP9. Only some chronic patients with El Bagre-EPF were positive to MMP9 in the dermis, in proximity to telocytes. TIMP-1 and metallothionein were positive in half of the biopsies from BP patients at the basement membrane of the skin, within several skin appendices, in areas of dermal blood vessel inflammation and within dermal mesenchymal-epithelial cell junctions.

  16. Structural investigation of a C-terminal EphA2 receptor mutant: Does mutation affect the structure and interaction properties of the Sam domain?

    Science.gov (United States)

    Mercurio, Flavia A; Costantini, Susan; Di Natale, Concetta; Pirone, Luciano; Guariniello, Stefano; Scognamiglio, Pasqualina L; Marasco, Daniela; Pedone, Emilia M; Leone, Marilisa

    2017-09-01

    Ephrin A2 receptor (EphA2) plays a key role in cancer, it is up-regulated in several types of tumors and the process of ligand-induced receptor endocytosis, followed by degradation, is considered as a potential path to diminish tumor malignancy. Protein modulators of this mechanism are recruited at the cytosolic Sterile alpha motif (Sam) domain of EphA2 (EphA2-Sam) through heterotypic Sam-Sam associations. These interactions engage the C-terminal helix of EphA2 and close loop regions (the so called End Helix side). In addition, several studies report on destabilizing mutations in EphA2 related to cataract formation and located in/or close to the Sam domain. Herein, we analyzed from a structural point of view, one of these mutants characterized by the insertion of a novel 39 residue long polypeptide at the C-terminus of EphA2-Sam. A 3D structural model was built by computational methods and revealed partial disorder in the acquired C-terminal tail and a few residues participating in an α-helix and two short β-strands. We investigated by CD and NMR studies the conformational properties in solution of two peptides encompassing the whole C-terminal tail and its predicted helical region, respectively. NMR binding experiments demonstrated that these peptides do not interact relevantly with either EphA2-Sam or its interactor Ship2-Sam. Molecular dynamics (MD) simulations further indicated that the EphA2 mutant could be represented only through a conformational ensemble and that the C-terminal tail should not largely wrap the EphA2-Sam End-Helix interface and affect binding to other Sam domains. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Weighted Clustering

    DEFF Research Database (Denmark)

    Ackerman, Margareta; Ben-David, Shai; Branzei, Simina

    2012-01-01

    We investigate a natural generalization of the classical clustering problem, considering clustering tasks in which different instances may have different weights.We conduct the first extensive theoretical analysis on the influence of weighted data on standard clustering algorithms in both...... the partitional and hierarchical settings, characterizing the conditions under which algorithms react to weights. Extending a recent framework for clustering algorithm selection, we propose intuitive properties that would allow users to choose between clustering algorithms in the weighted setting and classify...

  18. Spontaneous complement activation on human B cells results in localized membrane depolarization and the clustering of complement receptor type 2 and C3 fragments

    DEFF Research Database (Denmark)

    Løbner, Morten; Leslie, Robert G Q; Prodinger, Wolfgang M

    2009-01-01

    While our previous studies have demonstrated that complement activation induced by complement receptors type 2 (CR2/CD21) and 1 (CR1/CD35) results in C3-fragment deposition and membrane attack complex (MAC) formation in human B cells, the consequences of these events for B-cell functions remain u...

  19. Alginate oligosaccharide indirectly affects toll-like receptor signaling via the inhibition of microRNA-29b in aneurysm patients after endovascular aortic repair

    Directory of Open Access Journals (Sweden)

    Yang Y

    2017-09-01

    Full Text Available Yong Yang,1–4,* Zhenhuan Ma,1–4,* Guokai Yang,1–4 Jia Wan,1–4 Guojian Li,1–4 Lingjuan Du,1–4 Ping Lu1–4 1Department of Vascular Surgery, The Second People’s Hospital of Yunnan Province, Kunming, China; 2Department of Vascular Surgery, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, China; 3Department of Vascular Surgery, Vascular Surgery Centre in Yunnan Province, Kunming, China; 4Department of Vascular Surgery, Abdominal Surgery Centre in Yunnan Province, Kunming, China *These authors contributed equally to this work Abstract: Endovascular aortic repair (EVAR is often followed by aneurysm recurrence. Alginate oligosaccharide (AOS has potential antitumor properties as a natural product while the related mechanisms remain unclear. Toll-like receptor (TLR signaling is associated with inflammatory activity of aneurysm and may be affected by miR-29b. Thus, inhibitory function of AOS on aneurysms was explored by measuring the important molecules in TLR4 signaling. After EVAR, a total of 248 aortic aneurysm patients were recruited and randomly assigned into two groups: AOS group (AG, oral administration 10-mg AOS daily and control group (CG, placebo daily. The size of residual aneurysms, aneurysm recurrence, and side effects were investigated. Aneurysm recurrence was determined by Kaplan–Meier analysis. After 2 years, eight and two patients died in the CG and AG, respectively. The sizes of residual aneurysms were significantly larger in the CG than in the AG (P<0.05. The incidence of aneurysm recurrence was also significantly higher in the CG than in the AG (P<0.05. AOS treatment reduced the levels of miR-29b, TLR4, mitogen-activated protein kinase (MAPK, nuclear factor kappa B (NF-kappa B, interleukin 1 (IL-1 beta, and interleukin 6 (IL-6. Overexpression and silence of miR-29b increased and reduced the level of TLR4, phospho-p65 NF-kappa B, phospho-p38 MAPK, IL-1 beta, and IL-6. Spearman’s rank correlation

  20. Cluster management.

    Science.gov (United States)

    Katz, R

    1992-11-01

    Cluster management is a management model that fosters decentralization of management, develops leadership potential of staff, and creates ownership of unit-based goals. Unlike shared governance models, there is no formal structure created by committees and it is less threatening for managers. There are two parts to the cluster management model. One is the formation of cluster groups, consisting of all staff and facilitated by a cluster leader. The cluster groups function for communication and problem-solving. The second part of the cluster management model is the creation of task forces. These task forces are designed to work on short-term goals, usually in response to solving one of the unit's goals. Sometimes the task forces are used for quality improvement or system problems. Clusters are groups of not more than five or six staff members, facilitated by a cluster leader. A cluster is made up of individuals who work the same shift. For example, people with job titles who work days would be in a cluster. There would be registered nurses, licensed practical nurses, nursing assistants, and unit clerks in the cluster. The cluster leader is chosen by the manager based on certain criteria and is trained for this specialized role. The concept of cluster management, criteria for choosing leaders, training for leaders, using cluster groups to solve quality improvement issues, and the learning process necessary for manager support are described.

  1. Genetic predisposition of donors affects the allograft outcome in kidney transplantation; polymorphisms of stromal-derived factor-1 and CXC receptor 4.

    Directory of Open Access Journals (Sweden)

    Jung Pyo Lee

    Full Text Available Genetic interaction between donor and recipient may dictate the impending responses after transplantation. In this study, we evaluated the role of the genetic predispositions of stromal-derived factor-1 (SDF1 [rs1801157 (G>A] and CXC receptor 4 (CXCR4 [rs2228014 (C>T] on renal allograft outcomes. A total of 335 pairs of recipients and donors were enrolled. Biopsy-proven acute rejection (BPAR and long-term graft survival were traced. Despite similar allele frequencies between donors and recipients, minor allele of SDF1 rs1801157 (GA+AA from donor, not from recipients, has a protective effect on the development of BPAR compared to wild type donor (GG (P  = 0.005. Adjustment for multiple covariates did not affect this result (odds ratio 0.39, 95% C.I 0.20-0.76, P = 0.006. CXCR4 rs2228014 polymorphisms from donor or recipient did not affect the incidence of acute rejection. SDF1 was differentially expressed in renal tubular epithelium with acute rejection according to genetic variations of donor rs1801157 showing higher expressions in the grafts from GG donors. Contrary to the development of BPAR, the presence of minor allele rs1801157 A, especially homozygocity, predisposed poor graft survival (P = 0.001. This association was significant after adjusting for several risk factors (hazard ratio 3.01; 95% C.I = 1.19-7.60; P = 0.020. The allelic variation of recipients, however, was not associated with graft loss. A donor-derived genetic polymorphism of SDF1 has influenced the graft outcome. Thus, the genetic predisposition of donor should be carefully considered in transplantation.

  2. AMP-Activated Protein Kinase Interacts with the Peroxisome Proliferator-Activated Receptor Delta to Induce Genes Affecting Fatty Acid Oxidation in Human Macrophages.

    Directory of Open Access Journals (Sweden)

    Marina Kemmerer

    Full Text Available AMP-activated protein kinase (AMPK maintains energy homeostasis by suppressing cellular ATP-consuming processes and activating catabolic, ATP-producing pathways such as fatty acid oxidation (FAO. The transcription factor peroxisome proliferator-activated receptor δ (PPARδ also affects fatty acid metabolism, stimulating the expression of genes involved in FAO. To question the interplay of AMPK and PPARδ in human macrophages we transduced primary human macrophages with lentiviral particles encoding for the constitutively active AMPKα1 catalytic subunit, followed by microarray expression analysis after treatment with the PPARδ agonist GW501516. Microarray analysis showed that co-activation of AMPK and PPARδ increased expression of FAO genes, which were validated by quantitative PCR. Induction of these FAO-associated genes was also observed upon infecting macrophages with an adenovirus coding for AMPKγ1 regulatory subunit carrying an activating R70Q mutation. The pharmacological AMPK activator A-769662 increased expression of several FAO genes in a PPARδ- and AMPK-dependent manner. Although GW501516 significantly increased FAO and reduced the triglyceride amount in very low density lipoproteins (VLDL-loaded foam cells, AMPK activation failed to potentiate this effect, suggesting that increased expression of fatty acid catabolic genes alone may be not sufficient to prevent macrophage lipid overload.

  3. The Common Follicle-Stimulating Hormone Receptor (FSHR Promoter Polymorphism FSHR −29G > A Affects Androgen Production in Normal Human Small Antral Follicles

    Directory of Open Access Journals (Sweden)

    Tanni Borgbo

    2017-06-01

    Full Text Available Follicle-stimulating hormone receptors (FSHRs are almost exclusively expressed on granulosa cells, and FSH action is probably most clearly reflected in intrafollicular hormone milieu of antral follicles. Little is known about the possible effects of the common single nucleotide polymorphism (SNP FSHR −29G > A (rs1394205 on hormonal conditions in humsan small antral follicles (hSAFs obtained from women in the natural menstrual cycle. This study investigated the follicle fluid (FF concentrations of anti-Müllerian hormone, estradiol, progesterone, androstenedione, and testosterone in hSAF in relation to the different genotypes of FSHR −29G > A. FF from 362 follicles was collected in 95 women undergoing fertility preservation, who did not suffer from a disease that directly affected ovarian function. The testosterone levels of the minor A/A genotype were significantly increased compared to the A/G and the G/G genotype. Furthermore, significantly reduced androstenedione levels were observed for the G/G genotype, as compared to the A/G genotype, while the other hormones did not show statistical significant differences. In conclusion, the androgen levels of hSAF were significantly elevated in the minor SNP genotype in the FSHR promoter polymorphism FSHR −29G > A.

  4. Circadian clock gene aryl hydrocarbon receptor nuclear translocator-like polymorphisms are associated with seasonal affective disorder: An Indian family study.

    Science.gov (United States)

    Rajendran, Bhagya; Janakarajan, Veeramahali Natarajan

    2016-01-01

    Polymorphisms in aryl hydrocarbon receptor nuclear translocator-like (ARNTL) gene, the key component of circadian clock manifests circadian rhythm abnormalities. As seasonal affective disorder (SAD) is associated with disrupted circadian rhythms, the main objective of this study was to screen an Indian family with SAD for ARNTL gene polymorphisms. In this study, 30 members of close-knit family with SAD, 30 age- and sex-matched controls of the same caste with no prior history of psychiatric illness and 30 age- and sex-matched controls belonging to 17 different castes with no prior history of psychiatric illness were genotyped for five different single nucleotide polymorphisms (SNPs) in ARNTL gene by TaqMan allele-specific genotyping assay. Statistical significance was assessed by more powerful quasi-likelihood score test-XM. Most of the family members carried the risk alleles and we observed a highly significant SNP rs2279287 (A/G) in ARNTL gene with an allelic frequency of 0.75. Polymorphisms in ARNTL gene disrupt circadian rhythms causing SAD and genetic predisposition becomes more deleterious in the presence of adverse environment.

  5. Isotopic clusters

    International Nuclear Information System (INIS)

    Geraedts, J.M.P.

    1983-01-01

    Spectra of isotopically mixed clusters (dimers of SF 6 ) are calculated as well as transition frequencies. The result leads to speculations about the suitability of the laser-cluster fragmentation process for isotope separation. (Auth.)

  6. Cluster Headache

    Science.gov (United States)

    ... a role. Unlike migraine and tension headache, cluster headache generally isn't associated with triggers, such as foods, hormonal changes or stress. Once a cluster period begins, however, drinking alcohol ...

  7. Cluster Headache

    OpenAIRE

    Pearce, Iris

    1985-01-01

    Cluster headache is the most severe primary headache with recurrent pain attacks described as worse than giving birth. The aim of this paper was to make an overview of current knowledge on cluster headache with a focus on pathophysiology and treatment. This paper presents hypotheses of cluster headache pathophysiology, current treatment options and possible future therapy approaches. For years, the hypothalamus was regarded as the key structure in cluster headache, but is now thought to be pa...

  8. Categorias Cluster

    OpenAIRE

    Queiroz, Dayane Andrade

    2015-01-01

    Neste trabalho apresentamos as categorias cluster, que foram introduzidas por Aslak Bakke Buan, Robert Marsh, Markus Reineke, Idun Reiten e Gordana Todorov, com o objetivo de categoriíicar as algebras cluster criadas em 2002 por Sergey Fomin e Andrei Zelevinsky. Os autores acima, em [4], mostraram que existe uma estreita relação entre algebras cluster e categorias cluster para quivers cujo grafo subjacente é um diagrama de Dynkin. Para isto desenvolveram uma teoria tilting na estrutura triang...

  9. Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids in both humans and baboons

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Qian-fei; Liu, Xin; O' Connell, Jeff; Peng, Ze; Krauss, Ronald M.; Rainwater, David L.; VandeBerg, John L.; Rubin, Edward M.; Cheng, Jan-Fang; Pennacchio, Len A.

    2003-09-15

    Genetic studies in non-human primates serve as a potential strategy for identifying genomic intervals where polymorphisms impact upon human disease-related phenotypes. It remains unclear, however, whether independently arising polymorphisms in orthologous regions of non-human primates leads to similar variation in a quantitative trait found in both species. To explore this paradigm, we studied a baboon apolipoprotein gene cluster (APOA1/C3/A4/A5) for which the human gene orthologs have well established roles in influencing plasma HDL-cholesterol and triglyceride concentrations. Our extensive polymorphism analysis of this 68 kb gene cluster in 96 pedigreed baboons identified several haplotype blocks each with limited diversity, consistent with haplotype findings in humans. To determine whether baboons, like humans, also have particular haplotypes associated with lipid phenotypes, we genotyped 634 well characterized baboons using 16 haplotype tagging SNPs. Genetic analysis of single SNPs, as well as haplotypes, revealed an association of APOA5 and APOC3 variants with HDL cholesterol and triglyceride concentrations, respectively. Thus, independent variation in orthologous genomic intervals does associate with similar quantitative lipid traits in both species, supporting the possibility of uncovering human QTL genes in a highly controlled non-human primate model.

  10. Meaningful Clusters

    Energy Technology Data Exchange (ETDEWEB)

    Sanfilippo, Antonio P.; Calapristi, Augustin J.; Crow, Vernon L.; Hetzler, Elizabeth G.; Turner, Alan E.

    2004-05-26

    We present an approach to the disambiguation of cluster labels that capitalizes on the notion of semantic similarity to assign WordNet senses to cluster labels. The approach provides interesting insights on how document clustering can provide the basis for developing a novel approach to word sense disambiguation.

  11. Horticultural cluster

    OpenAIRE

    SHERSTIUK S.V.; POSYLAYEVA K.I.

    2013-01-01

    In the article there are the theoretical and methodological approaches to the nature and existence of the cluster. The cluster differences from other kinds of cooperative and integration associations. Was develop by scientific-practical recommendations for forming a competitive horticultur cluster.

  12. Prenatal Lipid-Based Nutrient Supplements Do Not Affect Pregnancy or Childbirth Complications or Cesarean Delivery in Bangladesh: A Cluster-Randomized Controlled Effectiveness Trial.

    Science.gov (United States)

    Mridha, Malay K; Matias, Susana L; Paul, Rina Rani; Hussain, Sohrab; Sarker, Mostofa; Hossain, Mokbul; Peerson, Janet M; Vosti, Stephen A; Dewey, Kathryn G

    2017-09-01

    Background: Pregnancy and childbirth complications and cesarean delivery are common in Bangladesh. Objective: We evaluated the effect of lipid-based nutrient supplements for pregnant and lactating women (LNS-PL) on pregnancy and childbirth complications and cesarean delivery. Methods: We conducted the Rang-Din Nutrition Study, a cluster-randomized controlled effectiveness trial within a community health program in rural Bangladesh. We enrolled 4011 pregnant women in early pregnancy. Women in 48 clusters received iron and folic acid (IFA; 60 mg Fe + 400 μg folic acid/d) and women in 16 clusters received LNS-PL (20 g/d, 118 kcal) containing essential fatty acids and 22 vitamins and minerals. Pregnancy and childbirth complications and the cesarean delivery rate were secondary outcomes of the study. Results: Women in the LNS-PL group did not differ significantly from the IFA group with respect to mean systolic blood pressure at 36 wk gestation (113 and 112 mm Hg; P = 0.17), diastolic blood pressure at 36 wk gestation (68.9 and 68.7 mmHg; P = 0.88), or mean total number of pregnancy and childbirth complications (0.32 and 0.31; P = 0.86). They also did not differ significantly with respect to the prevalence of high blood pressure at 36 wk (1.74% and 2.03%; P = 0.62), antepartum hemorrhage (0.83% and 1.39%; P = 0.21), prolonged labor (8.34% and 8.79%; P = 0.68), early rupture of membranes (9.30% and 8.45%; P = 0.43), convulsions (1.57% and 1.08%; P = 0.24), high blood pressure in labor (1.54% and 1.19%; P = 0.46), obstructed labor (2.83% and 2.91%; P = 0.90), any complications during pregnancy or childbirth (35.9% and 37.1%; P = 0.64), episiotomy (6.31% and 6.44%; P = 0.90), or cesarean delivery (15.6% and 14.2%; P = 0.48). Conclusion: Compared with IFA, antenatal LNS-PL did not increase or decrease pregnancy and childbirth complications or cesarean delivery among women in rural Bangladesh. This trial was registered at clinicaltrials.gov as NCT01715038. © 2017 American

  13. Cluster Matters

    DEFF Research Database (Denmark)

    Gulati, Mukesh; Lund-Thomsen, Peter; Suresh, Sangeetha

    2018-01-01

    sell their products successfully in international markets, but there is also an increasingly large consumer base within India. Indeed, Indian industrial clusters have contributed to a substantial part of this growth process, and there are several hundred registered clusters within the country...... of this handbook, which focuses on the role of CSR in MSMEs. Hence we contribute to the literature on CSR in industrial clusters and specifically CSR in Indian industrial clusters by investigating the drivers of CSR in India’s industrial clusters....

  14. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection

    NARCIS (Netherlands)

    Hazenberg, Mette D.; Borleffs, J.C.C.; Otto, S.A.; Cohen Stuart, J.W.T. (James Willem Theodoor); Verschuren, M.C.M. (Martie); Boucher, C.A.B.; Coutinho, R.A.; Lange, Joep M.A.; Rinke de Wit, T.F. (Tobias); Tsegaye, A. (Aster); Dongen, J.J.M. (Jaques) van; Hamann, D. (Dörte); Boer, R.J. de; Miedema, F.

    2000-01-01

    Recent thymic emigrants can be identified by T cell receptor excision circles (TRECs) formed during T-cell receptor rearrangement. Decreasing numbers of TRECs have been observed with aging and in human immunodeficiency virus (HIV)-1 infected individuals, suggesting for thymic impairment. Here,

  15. G-231A and G+70C polymorphisms of endothelin receptor type-A gene could affect the psoriasis area and severity index score and endothelin 1 levels

    Directory of Open Access Journals (Sweden)

    Gökhan Okan

    2015-01-01

    Full Text Available Background: The etiopathogenesis of psoriasis has not been clearly elucidated although the role of chronic inflammation, imbalance between pro- and anti-inflammatory cytokines, and many immunological events have been established. Endothelin 1 (EDN1 and endothelin receptor type-A (EDNRA are implicated in the inflammatory process. The relationships between EDN1 and EDNRA polymorphisms with several diseases have been found. Aims and Objectives: This study examined the possible association of EDN1 (G5665T and T-1370G and EDNRA (G-231A and G + 70C single nucleotide polymorphisms (SNPs with the occurence of psoriasis, and evaluated the relationship between genotypes and clinical/laboratory manifestation of psoriasis. Materials and Methods: We analyzed genotype and allele distributions of the above-mentioned polymorphisms in 151 patients with psoriasis and 152 healthy controls by real-time PCR combined with melting curve analysis. Results: We did not find significant differences in the genotype and allele distributions of EDN1 T-1370G, EDNRA G-231A, and EDNRA G+70C polymorphisms between patients with psoriasis and healthy controls. Psoriasis area and severity index (PASI score of EDNRA -231 polymorphic A allele carrying subjects (AA and AA + AG was higher than that of wild homozygotes (P = 0.044 and P = 0.027, respectively. In addition, EDN1 levels in EDNRA+70 polymorphic C allele carriers (CC + CG were elevated when compared with GG genotype; however, the difference was at borderline significance (P = 0.05. Conclusion: Although there were no associations between studied polymorphisms and psoriasis susceptibility, the PASI score and EDN1 levels seem to be affected by EDNRA G-231A and G + 70C polymorphisms.

  16. Dopamine receptor blockade attenuates the general incentive motivational effects of noncontingently delivered rewards and reward-paired cues without affecting their ability to bias action selection.

    Science.gov (United States)

    Ostlund, Sean B; Maidment, Nigel T

    2012-01-01

    Environmental cues affect our behavior in a variety of ways. Despite playing an invaluable role in guiding our daily activities, such cues also appear to trigger the harmful, compulsive behaviors that characterize addiction and other disorders of behavioral control. In instrumental conditioning, rewards and reward-paired cues bias action selection and invigorate reward-seeking behaviors, and appear to do so through distinct neurobehavioral processes. Although reward-paired cues are known to invigorate performance through a dopamine-dependent incentive motivational process, it is not known if dopamine also mediates the influence of rewards and reward-paired cues over action selection. The current study contrasted the effects of systemic administration of the nonspecific dopamine receptor antagonist flupentixol on response invigoration and action bias in Pavlovian-instrumental transfer, a test of cue-elicited responding, and in instrumental reinstatement, a test of noncontingent reward-elicited responding. Hungry rats were trained on two different stimulus-outcome relationships (eg, tone-grain pellets and noise-sucrose solution) and two different action-outcome relationships (eg, left press-grain and right press-sucrose). At test, we found that flupentixol pretreatment blocked the response invigoration generated by the cues but spared their ability to bias action selection to favor the action whose outcome was signaled by the cue being presented. The response-biasing influence of noncontingent reward deliveries was also unaffected by flupentixol. Interestingly, although flupentixol had a modest effect on the immediate response invigoration produced by those rewards, it was particularly potent in countering the lingering enhancement of responding produced by multiple reward deliveries. These findings indicate that dopamine mediates the general incentive motivational effects of noncontingent rewards and reward-paired cues but does not support their ability to bias

  17. Deficiency of Interleukin-1 Receptor Antagonist (DIRA): Report of the First Indian Patient and a Novel Deletion Affecting IL1RN.

    Science.gov (United States)

    Mendonca, Leonardo O; Malle, Louise; Donovan, Frank X; Chandrasekharappa, Settara C; Montealegre Sanchez, Gina A; Garg, Megha; Tedgard, Ulf; Castells, Mariana; Saini, Shiv S; Dutta, Sourabh; Goldbach-Mansky, Raphaela; Suri, Deepti; Jesus, Adriana A

    2017-07-01

    Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autoinflammatory disease caused by autosomal recessive mutations in IL1RN. DIRA presents clinically with early onset generalized pustulosis, multifocal osteomyelitis, and elevation of acute phase reactants. We evaluated and treated an antibiotic-unresponsive patient with presumed DIRA with recombinant IL-1Ra (anakinra). The patient developed anaphylaxis to anakinra and was subsequently desensitized. Genetic analysis of IL1RN was undertaken and treatment with anakinra was initiated. A 5-month-old Indian girl born to healthy non-consanguineous parents presented at the third week of life with irritability, sterile multifocal osteomyelitis including ribs and clavicles, a mild pustular rash, and elevated acute phase reactants. SNP array of the patient's genomic DNA revealed a previously unrecognized homozygous deletion of approximately 22.5 Kb. PCR and Sanger sequencing of the borders of the deleted area allowed identification of the breakpoints of the deletion, thus confirming a homozygous 22,216 bp deletion that spans the first four exons of IL1RN. Due to a clinical suspicion of DIRA, anakinra was initiated which resulted in an anaphylactic reaction that triggered desensitization with subsequent marked and sustained clinical and laboratory improvement. We report a novel DIRA-causing homozygous deletion affecting IL1RN in an Indian patient. The mutation likely is a founder mutation; the design of breakpoint-specific primers will enable genetic screening in Indian patients suspected of DIRA. The patient developed anaphylaxis to anakinra, was desensitized, and is in clinical remission on continued treatment.

  18. Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia.

    Science.gov (United States)

    Underwood, S L; Christoforou, A; Thomson, P A; Wray, N R; Tenesa, A; Whittaker, J; Adams, R A; Le Hellard, S; Morris, S W; Blackwood, D H R; Muir, W J; Porteous, D J; Evans, K L

    2006-04-01

    The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a sample of 377 BPAD, 392 schizophrenia (SCZ) and 470 control individuals. Using standard chi(2) statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (chi(2) P=0.044; LRT P=0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR)=1.688, 95% confidence intervals (CI): 1.104-2.581) and uncorrected genotype P-value of 0.015 (OR=5.991, 95% CI: 1.545-23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR=5.618, 95% CI: 1.460-21.617) and remained significant after correcting for multiple testing (P=0.017). No single-marker association was detected in the SCZ males, in the BPAD individuals or with any other SNP. Haplotype analysis of the case-control samples revealed several global and individual haplotypes, with P-values <0.05, all but one of which contained SNP rs1282. After correcting for multiple testing, two haplotypes remained significant in both the female BPAD individuals (P=0.038 and 0.032) and in the full sample of affected female individuals (P=0.044 and 0.033). Our results provide preliminary evidence for the involvement of GPR78 in susceptibility to BPAD and SCZ in the Scottish population. Molecular Psychiatry (2006) 11, 384-394. doi:10.1038/sj.mp.4001786; published online 3 January 2006.

  19. Data Clustering

    Science.gov (United States)

    Wagstaff, Kiri L.

    2012-03-01

    On obtaining a new data set, the researcher is immediately faced with the challenge of obtaining a high-level understanding from the observations. What does a typical item look like? What are the dominant trends? How many distinct groups are included in the data set, and how is each one characterized? Which observable values are common, and which rarely occur? Which items stand out as anomalies or outliers from the rest of the data? This challenge is exacerbated by the steady growth in data set size [11] as new instruments push into new frontiers of parameter space, via improvements in temporal, spatial, and spectral resolution, or by the desire to "fuse" observations from different modalities and instruments into a larger-picture understanding of the same underlying phenomenon. Data clustering algorithms provide a variety of solutions for this task. They can generate summaries, locate outliers, compress data, identify dense or sparse regions of feature space, and build data models. It is useful to note up front that "clusters" in this context refer to groups of items within some descriptive feature space, not (necessarily) to "galaxy clusters" which are dense regions in physical space. The goal of this chapter is to survey a variety of data clustering methods, with an eye toward their applicability to astronomical data analysis. In addition to improving the individual researcher’s understanding of a given data set, clustering has led directly to scientific advances, such as the discovery of new subclasses of stars [14] and gamma-ray bursts (GRBs) [38]. All clustering algorithms seek to identify groups within a data set that reflect some observed, quantifiable structure. Clustering is traditionally an unsupervised approach to data analysis, in the sense that it operates without any direct guidance about which items should be assigned to which clusters. There has been a recent trend in the clustering literature toward supporting semisupervised or constrained

  20. Root-zone temperatures affect phenology of bud break, flower cluster development, shoot extension growth and gas exchange of 'Braeburn' (Malus domestica) apple trees.

    Science.gov (United States)

    Greer, Dennis H; Wünsche, Jens N; Norling, Cara L; Wiggins, Harry N

    2006-01-01

    We investigated the effects of root-zone temperature on bud break, flowering, shoot growth and gas exchange of potted mature apple (Malus domestica (Borkh.)) trees with undisturbed roots. Soil respiration was also determined. Potted 'Braeburn' apple trees on M.9 rootstock were grown for 70 days in a constant day/night temperature regime (25/18 degrees C) and one of three constant root-zone temperatures (7, 15 and 25 degrees C). Both the proportion and timing of bud break were significantly enhanced as root-zone temperature increased. Rate of floral cluster opening was also markedly increased with increasing root-zone temperature. Shoot length increased but shoot girth growth declined as root-zone temperatures increased. Soil respiration and leaf photosynthesis generally increased as root-zone temperatures increased. Results indicate that apple trees growing in regions where root zone temperatures are or = 15 degrees C. The effect of root-zone temperature on shoot performance may be mediated through the mobilization of root reserves, although the role of phytohormones cannot be discounted. Variation in leaf photosynthesis across the temperature treatments was inadequately explained by stomatal conductance. Given that root growth increases with increasing temperature, changes in sink activity induced by the root-zone temperature treatments provide a possible explanation for the non-stomatal effect on photosynthesis. Irrespective of underlying mechanisms, root-zone temperatures influence bud break and flowering in apple trees.

  1. Cluster evolution

    International Nuclear Information System (INIS)

    Schaeffer, R.

    1987-01-01

    The galaxy and cluster luminosity functions are constructed from a model of the mass distribution based on hierarchical clustering at an epoch where the matter distribution is non-linear. These luminosity functions are seen to reproduce the present distribution of objects as can be inferred from the observations. They can be used to deduce the redshift dependence of the cluster distribution and to extrapolate the observations towards the past. The predicted evolution of the cluster distribution is quite strong, although somewhat less rapid than predicted by the linear theory

  2. Zolpidem, a clinical hypnotic that affects electronic transfer, alters synaptic activity through potential GABA receptors in the nervous system without significant free radical generation

    OpenAIRE

    Kovacic, Peter; Somanathan, Ratnasamy

    2009-01-01

    Zolpidem (trade name Ambien) has attracted much interest as a sleep-inducing agent and also in research. Attention has been centered mainly on receptor binding and electrochemistry in the central nervous system which are briefly addressed herein. A novel integrated approach to mode of action is presented. The pathways to be discussed involve basicity, reduction potential, electrostatics, cell signaling, GABA receptor binding, electron transfer (ET), pharmacodynamics, structure activity relati...

  3. Evidence from cluster surveys on the association between home-based counseling and use of family planning in conflict-affected Darfur.

    Science.gov (United States)

    Adam, Izzeldin F

    2016-05-01

    To examine the association between home counseling and awareness and use of modern family planning (FP) methods among women in internally displaced person (IDP) camps in conflict-affected West Darfur, Sudan. In a community-based cross-sectional study, two questionnaire-based surveys were performed in three camps. Home-based counseling had been introduced in March 2006. An initial survey (February 2007) and a follow-up survey (April 2009) targeted women of child-bearing age. A sample of 640 randomly selected women aged 15-49 years who had experienced pregnancy after joining the camp were interviewed for each survey. Overall, modern FP use increased from 10.9% (70/640) in 2007 to 21.6% (138/640) in 2009 (P<0.001). As compared with the initial survey, women in the follow-up survey were more likely to be aware of and to use any modern FP method (adjusted odds ratio [aOR] 5.4, 95% confidence interval [CI] 3.9-7.4; and aOR 2.8, 95% CI 2.0-4.1, respectively). Contraceptive pills were the most common modern method used. Home counseling and loss of a child under 5years were the most significant predictors of awareness and use of modern FP methods. After the introduction of home-based FP counseling for couples and FP services in clinics, women's awareness and use of modern FP methods increased in a conflict-affected setting. Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  4. Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels

    DEFF Research Database (Denmark)

    Klein, Anders Bue; Trajkovska, Viktorija; Erritzoe, David

    2010-01-01

    Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT(2A......)) receptor or serotonin transporter (SERT) binding in healthy subjects. No statistically significant differences in 5-HT(2A) receptor or SERT binding were found between the val/val and met carriers, nor were blood BDNF values associated with SERT binding or 5-HT(2A) receptor binding. In conclusion, val66met...... BDNF polymorphism status is not associated with changes in the serotonergic system. Moreover, BDNF levels in blood do not correlate with either 5-HT(2A) or SERT binding....

  5. Localization and orientation of heavy-atom cluster compounds in protein crystals using molecular replacement.

    Science.gov (United States)

    Dahms, Sven O; Kuester, Miriam; Streb, Carsten; Roth, Christian; Sträter, Norbert; Than, Manuel E

    2013-02-01

    Heavy-atom clusters (HA clusters) containing a large number of specifically arranged electron-dense scatterers are especially useful for experimental phase determination of large complex structures, weakly diffracting crystals or structures with large unit cells. Often, the determination of the exact orientation of the HA cluster and hence of the individual heavy-atom positions proves to be the critical step in successful phasing and subsequent structure solution. Here, it is demonstrated that molecular replacement (MR) with either anomalous or isomorphous differences is a useful strategy for the correct placement of HA cluster compounds. The polyoxometallate cluster hexasodium α-metatungstate (HMT) was applied in phasing the structure of death receptor 6. Even though the HA cluster is bound in alternate partially occupied orientations and is located at a special position, its correct localization and orientation could be determined at resolutions as low as 4.9 Å. The broad applicability of this approach was demonstrated for five different derivative crystals that included the compounds tantalum tetradecabromide and trisodium phosphotungstate in addition to HMT. The correct placement of the HA cluster depends on the length of the intramolecular vectors chosen for MR, such that both a larger cluster size and the optimal choice of the wavelength used for anomalous data collection strongly affect the outcome.

  6. Clustering analysis

    International Nuclear Information System (INIS)

    Romli

    1997-01-01

    Cluster analysis is the name of group of multivariate techniques whose principal purpose is to distinguish similar entities from the characteristics they process.To study this analysis, there are several algorithms that can be used. Therefore, this topic focuses to discuss the algorithms, such as, similarity measures, and hierarchical clustering which includes single linkage, complete linkage and average linkage method. also, non-hierarchical clustering method, which is popular name K -mean method ' will be discussed. Finally, this paper will be described the advantages and disadvantages of every methods

  7. Cluster analysis

    CERN Document Server

    Everitt, Brian S; Leese, Morven; Stahl, Daniel

    2011-01-01

    Cluster analysis comprises a range of methods for classifying multivariate data into subgroups. By organizing multivariate data into such subgroups, clustering can help reveal the characteristics of any structure or patterns present. These techniques have proven useful in a wide range of areas such as medicine, psychology, market research and bioinformatics.This fifth edition of the highly successful Cluster Analysis includes coverage of the latest developments in the field and a new chapter dealing with finite mixture models for structured data.Real life examples are used throughout to demons

  8. Cluster editing

    DEFF Research Database (Denmark)

    Böcker, S.; Baumbach, Jan

    2013-01-01

    . The problem has been the inspiration for numerous algorithms in bioinformatics, aiming at clustering entities such as genes, proteins, phenotypes, or patients. In this paper, we review exact and heuristic methods that have been proposed for the Cluster Editing problem, and also applications......The Cluster Editing problem asks to transform a graph into a disjoint union of cliques using a minimum number of edge modifications. Although the problem has been proven NP-complete several times, it has nevertheless attracted much research both from the theoretical and the applied side...

  9. Peroxisome Proliferator-Activated Receptor-alpha Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

    NARCIS (Netherlands)

    Lalloyer, Fanny; Wouters, Kristiaan; Baron, Morgane; Caron, Sandrine; Vallez, Emmanuelle; Vanhoutte, Jonathan; Bauge, Eric; Shiri-Sverdlov, Ronit; Hofker, Marten; Staels, Bart; Tailleux, Anne

    Objective-Peroxisome proliferator-activated receptor-alpha (PPAR alpha) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPAR alpha is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence

  10. A new LH receptor splice mutation responsible for male hypogonadism with subnormal sperm production in the propositus, and infertility with regular cycles in an affected sister

    NARCIS (Netherlands)

    M.W.P. Bruysters (Martijn); S. Christin-Maitre (Sophie); M. Verhoef-Post (Miriam); C. Sultan; J. Auger; I. Faugeron; L. Larue; S. Lumbroso; A.P.N. Themmen (Axel); P. Bouchard (Philippe)

    2008-01-01

    textabstractBACKGROUND: Inactivating LH receptor (LHR) mutations have been described so far in men as well as in women. Phenotypes in men have been variable with in nearly all cases impairment of sex differentiation or azoospermia. We report a milder reproductive phenotype both in a male patient and

  11. Y5 neuropeptide Y receptor overexpression in mice neither affects anxiety- and depression-like behaviours nor seizures but confers moderate hyperactivity

    DEFF Research Database (Denmark)

    Olesen, Mikkel V; Christiansen, Søren Hofman Oliveira; Gøtzsche, Casper René

    2012-01-01

    Neuropeptide Y (NPY) has been implicated in anxiolytic- and antidepressant-like behaviour as well as seizure-suppressant effects in rodents. Although these effects appear to be predominantly mediated via other NPY receptors (Y1 and/or Y2), several studies have also indicated a role for Y5 recepto...

  12. Occupational Clusters.

    Science.gov (United States)

    Pottawattamie County School System, Council Bluffs, IA.

    The 15 occupational clusters (transportation, fine arts and humanities, communications and media, personal service occupations, construction, hospitality and recreation, health occupations, marine science occupations, consumer and homemaking-related occupations, agribusiness and natural resources, environment, public service, business and office…

  13. Fuzzy Clustering

    DEFF Research Database (Denmark)

    Berks, G.; Keyserlingk, Diedrich Graf von; Jantzen, Jan

    2000-01-01

    A symptom is a condition indicating the presence of a disease, especially, when regarded as an aid in diagnosis.Symptoms are the smallest units indicating the existence of a disease. A syndrome on the other hand is an aggregate, set or cluster of concurrent symptoms which together indicate...... and clustering are the basic concerns in medicine. Classification depends on definitions of the classes and their required degree of participant of the elements in the cases' symptoms. In medicine imprecise conditions are the rule and therefore fuzzy methods are much more suitable than crisp ones. Fuzzy c......-mean clustering is an easy and well improved tool, which has been applied in many medical fields. We used c-mean fuzzy clustering after feature extraction from an aphasia database. Factor analysis was applied on a correlation matrix of 26 symptoms of language disorders and led to five factors. The factors...

  14. Cluster generator

    Science.gov (United States)

    Donchev, Todor I [Urbana, IL; Petrov, Ivan G [Champaign, IL

    2011-05-31

    Described herein is an apparatus and a method for producing atom clusters based on a gas discharge within a hollow cathode. The hollow cathode includes one or more walls. The one or more walls define a sputtering chamber within the hollow cathode and include a material to be sputtered. A hollow anode is positioned at an end of the sputtering chamber, and atom clusters are formed when a gas discharge is generated between the hollow anode and the hollow cathode.

  15. Cluster Bulleticity

    OpenAIRE

    Massey, Richard; Kitching, Thomas; Nagai, Daisuke

    2010-01-01

    The unique properties of dark matter are revealed during collisions between clusters of galaxies, such as the bullet cluster (1E 0657−56) and baby bullet (MACS J0025−12). These systems provide evidence for an additional, invisible mass in the separation between the distributions of their total mass, measured via gravitational lensing, and their ordinary ‘baryonic’ matter, measured via its X-ray emission. Unfortunately, the information available from these systems is limited by their rarity. C...

  16. 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

  17. Progestogen treatments for cycle management in a sheep model of assisted conception affect the growth patterns, the expression of luteinizing hormone receptors, and the progesterone secretion of induced corpora lutea.

    Science.gov (United States)

    Letelier, Claudia; García-Fernández, Rosa Ana; Contreras-Solis, Ignacio; Sanchez, María Angeles; Garcia-Palencia, Pilar; Sanchez, Belen; Gonzalez-Bulnes, Antonio; Flores, Juana María

    2010-03-01

    To determine, in a sheep model, the effect of a short-term progestative treatment on growth dynamics and functionality of induced corpora lutea. Observational, model study. Public university. Sixty adult female sheep. Synchronization and induction of ovulation with progestogens and prostaglandin analogues; ovarian ultrasonography, blood sampling, and ovariectomy. Determination of pituitary function and morphologic characteristics, expression of luteinizing hormone (LH) receptors, and progesterone secretion of corpora lutea. The use of progestative pretreatments for assisted conception affect the growth patterns, the expression of LH receptors, and the progesterone secretion of induced corpora lutea. The current study indicates, in a sheep model, the existence of deleterious effects from progestogens on functionality of induced corpora lutea. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  18. Zolpidem, A Clinical Hypnotic that Affects Electronic Transfer, Alters Synaptic Activity Through Potential Gaba Receptors in the Nervous System Without Significant Free Radical Generation

    Directory of Open Access Journals (Sweden)

    Peter Kovacic

    2009-01-01

    Full Text Available Zolpidem (trade name Ambien has attracted much interest as a sleep-inducing agent and also in research. Attention has been centered mainly on receptor binding and electrochemistry in the central nervous system which are briefly addressed herein. A novel integrated approach to mode of action is presented. The pathways to be discussed involve basicity, reduction potential, electrostatics, cell signaling, GABA receptor binding, electron transfer (ET, pharmacodynamics, structure activity relationships (SAR and side effects. The highly conjugated pyridinium salt formed by protonation of the amidine moiety is proposed to be the active form acting as an ET agent. Extrapolation of reduction potentials for related compounds supports the premise that zolpidem may act as an ET species in vivo. From recent literature reports, electrostatics is believed to play a significant role in drug action.

  19. The Arabidopsis thaliana lectin receptor kinase LecRK-I.9 is required for full resistance to Pseudomonas syringae and affects jasmonate signalling.

    Science.gov (United States)

    Balagué, Claudine; Gouget, Anne; Bouchez, Olivier; Souriac, Camille; Haget, Nathalie; Boutet-Mercey, Stéphanie; Govers, Francine; Roby, Dominique; Canut, Hervé

    2017-09-01

    On microbial attack, plants can detect invaders and activate plant innate immunity. For the detection of pathogen molecules or cell wall damage, plants employ receptors that trigger the activation of defence responses. Cell surface proteins that belong to large families of lectin receptor kinases are candidates to function as immune receptors. Here, the function of LecRK-I.9 (At5g60300), a legume-type lectin receptor kinase involved in cell wall-plasma membrane contacts and in extracellular ATP (eATP) perception, was studied through biochemical, gene expression and reverse genetics approaches. In Arabidopsis thaliana, LecRK-I.9 expression is rapidly, highly and locally induced on inoculation with avirulent strains of Pseudomonas syringae pv. tomato (Pst). Two allelic lecrk-I.9 knock-out mutants showed decreased resistance to Pst. Conversely, over-expression of LecRK-I.9 led to increased resistance to Pst. The analysis of defence gene expression suggests an alteration of both the salicylic acid (SA) and jasmonic acid (JA) signalling pathways. In particular, LecRK-I.9 expression during plant-pathogen interaction was dependent on COI1 (CORONATINE INSENSITIVE 1) and JAR1 (JASMONATE RESISTANT 1) components, and JA-responsive transcription factors (TFs) showed altered levels of expression in plants over-expressing LecRK-I.9. A similar misregulation of these TFs was obtained by JA treatment. This study identified LecRK-I.9 as necessary for full resistance to Pst and demonstrated its involvement in the control of defence against pathogens through a regulation of JA signalling components. The role of LecRK-I.9 is discussed with regard to the potential molecular mechanisms linking JA signalling to cell wall damage and/or eATP perception. © 2016 BSPP AND JOHN WILEY & SONS LTD.

  20. Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration*

    Science.gov (United States)

    Ou, Young; Chan, Gordon; Zuo, Jeremy; Rattner, Jerome B.; van der Hoorn, Frans A.

    2016-01-01

    The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process. PMID:27226580

  1. Internalization and desensitization of the human glucose-dependent-insulinotropic receptor is affected by N-terminal acetylation of the agonist.

    Science.gov (United States)

    Ismail, Sadek; Dubois-Vedrenne, Ingrid; Laval, Marie; Tikhonova, Irina G; D'Angelo, Romina; Sanchez, Claire; Clerc, Pascal; Gherardi, Marie-Julie; Gigoux, Véronique; Magnan, Remi; Fourmy, Daniel

    2015-10-15

    How incretins regulate presence of their receptors at the cell surface and their activity is of paramount importance for the development of therapeutic strategies targeting these receptors. We have studied internalization of the human Glucose-Insulinotropic Polypeptide receptor (GIPR). GIP stimulated rapid robust internalization of the GIPR, the major part being directed to lysosomes. GIPR internalization involved mainly clathrin-coated pits, AP-2 and dynamin. However, neither GIPR C-terminal region nor β-arrestin1/2 was required. Finally, N-acetyl-GIP recognized as a dipeptidyl-IV resistant analogue, fully stimulated cAMP production with a ∼15-fold lower potency than GIP and weakly stimulated GIPR internalization and desensitization of cAMP response. Furthermore, docking N-acetyl-GIP in the binding site of modeled GIPR showed slighter interactions with residues of helices 6 and 7 of GIPR compared to GIP. Therefore, incomplete or partial activity of N-acetyl-GIP on signaling involved in GIPR desensitization and internalization contributes to the enhanced incretin activity of this peptide. Copyright © 2015. Published by Elsevier Ireland Ltd.

  2. Local Clusters in a Globalized World

    DEFF Research Database (Denmark)

    Reinau, Kristian Hegner

    Currently there is growing focus on how cluster internal and cluster external relations affect the creation of knowledge in companies placed in clusters. However, the current theories on this topic are too simple and the interplay between internal and external relations is relatively unknown. Thi...

  3. Homo-FRET imaging as a tool to quantify protein and lipid clustering.

    Science.gov (United States)

    Bader, Arjen N; Hoetzl, Sandra; Hofman, Erik G; Voortman, Jarno; van Bergen en Henegouwen, Paul M P; van Meer, Gerrit; Gerritsen, Hans C

    2011-02-25

    Homo-FRET, Förster resonance energy transfer between identical fluorophores, can be conveniently measured by observing its effect on the fluorescence anisotropy. This review aims to summarize the possibilities of fluorescence anisotropy imaging techniques to investigate clustering of identical proteins and lipids. Homo-FRET imaging has the ability to determine distances between fluorophores. In addition it can be employed to quantify cluster sizes as well as cluster size distributions. The interpretation of homo-FRET signals is complicated by the fact that both the mutual orientations of the fluorophores and the number of fluorophores per cluster affect the fluorescence anisotropy in a similar way. The properties of the fluorescence probes are very important. Taking these properties into account is critical for the correct interpretation of homo-FRET signals in protein- and lipid-clustering studies. This is be exemplified by studies on the clustering of the lipid raft markers GPI and K-ras, as well as for EGF receptor clustering in the plasma membrane. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Methamphetamine-induced short-term increase and long-term decrease in spatial working memory affects protein Kinase M zeta (PKMζ), dopamine, and glutamate receptors.

    Science.gov (United States)

    Braren, Stephen H; Drapala, Damian; Tulloch, Ingrid K; Serrano, Peter A

    2014-01-01

    Methamphetamine (MA) is a toxic, addictive drug shown to modulate learning and memory, yet the neural mechanisms are not fully understood. We investigated the effects of 2 weekly injections of MA (30 mg/kg) on working memory using the radial 8-arm maze (RAM) across 5 weeks in adolescent-age mice. MA-treated mice show a significant improvement in working memory performance 1 week following the first MA injection compared to saline-injected controls. Following 5 weeks of MA abstinence mice were re-trained on a reference and working memory version of the RAM to assess cognitive flexibility. MA-treated mice show significantly more working memory errors without effects on reference memory performance. The hippocampus and dorsal striatum were assessed for expression of glutamate receptors subunits, GluA2 and GluN2B; dopamine markers, dopamine 1 receptor (D1), dopamine transporter (DAT) and tyrosine hydroxylase (TH); and memory markers, protein kinase M zeta (PKMζ) and protein kinase C zeta (PKCζ). Within the hippocampus, PKMζ and GluA2 are both significantly reduced after MA supporting the poor memory performance. Additionally, a significant increase in GluN2B and decrease in D1 identifies dysregulated synaptic function. In the striatum, MA treatment increased cytosolic DAT and TH levels associated with dopamine hyperfunction. MA treatment significantly reduced GluN2B while increasing both PKMζ and PKCζ within the striatum. We discuss the potential role of PKMζ/PKCζ in modulating dopamine and glutamate receptors after MA treatment. These results identify potential underlying mechanisms for working memory deficits induced by MA.

  5. Methamphetamine-induced short-term increase and long-term decrease in spatial working memory affects Protein Kinase M zeta (PKMζ, dopamine, and glutamate receptors

    Directory of Open Access Journals (Sweden)

    Stephen H Braren

    2014-12-01

    Full Text Available Methamphetamine (MA is a toxic, addictive drug shown to modulate learning and memory, yet the neural mechanisms are not fully understood. We investigated the effects of 2 weekly injections of MA (30 mg/kg on working memory using the radial 8-arm maze (RAM across 5 weeks in adolescent-age mice. MA-treated mice show a significant improvement in working memory performance 1 week following the first MA injection compared to saline-injected controls. Following 5 weeks of MA abstinence mice were re-trained on a reference and working memory version of the RAM to assess cognitive flexibility. MA-treated mice show significantly more working memory errors without effects on reference memory performance. The hippocampus and dorsal striatum were assessed for expression of glutamate receptors subunits, GluA2 and GluN2B; dopamine markers, dopamine 1 receptor (D1, dopamine transporter (DAT and tyrosine hydroxylase (TH; and memory markers, protein kinase M zeta (PKMζ and protein kinase C zeta (PKCζ. Within the hippocampus, PKMζ and GluA2 are both significantly reduced after MA supporting the poor memory performance. Additionally, a significant increase in GluN2B and decrease in D1 identifies dysregulated synaptic function. In the striatum, MA treatment increased cytosolic DAT and TH levels associated with dopamine hyperfunction. MA treatment significantly reduced GluN2B while increasing both PKMζ and PKCζ within the striatum. We discuss the potential role of PKMζ/PKCζ in modulating dopamine and glutamate receptors after MA treatment. These results identify potential underlying mechanisms for working memory deficits induced by MA.

  6. Expression of NR1 subunit of NMDA receptor and PSD-93/95 in rat hippocampus affected by NR1/NR2 antisense oligodeoxynucleotide

    Czech Academy of Sciences Publication Activity Database

    Vrajová, M.; Bubeníková-Valešová, V.; Klaschka, Jan

    2010-01-01

    Roč. 9, Suppl.1 (2010), S147 ISSN 1744-859X. [International Congress on Neurobiology and Clinical Psychopharmacology and European Psychiatric Association Conference on Treatment Guidance /1./. 19.11.2009-22.11.2009, Thessaloniki] R&D Projects: GA ČR GD309/09/H072; GA MŠk(CZ) 1M0517 Institutional research plan: CEZ:AV0Z10300504 Keywords : schizophrenia * animal model * NMDA receptor * aODN-NR1/NR2 * PPI Subject RIV: FL - Psychiatry, Sexuology

  7. Manipulation of D2 receptors with quinpirole and sulpiride affects locomotor activity before spatial behavior of rats in an active place avoidance task

    Czech Academy of Sciences Publication Activity Database

    Stuchlík, Aleš; Řeháková, Lenka; Rambousek, Lukáš; Svoboda, Jan; Valeš, Karel

    2007-01-01

    Roč. 58, č. 2 (2007), s. 133-139 ISSN 0168-0102 R&D Projects: GA ČR(CZ) GA309/07/0341; GA ČR(CZ) GA309/06/1231; GA MŠk(CZ) 1M0517; GA MŠk(CZ) LC554; GA MZd(CZ) NR9178; GA MZd(CZ) NR9180 Institutional research plan: CEZ:AV0Z50110509 Keywords : dopamine receptor * memory * cognition Subject RIV: FH - Neurology Impact factor: 2.121, year: 2007

  8. Clustering Dycom

    KAUST Repository

    Minku, Leandro L.; Hou, Siqing

    2017-01-01

    baseline WC model is also included in the analysis. Results: Clustering Dycom with K-Means can potentially help to split the CC projects, managing to achieve similar or better predictive performance than Dycom. However, K-Means still requires the number

  9. Clustering with Obstacles in Spatial Databases

    OpenAIRE

    El-Zawawy, Mohamed A.; El-Sharkawi, Mohamed E.

    2009-01-01

    Clustering large spatial databases is an important problem, which tries to find the densely populated regions in a spatial area to be used in data mining, knowledge discovery, or efficient information retrieval. However most algorithms have ignored the fact that physical obstacles such as rivers, lakes, and highways exist in the real world and could thus affect the result of the clustering. In this paper, we propose CPO, an efficient clustering technique to solve the problem of clustering in ...

  10. Transferrin-polycation-mediated introduction of DNA into human leukemic cells: Stimulation by agents that affect the survival of transfected DNA or modulate transferrin receptor levels

    International Nuclear Information System (INIS)

    Cotten, M.; Laengle-Rouault, F.; Kirlappos, H.; Wagner, E.; Mechtler, K.; Zenke, M.; Beug, H.; Birnstiel, M.L.

    1990-01-01

    The authors have subverted a receptor-mediated endocytosis event to transport genes into human leukemic cells. By coupling the natural iron-delivery protein transferrin to the DNA-binding polycations polylysine or protamine, they have created protein conjugates that bind nucleic acids and carry them into the cell during the normal transferrin cycle. They demonstrate here that this procedure is useful for a human leukemic cell line. They enhanced the rate of gene delivery by (i) increasing the transferrin receptor density through treatment of the cells with the cell permeable iron chelator desferrioxamine, (ii) interfering with the synthesis of heme with succinyl acetone treatment, or (iii) stimulating the degradation of heme with cobalt chloride treatment. Consistent with gene delivery as an endocytosis event, they show that the subsequent expression in K-562 cells of a gene included in the transported DNA depends upon the cellular presence of the lysosomotropic agent chloroquine. By contrast, monensin blocks transferrinfection, as does incubation of the cells at 18 degree C

  11. Lysophosphatidic acid receptor activation affects the C13NJ microglia cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture

    Science.gov (United States)

    Bernhart, Eva; Kollroser, Manfred; Rechberger, Gerald; Reicher, Helga; Heinemann, Akos; Schratl, Petra; Hallström, Seth; Wintersperger, Andrea; Nusshold, Christoph; DeVaney, Trevor; Zorn-Pauly, Klaus; Malli, Roland; Graier, Wolfgang; Malle, Ernst; Sattler, Wolfgang

    2014-01-01

    Microglia, the immunocompetent cells of the CNS, are rapidly activated in response to injury and microglia migration towards and homing at damaged tissue plays a key role in CNS regeneration. Lysophosphatidic acid (LPA) is involved in signaling events evoking microglia responses through cognate G protein-coupled receptors. Here we show that human immortalized C13NJ microglia express LPA receptor subtypes LPA1, LPA2, and LPA3 on mRNA and protein level. LPA activation of C13NJ cells induced Rho and extracellular signal-regulated kinase activation and enhanced cellular ATP production. In addition, LPA induced process retraction, cell spreading, led to pronounced changes of the actin cytoskeleton and reduced cell motility, which could be reversed by inhibition of Rho activity. To get an indication about LPA-induced global alterations in protein expression patterns a 2-D DIGE/LC-ESI-MS proteomic approach was applied. On the proteome level the most prominent changes in response to LPA were observed for glycolytic enzymes and proteins regulating cell motility and/or cytoskeletal dynamics. The present findings suggest that naturally occurring LPA is a potent regulator of microglia biology. This might be of particular relevance in the pathophysiological context of neurodegenerative disorders where LPA concentrations can be significantly elevated in the CNS. PMID:19899077

  12. Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, a 250-Fold Selective Melanocortin-4 Receptor (MC4R) Antagonist over the Melanocortin-3 Receptor (MC3R), Affects Energy Homeostasis in Male and Female Mice Differently.

    Science.gov (United States)

    Lensing, Cody J; Adank, Danielle N; Doering, Skye R; Wilber, Stacey L; Andreasen, Amy; Schaub, Jay W; Xiang, Zhimin; Haskell-Luevano, Carrie

    2016-09-21

    The melanocortin-4 receptor (MC4R) has been indicated as a therapeutic target for metabolic disorders such as anorexia, cachexia, and obesity. The current study investigates the in vivo effects on energy homeostasis of a 15 nM MC4R antagonist SKY2-23-7, Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, that is a 3700 nM melanocortin-3 receptor (MC3R) antagonist with minimal MC3R and MC4R agonist activity. When monitoring both male and female mice in TSE metabolic cages, sex-specific responses were observed in food intake, respiratory exchange ratio (RER), and energy expenditure. A 7.5 nmol dose of SKY2-23-7 increased food intake, increased RER, and trended toward decreasing energy expenditure in male mice. However, this compound had minimal effect on female mice's food intake and RER at the 7.5 nmol dose. A 2.5 nmol dose of SKY2-23-7 significantly increased female food intake, RER, and energy expenditure while having a minimal effect on male mice at this dose. The observed sex differences of SKY2-23-7 administration result in the discovery of a novel chemical probe for elucidating the molecular mechanisms of the sexual dimorphism present within the melanocortin pathway. To further explore the melanocortin sexual dimorphism, hypothalamic gene expression was examined. The mRNA expression of the MC3R and proopiomelanocortin (POMC) were not significantly different between sexes. However, the expression of agouti-related peptide (AGRP) was significantly higher in female mice which may be a possible mechanism for the sex-specific effects observed with SKY2-23-7.

  13. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study

    Directory of Open Access Journals (Sweden)

    Udvardi PT

    2013-12-01

    Full Text Available Patrick T Udvardi,1,2 Karl J Föhr,3 Carolin Henes,1,2 Stefan Liebau,2 Jens Dreyhaupt,4 Tobias M Boeckers,2 Andrea G Ludolph11Department of Child and Adolescent Psychiatry and Psychotherapy, 2Institute of Anatomy and Cell Biology, 3Department of Anaesthesiology, 4Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, GermanyAbstract: Attention-deficit/hyperactivity disorder (ADHD is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR antagonist. The compound's effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip] or saline (0.9%, ip for 21 consecutive days on postnatal days (PND 21–41. In humans, atomoxetine's earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR, mesencephalon (MES, and hippocampus (HC was analyzed either directly after treatment (PND 42 or 2 months after termination of treatment (PND 101 to assess the compound's long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine's effects

  14. Length and amino acid sequence of peptides substituted for the 5-HT3A receptor M3M4 loop may affect channel expression and desensitization.

    Directory of Open Access Journals (Sweden)

    Nicole K McKinnon

    Full Text Available 5-HT3A receptors are pentameric neurotransmitter-gated ion channels in the Cys-loop receptor family. Each subunit contains an extracellular domain, four transmembrane segments (M1, M2, M3, M4 and a 115 residue intracellular loop between M3 and M4. In contrast, the M3M4 loop in prokaryotic homologues is <15 residues. To investigate the limits of M3M4 loop length and composition on channel function we replaced the 5-HT3A M3M4 loop with two to seven alanine residues (5-HT3A-A(n = 2-7. Mutants were expressed in Xenopus laevis oocytes and characterized using two electrode voltage clamp recording. All mutants were functional. The 5-HT EC(50's were at most 5-fold greater than wild-type (WT. The desensitization rate differed significantly among the mutants. Desensitization rates for 5-HT3A-A(2, 5-HT3A-A(4, 5-HT3A-A(6, and 5-HT3A-A(7 were similar to WT. In contrast, 5-HT3A-A(3 and 5-HT3A-A(5 had desensitization rates at least an order of magnitude faster than WT. The one Ala loop construct, 5-HT3A-A(1, entered a non-functional state from which it did not recover after the first 5-HT application. These results suggest that the large M3M4 loop of eukaryotic Cys-loop channels is not required for receptor assembly or function. However, loop length and amino acid composition can effect channel expression and desensitization. We infer that the cytoplasmic ends of the M3 and M4 segments may undergo conformational changes during channel gating and desensitization and/or the loop may influence the position and mobility of these segments as they undergo gating-induced conformational changes. Altering structure or conformational mobility of the cytoplasmic ends of M3 and M4 may be the basis by which phosphorylation or protein binding to the cytoplasmic loop alters channel function.

  15. Functional expression of P2X family receptors in macrophages is affected by microenvironment in mouse T cell acute lymphoblastic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Shayan; Feng, Wenli; Yang, Xiao; Yang, Wanzhu; Ru, Yongxin; Liao, Jinfeng; Wang, Lina; Lin, Yongmin; Ren, Qian [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China); Zheng, Guoguang, E-mail: zhengggtjchn@aliyun.com [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China); Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing 100730 (China)

    2014-04-18

    Highlights: • We study the impact of leukemic microenvironment on P2X family receptors in Mφs. • Bone marrow and spleen Mφs are studied in Notch1-induced mouse leukemia model. • Increased expression of P2X7R is found in Mφs during the development of leukemia. • Elevated P2X7R-mediated calcium response is found in Mφs at late stage of leukemia. • More apoptotic Mφs are found in bone marrow and spleen at late stage of leukemia. - Abstract: Nucleotides are important players in intercellular signaling communication network. P2X family receptors (P2XRs) are ATP-gated plasma membrane ion channels with diverse biological functions. Macrophages are important components in the microenvironment of hematopoiesis participating in both physiological and pathological processes. However, the role of P2XRs in macrophages in leukemia has not been established. Here we investigated expression pattern and functions of P2XRs in macrophages from bone marrow (BM) and spleen of Notch1-induced T-ALL mice. Real-time PCR showed that P2XRs except P2X5R were expressed in BM and spleen macrophages. Furthermore, with the development of leukemia, the expression of P2X7R increased in both BM and spleen macrophages whereas expression of P2X1R increased in spleen macrophages. Live cell imaging recoding the Ca{sup 2+} response demonstrated that P2X7R expressed in macrophages was functional. TUNEL and electron microscopy analysis found that apoptotic macrophages were frequently observed in BM and spleen at late stage of leukemia, which was partly contributed by the activation of overexpressed P2X7R. Our results suggested that the intercellular communication mediated by nucleotides might orchestrate in the pathological process of leukemia and could be a potential target for the treatment of leukemia.

  16. Functional expression of P2X family receptors in macrophages is affected by microenvironment in mouse T cell acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Chen, Shayan; Feng, Wenli; Yang, Xiao; Yang, Wanzhu; Ru, Yongxin; Liao, Jinfeng; Wang, Lina; Lin, Yongmin; Ren, Qian; Zheng, Guoguang

    2014-01-01

    Highlights: • We study the impact of leukemic microenvironment on P2X family receptors in Mφs. • Bone marrow and spleen Mφs are studied in Notch1-induced mouse leukemia model. • Increased expression of P2X7R is found in Mφs during the development of leukemia. • Elevated P2X7R-mediated calcium response is found in Mφs at late stage of leukemia. • More apoptotic Mφs are found in bone marrow and spleen at late stage of leukemia. - Abstract: Nucleotides are important players in intercellular signaling communication network. P2X family receptors (P2XRs) are ATP-gated plasma membrane ion channels with diverse biological functions. Macrophages are important components in the microenvironment of hematopoiesis participating in both physiological and pathological processes. However, the role of P2XRs in macrophages in leukemia has not been established. Here we investigated expression pattern and functions of P2XRs in macrophages from bone marrow (BM) and spleen of Notch1-induced T-ALL mice. Real-time PCR showed that P2XRs except P2X5R were expressed in BM and spleen macrophages. Furthermore, with the development of leukemia, the expression of P2X7R increased in both BM and spleen macrophages whereas expression of P2X1R increased in spleen macrophages. Live cell imaging recoding the Ca 2+ response demonstrated that P2X7R expressed in macrophages was functional. TUNEL and electron microscopy analysis found that apoptotic macrophages were frequently observed in BM and spleen at late stage of leukemia, which was partly contributed by the activation of overexpressed P2X7R. Our results suggested that the intercellular communication mediated by nucleotides might orchestrate in the pathological process of leukemia and could be a potential target for the treatment of leukemia

  17. Cluster forcing

    DEFF Research Database (Denmark)

    Christensen, Thomas Budde

    The cluster theory attributed to Michael Porter has significantly influenced industrial policies in countries across Europe and North America since the beginning of the 1990s. Institutions such as the EU, OECD and the World Bank and governments in countries such as the UK, France, The Netherlands...... or management. Both the Accelerate Wales and the Accelerate Cluster programmes target this issue by trying to establish networks between companies that can be used to supply knowledge from research institutions to manufacturing companies. The paper concludes that public sector interventions can make...... businesses. The universities were not considered by the participating companies to be important parts of the local business environment and inputs from universities did not appear to be an important source to access knowledge about new product development or new techniques in production, distribution...

  18. Filaments and clusters of galaxies

    International Nuclear Information System (INIS)

    Soltan, A.

    1987-01-01

    A statistical test to investigate filaments of galaxies is performed. Only particular form of filaments is considered, viz. filaments connecting Abell clusters of galaxies. Relative position of triplets ''cluster - field object - cluster'' is analysed. Though neither cluster sample nor field object sample are homogeneous and complete only peculiar form of selection effects could affect the present statistics. Comparison of observational data with simulations shows that less than 15 per cent of all field galaxies is concentrated in filaments connecting rich clusters. Most of the field objects used in the analysis are not normal galaxies and it is possible that this conclusion is not in conflict with apparent filaments seen in the Lick counts and in some nearby 3D maps of the galaxy distribution. 26 refs., 2 figs. (author)

  19. Regional Innovation Clusters

    Data.gov (United States)

    Small Business Administration — The Regional Innovation Clusters serve a diverse group of sectors and geographies. Three of the initial pilot clusters, termed Advanced Defense Technology clusters,...

  20. Cluster analysis

    OpenAIRE

    Mucha, Hans-Joachim; Sofyan, Hizir

    2000-01-01

    As an explorative technique, duster analysis provides a description or a reduction in the dimension of the data. It classifies a set of observations into two or more mutually exclusive unknown groups based on combinations of many variables. Its aim is to construct groups in such a way that the profiles of objects in the same groups are relatively homogenous whereas the profiles of objects in different groups are relatively heterogeneous. Clustering is distinct from classification techniques, ...

  1. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study

    Science.gov (United States)

    Udvardi, Patrick T; Föhr, Karl J; Henes, Carolin; Liebau, Stefan; Dreyhaupt, Jens; Boeckers, Tobias M; Ludolph, Andrea G

    2013-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound’s effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B) are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip]) or saline (0.9%, ip) for 21 consecutive days on postnatal days (PND) 21–41. In humans, atomoxetine’s earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR), mesencephalon (MES), and hippocampus (HC) was analyzed either directly after treatment (PND 42) or 2 months after termination of treatment (PND 101) to assess the compound’s long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine’s effects beyond NET inhibition. Taken together, these data reveal that atomoxetine seems to decrease glutamatergic transmission in a brain region-specific manner. Long-term data show that the compound’s impact is not due to an acute pharmacological effect but lasts or even amplifies after a drug-free period of 2 months, leading to altered development of

  2. Androgen Signaling Disruption during Fetal and Postnatal Development Affects Androgen Receptor and Connexin 43 Expression and Distribution in Adult Boar Prostate

    Directory of Open Access Journals (Sweden)

    Anna Hejmej

    2013-01-01

    Full Text Available To date, limited knowledge exists regarding the role of the androgen signaling during specific periods of development in the regulation of androgen receptor (AR and connexin 43 (Cx43 in adult prostate. Therefore, in this study we examined mRNA and protein expression, and tissue distribution of AR and Cx43 in adult boar prostates following fetal (GD20, neonatal (PD2, and prepubertal (PD90 exposure to an antiandrogen flutamide (50 mg/kg bw. In GD20 and PD2 males we found the reduction of the luminal compartment, inflammatory changes, decreased AR and increased Cx43 expression, and altered localization of both proteins. Moreover, enhanced apoptosis and reduced proliferation were detected in the prostates of these animals. In PD90 males the alterations were less evident, except that Cx43 expression was markedly upregulated. The results presented herein indicate that in boar androgen action during early fetal and neonatal periods plays a key role in the maintenance of normal phenotype and functions of prostatic cells at adulthood. Furthermore, we demonstrated that modulation of Cx43 expression in the prostate could serve as a sensitive marker of hormonal disruption during different developmental stages.

  3. Coxsackie- and adenovirus receptor (CAR) is expressed in lymphatic vessels in human skin and affects lymphatic endothelial cell function in vitro

    International Nuclear Information System (INIS)

    Vigl, Benjamin; Zgraggen, Claudia; Rehman, Nadia; Banziger-Tobler, Nadia E.; Detmar, Michael; Halin, Cornelia

    2009-01-01

    Lymphatic vessels play an important role in tissue fluid homeostasis, intestinal fat absorption and immunosurveillance. Furthermore, they are involved in pathologic conditions, such as tumor cell metastasis and chronic inflammation. In comparison to blood vessels, the molecular phenotype of lymphatic vessels is less well characterized. Performing comparative gene expression analysis we have recently found that coxsackie- and adenovirus receptor (CAR) is significantly more highly expressed in cultured human, skin-derived lymphatic endothelial cells (LECs), as compared to blood vascular endothelial cells. Here, we have confirmed these results at the protein level, using Western blot and FACS analysis. Immunofluorescence performed on human skin confirmed that CAR is expressed at detectable levels in lymphatic vessels, but not in blood vessels. To address the functional significance of CAR expression, we modulated CAR expression levels in cultured LECs in vitro by siRNA- and vector-based transfection approaches. Functional assays performed with the transfected cells revealed that CAR is involved in distinct cellular processes in LECs, such as cell adhesion, migration, tube formation and the control of vascular permeability. In contrast, no effect of CAR on LEC proliferation was observed. Overall, our data suggest that CAR stabilizes LEC-LEC interactions in the skin and may contribute to lymphatic vessel integrity

  4. Gene variation in IL-7 receptor (IL-7R)α affects IL-7R response in CD4+ T cells in HIV-infected individuals

    DEFF Research Database (Denmark)

    Hartling, Hans Jakob; Ryder, Lars P.; Ullum, Henrik

    2017-01-01

    Optimal CD4+ T cell recovery after initiating combination antiretroviral treatment (cART) in HIV infection reduces risk of morbidity and mortality. T-allele homozygosity (‘TT’) in the single nucleotide polymorphism, rs6897932(C/T), in the IL-7 receptor α (IL-7RA) is associated with faster CD4+ T...... cell recovery after cART initiation compared to C-allele homozygosity in rs6897932 (‘CC’). However, underlying mechanisms are unknown. We aimed to examine potential mechanisms explaining the association between rs6897932 and CD4+ T cell recovery. Ten ‘TT’ and 10 ‘CC’ HIV-infected individuals matched...... on gender, age, and nadir and current CD4+ T cell counts were included in a cross-sectional study. ‘TT’ individuals had higher proportion of CD4+ T cells expressing pSTAT5 compared to ‘CC’ individuals after stimulating with IL-7, especially when co-stimulated with soluble IL7-RA (sIL-7RA). Furthermore, ‘TT...

  5. Localization and orientation of heavy-atom cluster compounds in protein crystals using molecular replacement

    International Nuclear Information System (INIS)

    Dahms, Sven O.; Kuester, Miriam; Streb, Carsten; Roth, Christian; Sträter, Norbert; Than, Manuel E.

    2013-01-01

    A new approach is presented that allows the efficient localization and orientation of heavy-atom cluster compounds used in experimental phasing by a molecular replacement procedure. This permits the calculation of meaningful phases up to the highest resolution of the diffraction data. Heavy-atom clusters (HA clusters) containing a large number of specifically arranged electron-dense scatterers are especially useful for experimental phase determination of large complex structures, weakly diffracting crystals or structures with large unit cells. Often, the determination of the exact orientation of the HA cluster and hence of the individual heavy-atom positions proves to be the critical step in successful phasing and subsequent structure solution. Here, it is demonstrated that molecular replacement (MR) with either anomalous or isomorphous differences is a useful strategy for the correct placement of HA cluster compounds. The polyoxometallate cluster hexasodium α-metatungstate (HMT) was applied in phasing the structure of death receptor 6. Even though the HA cluster is bound in alternate partially occupied orientations and is located at a special position, its correct localization and orientation could be determined at resolutions as low as 4.9 Å. The broad applicability of this approach was demonstrated for five different derivative crystals that included the compounds tantalum tetradecabromide and trisodium phosphotungstate in addition to HMT. The correct placement of the HA cluster depends on the length of the intramolecular vectors chosen for MR, such that both a larger cluster size and the optimal choice of the wavelength used for anomalous data collection strongly affect the outcome

  6. Down, But Not Out: Partial Elimination of Androgen Receptors in the Male Mouse Brain Does Not Affect Androgenic Regulation of Anxiety or HPA Activity.

    Science.gov (United States)

    Chen, Chieh V; Brummet, Jennifer L; Jordan, Cynthia L; Breedlove, S Marc

    2016-02-01

    We previously found that androgen receptor (AR) activity mediates two effects of T in adult male mice: reduction of anxiety-like behaviors and dampening of the hypothalamic-pituitary-adrenal response to stress. To determine whether brain ARs mediate these effects, we used the Cre/loxP technology seeking to disable AR throughout the central nervous system (CNS). Female mice carrying the floxed AR allele (ARlox) were crossed with males carrying cre recombinase transgene controlled by the nestin promoter (NesCre), producing cre in developing neurons and glia. Among male offspring, four genotypes resulted: males carrying ARlox and NesCre (NesARko), and three control groups (wild types, NesCre, and ARlox). Reporter mice indicated ubiquitous Cre expression throughout the CNS. Nevertheless, AR immunocytochemistry in NesARko mice revealed efficient knockout (KO) of AR in some brain regions (hippocampus and medial prefrontal cortex [mPFC]), but not others. Substantial AR protein was seen in the amygdala and hypothalamus among other regions, whereas negligible AR remained in others like the bed nucleus of the stria terminalis and dorsal periaqueductal gray. This selective KO allowed for testing the role of AR in hippocampus and mPFC. Males were castrated and implanted with T at postnatal day 60 before testing on postnatal day 90-100. In contrast with males with global KO of AR, T still modulated anxiety-related behavior and hypothalamic-pituitary-adrenal activity in NesARko males. These results leave open the possibility that AR acting in the CNS mediates these effects of T, but demonstrate that AR is not required in the hippocampus or mPFC for T's anxiolytic effects.

  7. Prenatal stress affects insulin-like growth factor-1 (IGF-1) level and IGF-1 receptor phosphorylation in the brain of adult rats.

    Science.gov (United States)

    Basta-Kaim, Agnieszka; Szczesny, Ewa; Glombik, Katarzyna; Stachowicz, Katarzyna; Slusarczyk, Joanna; Nalepa, Irena; Zelek-Molik, Agnieszka; Rafa-Zablocka, Katarzyna; Budziszewska, Boguslawa; Kubera, Marta; Leskiewicz, Monika; Lason, Wladyslaw

    2014-09-01

    It has been shown that stressful events occurring in early life have a powerful influence on the development of the central nervous system. Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation and survival of both neurons and glial cells and is thought to exert antidepressant-like activity. Thus, it is possible that disturbances in the function of the IGF-1 system may be responsible for disturbances observed over the course of depression. Prenatal stress was used as a valid model of depression. Adult male offspring of control and stressed rat dams were subjected to behavioural testing (forced swim test). The level of IGF-1 in the blood and the expression of IGF-1, IGF-1R, and IRS-1/2 in the hippocampus and frontal cortex using RT-PCR, ELISA and western blotting were measured. In addition the effect of intracerebroventricularly administered IGF-1 and/or the IGF-1R receptor antagonist JB1 in the forced swim test was studied. Prenatally stressed rats showed depressive like behaviour, including increased immobility time as well as decreased mobility and climbing. Intracerebroventricular administration of IGF-1 reversed these effects in stressed animals, whereas concomitant administration of the IGF-1R antagonist JB1 completely blocked the effects. Biochemical analysis of homogenates from the hippocampus and frontal cortex revealed decreases in IGF-1 level and IGF-1R phosphorylation along with disturbances in IRS-1 phosphorylation. These findings reveal that prenatal stress alters IGF-1 signalling, which may contribute to the behavioural changes observed in depression. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  8. Somatostatin receptors

    DEFF Research Database (Denmark)

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

    2003-01-01

    functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual......-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...

  9. 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...

  10. 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 in the f......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...... in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular...

  11. β-Arrestin-2 knockout prevents development of cellular μ-opioid receptor tolerance but does not affect opioid-withdrawal-related adaptations in single PAG neurons.

    Science.gov (United States)

    Connor, M; Bagley, E E; Chieng, B C; Christie, M J

    2015-01-01

    Tolerance to the behavioural effects of morphine is blunted in β-arrestin-2 knockout mice, but opioid withdrawal is largely unaffected. The cellular mechanisms of tolerance have been studied in some neurons from β-arrestin-2 knockouts, but tolerance and withdrawal mechanisms have not been examined at the cellular level in periaqueductal grey (PAG) neurons, which are crucial for central tolerance and withdrawal phenomena. μ-Opioid receptor (MOPr) inhibition of voltage-gated calcium channel currents (ICa ) was examined by patch-clamp recordings from acutely dissociated PAG neurons from wild-type and β-arrestin-2 knockout mice treated chronically with morphine (CMT) or vehicle. Opioid withdrawal-induced activation of GABA transporter type 1 (GAT-1) currents was determined using perforated patch recordings from PAG neurons in brain slices. MOPr inhibition of ICa in PAG neurons was unaffected by β-arrestin-2 deletion. CMT impaired coupling of MOPrs to ICa in PAG neurons from wild-type mice, but this cellular tolerance was not observed in neurons from CMT β-arrestin-2 knockouts. However, β-arrestin-2 knockouts displayed similar opioid-withdrawal-induced activation of GAT-1 currents as wild-type PAG neurons. In β-arrestin-2 knockout mice, the central neurons involved in the anti-nociceptive actions of opioids also fail to develop cellular tolerance to opioids following chronic morphine. The results also provide the first cellular physiological evidence that opioid withdrawal is not disrupted by β-arrestin-2 deletion. However, the unaffected basal sensitivity to opioids in PAG neurons provides further evidence that changes in basal MOPr sensitivity cannot account for the enhanced acute nociceptive response to morphine reported in β-arrestin-2 knockouts. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British

  12. Nuclear clustering - a cluster core model study

    International Nuclear Information System (INIS)

    Paul Selvi, G.; Nandhini, N.; Balasubramaniam, M.

    2015-01-01

    Nuclear clustering, similar to other clustering phenomenon in nature is a much warranted study, since it would help us in understanding the nature of binding of the nucleons inside the nucleus, closed shell behaviour when the system is highly deformed, dynamics and structure at extremes. Several models account for the clustering phenomenon of nuclei. We present in this work, a cluster core model study of nuclear clustering in light mass nuclei

  13. Systematic screening for mutations in the 5{prime}-regulatory region of the human dopamine D{sub 1} receptor (DRD1) gene in patients with schizophrenia and bipolar affective disorder

    Energy Technology Data Exchange (ETDEWEB)

    Cichon, S.; Noethen, M.M.; Stoeber, G. [Univ. of Bonn (Germany)] [and others

    1996-07-26

    A possible dysregulation of dopaminergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study we systematically searched for the presence of mutations in the 5{prime}-flanking region of the dopamine D{sub 1} receptor (DRD1) gene. This region has previously been shown to contain a functional promoter. We investigated 119 unrelated individuals (including 36 schizophrenic patients, 38 bipolar affective patients, and 45 healthy controls) using single-strand conformation analysis (SSCA). Eleven overlapping PCR fragments covered 2,189 bp of DNA sequence. We identified six single base substitutions: -2218T/C, -2102C/A, -2030T/C, -1992G/A, -1251G/C, and -800T/C. None of the mutations was found to be located in regions which have important influence on the level of transcriptional activity. Allele frequencies were similar in patients and controls, indicating that genetic variation in the 5{prime}-regulatory region of the DRD1 gene is unlikely to play a frequent, major role in the genetic predisposition to either schizophrenia or bipolar affective disorder. 31 refs., 3 tabs.

  14. Cancer Clusters

    Science.gov (United States)

    ... and number of cases of each type, the age of the people with cancer, and the area and time period over which the cancers were diagnosed. They also ask about specific environmental hazards or concerns in the affected area. If the review of ...

  15. Expression of angiopoietin-2 and vascular endothelial growth factor receptor-3 correlates with lymphangiogenesis and angiogenesis and affects survival of oral squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Chao Li

    Full Text Available BACKGROUND: Both Ang-2 and VEGFR-3 are major regulators of angiogenesis and lymphangiogenesis, respectively, and thus may affect prognosis of OSCC. We sought to determine the associations between Ang-2 and VEGFR-3 expression and survival of OSCC. METHODS: Ang-2 and VEGFR-3 expression was determined immunohistochemically in tumor tissues from 112 patients with OSCC; OSCC-adjacent noncancerous oral tissue from 85 OSCC patients; and normal oral mucosa from 37 cancer-free individuals. A log-rank test and Cox proportional hazard models were used to compare survival among different groups with expression of Ang-2 and VEGFR-3. RESULTS: Ang-2 and VEGFR-3 expression was upregulated in OSCC compared to nontumor tissue (all P<0.05. High Ang-2 expression positively correlated with microvessel density (MVD (P<0.01, and high VEGFR-3 expression positively correlated with lymph node metastasis (P<0.01 and lymphatic vessel density (LVD (P<0.01. The patients with high expression of Ang-2 alone or in combination with VEGFR-3 had a significantly worse survival than in patients with low expression of Ang-2 or any other co-expression status (all P<0.05, respectively. Furthermore, multivariable analysis showed that patients with high expression of Ang-2 alone or in combination with VEGFR-3 had a significantly increased risk of death compared with those with low expression of Ang-2 or any other co-expression status (HR, 2.7, 95% CI, 1.1-6.2 and 5.0, 1.3-15.4, respectively. CONCLUSIONS: These results suggest that increased expression in tumors of Ang-2 may individually, or in combination with VEGFR-3, predict poor prognosis of OSCC.

  16. Affects and Affect Consciousness

    Science.gov (United States)

    MONSEN, JON T.; EILERTSEN, DAG ERIK; MELGÅRD, TROND; ØDEGÅRD, PÅL

    1996-01-01

    Affect consciousness (AC) was operationalized as degrees of awareness, tolerance, nonverbal expression, and conceptual expression of nine specific affects. A semistructured interview (ACI) and separate scales were developed to assess these aspects of affect integration. Their psychometric properties were preliminarily explored by having 20 former psychiatric outpatients complete the interview. Concurrent validity was assessed by using DSM-III-R Axis I and II diagnoses, the Health-Sickness Rating Scale, SCL-90-R, and several indexes from the Minnesota Multiphasic Personality Inventory. Satisfactory interrater reliability and high levels of internal consistency supported the construct validity of the measure. Results suggest the most meaningful use of this instrument is in measuring specific affect and overall AC. Clinically, the ACI has provided highly specific and relevant qualitative data for use in planning psychotherapeutic interventions. PMID:22700292

  17. Brightest Cluster Galaxies in REXCESS Clusters

    Science.gov (United States)

    Haarsma, Deborah B.; Leisman, L.; Bruch, S.; Donahue, M.

    2009-01-01

    Most galaxy clusters contain a Brightest Cluster Galaxy (BCG) which is larger than the other cluster ellipticals and has a more extended profile. In the hierarchical model, the BCG forms through many galaxy mergers in the crowded center of the cluster, and thus its properties give insight into the assembly of the cluster as a whole. In this project, we are working with the Representative XMM-Newton Cluster Structure Survey (REXCESS) team (Boehringer et al 2007) to study BCGs in 33 X-ray luminous galaxy clusters, 0.055 < z < 0.183. We are imaging the BCGs in R band at the Southern Observatory for Astrophysical Research (SOAR) in Chile. In this poster, we discuss our methods and give preliminary measurements of the BCG magnitudes, morphology, and stellar mass. We compare these BCG properties with the properties of their host clusters, particularly of the X-ray emitting gas.

  18. Lexical preferences in Dutch verbal cluster ordering

    NARCIS (Netherlands)

    Bloem, J.; Bellamy, K.; Karvovskaya, E.; Kohlberger, M.; Saad, G.

    2016-01-01

    This study discusses lexical preferences as a factor affecting the word order variation in Dutch verbal clusters. There are two grammatical word orders for Dutch two-verb clusters, with no clear meaning difference. Using the method of collostructional analysis, I find significant associations

  19. Partitional clustering algorithms

    CERN Document Server

    2015-01-01

    This book summarizes the state-of-the-art in partitional clustering. Clustering, the unsupervised classification of patterns into groups, is one of the most important tasks in exploratory data analysis. Primary goals of clustering include gaining insight into, classifying, and compressing data. Clustering has a long and rich history that spans a variety of scientific disciplines including anthropology, biology, medicine, psychology, statistics, mathematics, engineering, and computer science. As a result, numerous clustering algorithms have been proposed since the early 1950s. Among these algorithms, partitional (nonhierarchical) ones have found many applications, especially in engineering and computer science. This book provides coverage of consensus clustering, constrained clustering, large scale and/or high dimensional clustering, cluster validity, cluster visualization, and applications of clustering. Examines clustering as it applies to large and/or high-dimensional data sets commonly encountered in reali...

  20. An analysis of hospital brand mark clusters.

    Science.gov (United States)

    Vollmers, Stacy M; Miller, Darryl W; Kilic, Ozcan

    2010-07-01

    This study analyzed brand mark clusters (i.e., various types of brand marks displayed in combination) used by hospitals in the United States. The brand marks were assessed against several normative criteria for creating brand marks that are memorable and that elicit positive affect. Overall, results show a reasonably high level of adherence to many of these normative criteria. Many of the clusters exhibited pictorial elements that reflected benefits and that were conceptually consistent with the verbal content of the cluster. Also, many clusters featured icons that were balanced and moderately complex. However, only a few contained interactive imagery or taglines communicating benefits.

  1. Diversity among galaxy clusters

    International Nuclear Information System (INIS)

    Struble, M.F.; Rood, H.J.

    1988-01-01

    The classification of galaxy clusters is discussed. Consideration is given to the classification scheme of Abell (1950's), Zwicky (1950's), Morgan, Matthews, and Schmidt (1964), and Morgan-Bautz (1970). Galaxies can be classified based on morphology, chemical composition, spatial distribution, and motion. The correlation between a galaxy's environment and morphology is examined. The classification scheme of Rood-Sastry (1971), which is based on clusters's morphology and galaxy population, is described. The six types of clusters they define include: (1) a cD-cluster dominated by a single large galaxy, (2) a cluster dominated by a binary, (3) a core-halo cluster, (4) a cluster dominated by several bright galaxies, (5) a cluster appearing flattened, and (6) an irregularly shaped cluster. Attention is also given to the evolution of cluster structures, which is related to initial density and cluster motion

  2. Fibroblast growth factor receptors in breast cancer.

    Science.gov (United States)

    Wang, Shuwei; Ding, Zhongyang

    2017-05-01

    Fibroblast growth factor receptors are growth factor receptor tyrosine kinases, exerting their roles in embryogenesis, tissue homeostasis, and development of breast cancer. Recent genetic studies have identified some subtypes of fibroblast growth factor receptors as strong genetic loci associated with breast cancer. In this article, we review the recent epidemiological findings and experiment results of fibroblast growth factor receptors in breast cancer. First, we summarized the structure and physiological function of fibroblast growth factor receptors in humans. Then, we discussed the common genetic variations in fibroblast growth factor receptors that affect breast cancer risk. In addition, we also introduced the potential roles of each fibroblast growth factor receptors isoform in breast cancer. Finally, we explored the potential therapeutics targeting fibroblast growth factor receptors for breast cancer. Based on the biological mechanisms of fibroblast growth factor receptors leading to the pathogenesis in breast cancer, targeting fibroblast growth factor receptors may provide new opportunities for breast cancer therapeutic strategies.

  3. 2,3,7,8-Tetrachlorodibenzo-p-dioxin activates the aryl hydrocarbon receptor and alters sex steroid hormone secretion without affecting growth of mouse antral follicles in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Karman, Bethany N., E-mail: bklement@illinois.edu; Basavarajappa, Mallikarjuna S., E-mail: mbshivapur@gmail.com; Craig, Zelieann R., E-mail: zelieann@illinois.edu; Flaws, Jodi A., E-mail: jflaws@illinois.edu

    2012-05-15

    The persistent environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an ovarian toxicant. These studies were designed to characterize the actions of TCDD on steroidogenesis and growth of intact mouse antral follicles in vitro. Specifically, these studies tested the hypothesis that TCDD exposure leads to decreased sex hormone production/secretion by antral follicles as well as decreased growth of antral follicles in vitro. Since TCDD acts through binding to the aryl hydrocarbon receptor (AHR), and the AHR has been identified as an important factor in ovarian function, we also conducted experiments to confirm the presence and activation of the AHR in our tissue culture system. To do so, we exposed mouse antral follicles for 96 h to a series of TCDD doses previously shown to have effects on ovarian tissues and cells in culture, which also encompass environmentally relevant and pharmacological exposures (0.1–100 nM), to determine a dose response for TCDD in our culture system for growth, hormone production, and expression of the Ahr and Cyp1b1. The results indicate that TCDD decreases progesterone, androstenedione, testosterone, and estradiol levels in a non-monotonic dose response manner without altering growth of antral follicles. The addition of pregnenolone substrate (10 μM) restores hormone levels to control levels. Additionally, Cyp1b1 levels were increased by 3–4 fold regardless of the dose of TCDD exposure, evidence of AHR activation. Overall, these data indicate that TCDD may act prior to pregnenolone formation and through AHR transcriptional control of Cyp1b1, leading to decreased hormone levels without affecting growth of antral follicles. -- Highlights: ►TCDD disrupts sex steroid hormone levels, but not growth of antral follicles. ►Pregnenolone co-treatment by-passes TCDD-induced steroid hormone disruption. ►TCDD affects steroid hormone levels through an AHR pathway in antral follicles.

  4. Dynamics of the actin cytoskeleton mediates receptor cross talk: An emerging concept in tuning receptor signaling

    Science.gov (United States)

    Mattila, Pieta K.; Batista, Facundo D.

    2016-01-01

    Recent evidence implicates the actin cytoskeleton in the control of receptor signaling. This may be of particular importance in the context of immune receptors, such as the B cell receptor, where dysregulated signaling can result in autoimmunity and malignancy. Here, we discuss the role of the actin cytoskeleton in controlling receptor compartmentalization, dynamics, and clustering as a means to regulate receptor signaling through controlling the interactions with protein partners. We propose that the actin cytoskeleton is a point of integration for receptor cross talk through modulation of protein dynamics and clustering. We discuss the implication of this cross talk via the cytoskeleton for both ligand-induced and low-level constitutive (tonic) signaling necessary for immune cell survival. PMID:26833785

  5. Exposure to 3,3',5-triiodothyronine affects histone and RNA polymerase II modifications, but not DNA methylation status, in the regulatory region of the Xenopus laevis thyroid hormone receptor βΑ gene.

    Science.gov (United States)

    Kasai, Kentaro; Nishiyama, Norihito; Izumi, Yushi; Otsuka, Shunsuke; Ishihara, Akinori; Yamauchi, Kiyoshi

    2015-11-06

    Thyroid hormones (THs) play a critical role in amphibian metamorphosis, during which the TH receptor (TR) gene, thrb, is upregulated in a tissue-specific manner. The Xenopus laevis thrb gene has 3 TH response elements (TREs) in the 5' flanking regulatory region and 1 TRE in the exon b region, around which CpG sites are highly distributed. To clarify whether exposure to 3,3',5-triiodothyronine (T3) affects histone and RNA polymerase II (RNAPII) modifications and the level of DNA methylation in the 5' regulatory region, we conducted reverse transcription-quantitative polymerase chain reaction, bisulfite sequencing and chromatin immunoprecipitation assay using X. laevis cultured cells and premetamorphic tadpoles treated with or without 2 nM T3. Exposure to T3 increased the amount of the thrb transcript, in parallel with enhanced histone H4 acetylation and RNAPII recruitment, and probably phosphorylation of RNAPII at serine 5, in the 5' regulatory and exon b regions. However, the 5' regulatory region remained hypermethylated even with exposure to T3, and there was no significant difference in the methylation status between DNAs from T3-untreated and -treated cultured cells or tadpole tissues. Our results demonstrate that exposure to T3 induced euchromatin-associated epigenetic marks by enhancing histone acetylation and RNAPII recruitment, but not by decreasing the level of DNA methylation, in the 5' regulatory region of the X. laevis thrb gene. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Functional inactivation of hypocretin 1 receptors in the medial prefrontal cortex affects the pyramidal neuron activity and gamma oscillations: An in vivo multiple-channel single-unit recording study.

    Science.gov (United States)

    He, C; Chen, Q-H; Ye, J-N; Li, C; Yang, L; Zhang, J; Xia, J-X; Hu, Z-A

    2015-06-25

    The hypocretin signaling is thought to play a critical role in maintaining wakefulness via stimulating the subcortical arousal pathways. Although the cortical areas, including the medial prefrontal cortex (mPFC), receive dense hypocretinergic fibers and express its receptors, it remains unclear whether the hypocretins can directly regulate the neural activity of the mPFC in vivo. In the present study, using multiple-channel single-unit recording study, we found that infusion of the SB-334867, a blocker for the Hcrtr1, beside the recording sites within the mPFC substantially exerted an inhibitory effect on the putative pyramidal neuron (PPN) activity in naturally behaving rats. In addition, functional blockade of the Hcrtr1 also selectively reduced the power of the gamma oscillations. The PPN activity and the power of the neural oscillations were not affected after microinjection of the TCS-OX2-29, a blocker for the Hcrtr2, within the mPFC. Together, these data indicate that endogenous hypocretins acting on the Hcrtr1 are required for the normal neural activity in the mPFC in vivo, and thus might directly contribute cortical arousal and mPFC-dependent cognitive processes. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. Clustering Coefficients for Correlation Networks.

    Science.gov (United States)

    Masuda, Naoki; Sakaki, Michiko; Ezaki, Takahiro; Watanabe, Takamitsu

    2018-01-01

    Graph theory is a useful tool for deciphering structural and functional networks of the brain on various spatial and temporal scales. The clustering coefficient quantifies the abundance of connected triangles in a network and is a major descriptive statistics of networks. For example, it finds an application in the assessment of small-worldness of brain networks, which is affected by attentional and cognitive conditions, age, psychiatric disorders and so forth. However, it remains unclear how the clustering coefficient should be measured in a correlation-based network, which is among major representations of brain networks. In the present article, we propose clustering coefficients tailored to correlation matrices. The key idea is to use three-way partial correlation or partial mutual information to measure the strength of the association between the two neighboring nodes of a focal node relative to the amount of pseudo-correlation expected from indirect paths between the nodes. Our method avoids the difficulties of previous applications of clustering coefficient (and other) measures in defining correlational networks, i.e., thresholding on the correlation value, discarding of negative correlation values, the pseudo-correlation problem and full partial correlation matrices whose estimation is computationally difficult. For proof of concept, we apply the proposed clustering coefficient measures to functional magnetic resonance imaging data obtained from healthy participants of various ages and compare them with conventional clustering coefficients. We show that the clustering coefficients decline with the age. The proposed clustering coefficients are more strongly correlated with age than the conventional ones are. We also show that the local variants of the proposed clustering coefficients (i.e., abundance of triangles around a focal node) are useful in characterizing individual nodes. In contrast, the conventional local clustering coefficients were strongly

  8. Clustering Coefficients for Correlation Networks

    Directory of Open Access Journals (Sweden)

    Naoki Masuda

    2018-03-01

    Full Text Available Graph theory is a useful tool for deciphering structural and functional networks of the brain on various spatial and temporal scales. The clustering coefficient quantifies the abundance of connected triangles in a network and is a major descriptive statistics of networks. For example, it finds an application in the assessment of small-worldness of brain networks, which is affected by attentional and cognitive conditions, age, psychiatric disorders and so forth. However, it remains unclear how the clustering coefficient should be measured in a correlation-based network, which is among major representations of brain networks. In the present article, we propose clustering coefficients tailored to correlation matrices. The key idea is to use three-way partial correlation or partial mutual information to measure the strength of the association between the two neighboring nodes of a focal node relative to the amount of pseudo-correlation expected from indirect paths between the nodes. Our method avoids the difficulties of previous applications of clustering coefficient (and other measures in defining correlational networks, i.e., thresholding on the correlation value, discarding of negative correlation values, the pseudo-correlation problem and full partial correlation matrices whose estimation is computationally difficult. For proof of concept, we apply the proposed clustering coefficient measures to functional magnetic resonance imaging data obtained from healthy participants of various ages and compare them with conventional clustering coefficients. We show that the clustering coefficients decline with the age. The proposed clustering coefficients are more strongly correlated with age than the conventional ones are. We also show that the local variants of the proposed clustering coefficients (i.e., abundance of triangles around a focal node are useful in characterizing individual nodes. In contrast, the conventional local clustering coefficients

  9. Clustering Coefficients for Correlation Networks

    Science.gov (United States)

    Masuda, Naoki; Sakaki, Michiko; Ezaki, Takahiro; Watanabe, Takamitsu

    2018-01-01

    Graph theory is a useful tool for deciphering structural and functional networks of the brain on various spatial and temporal scales. The clustering coefficient quantifies the abundance of connected triangles in a network and is a major descriptive statistics of networks. For example, it finds an application in the assessment of small-worldness of brain networks, which is affected by attentional and cognitive conditions, age, psychiatric disorders and so forth. However, it remains unclear how the clustering coefficient should be measured in a correlation-based network, which is among major representations of brain networks. In the present article, we propose clustering coefficients tailored to correlation matrices. The key idea is to use three-way partial correlation or partial mutual information to measure the strength of the association between the two neighboring nodes of a focal node relative to the amount of pseudo-correlation expected from indirect paths between the nodes. Our method avoids the difficulties of previous applications of clustering coefficient (and other) measures in defining correlational networks, i.e., thresholding on the correlation value, discarding of negative correlation values, the pseudo-correlation problem and full partial correlation matrices whose estimation is computationally difficult. For proof of concept, we apply the proposed clustering coefficient measures to functional magnetic resonance imaging data obtained from healthy participants of various ages and compare them with conventional clustering coefficients. We show that the clustering coefficients decline with the age. The proposed clustering coefficients are more strongly correlated with age than the conventional ones are. We also show that the local variants of the proposed clustering coefficients (i.e., abundance of triangles around a focal node) are useful in characterizing individual nodes. In contrast, the conventional local clustering coefficients were strongly

  10. Theory and simulations of adhesion receptor dimerization on membrane surfaces.

    Science.gov (United States)

    Wu, Yinghao; Honig, Barry; Ben-Shaul, Avinoam

    2013-03-19

    The equilibrium constants of trans and cis dimerization of membrane bound (2D) and freely moving (3D) adhesion receptors are expressed and compared using elementary statistical-thermodynamics. Both processes are mediated by the binding of extracellular subdomains whose range of motion in the 2D environment is reduced upon dimerization, defining a thin reaction shell where dimer formation and dissociation take place. We show that the ratio between the 2D and 3D equilibrium constants can be expressed as a product of individual factors describing, respectively, the spatial ranges of motions of the adhesive domains, and their rotational freedom within the reaction shell. The results predicted by the theory are compared to those obtained from a novel, to our knowledge, dynamical simulations methodology, whereby pairs of receptors perform realistic translational, internal, and rotational motions in 2D and 3D. We use cadherins as our model system. The theory and simulations explain how the strength of cis and trans interactions of adhesive receptors are affected both by their presence in the constrained intermembrane space and by the 2D environment of membrane surfaces. Our work provides fundamental insights as to the mechanism of lateral clustering of adhesion receptors after cell-cell contact and, more generally, to the formation of lateral microclusters of proteins on cell surfaces. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  11. What Makes Clusters Decline?

    DEFF Research Database (Denmark)

    Østergaard, Christian Richter; Park, Eun Kyung

    2015-01-01

    Most studies on regional clusters focus on identifying factors and processes that make clusters grow. However, sometimes technologies and market conditions suddenly shift, and clusters decline. This paper analyses the process of decline of the wireless communication cluster in Denmark. The longit...... but being quick to withdraw in times of crisis....

  12. Clustering of correlated networks

    OpenAIRE

    Dorogovtsev, S. N.

    2003-01-01

    We obtain the clustering coefficient, the degree-dependent local clustering, and the mean clustering of networks with arbitrary correlations between the degrees of the nearest-neighbor vertices. The resulting formulas allow one to determine the nature of the clustering of a network.

  13. Relevant Subspace Clustering

    DEFF Research Database (Denmark)

    Müller, Emmanuel; Assent, Ira; Günnemann, Stephan

    2009-01-01

    Subspace clustering aims at detecting clusters in any subspace projection of a high dimensional space. As the number of possible subspace projections is exponential in the number of dimensions, the result is often tremendously large. Recent approaches fail to reduce results to relevant subspace...... clusters. Their results are typically highly redundant, i.e. many clusters are detected multiple times in several projections. In this work, we propose a novel model for relevant subspace clustering (RESCU). We present a global optimization which detects the most interesting non-redundant subspace clusters...... achieves top clustering quality while competing approaches show greatly varying performance....

  14. CLUSTER DYNAMICS LARGELY SHAPES PROTOPLANETARY DISK SIZES

    Energy Technology Data Exchange (ETDEWEB)

    Vincke, Kirsten; Pfalzner, Susanne, E-mail: kvincke@mpifr-bonn.mpg.de [Max Planck Institute for Radio Astronomy, Auf dem Hügel 69, D-53121 Bonn (Germany)

    2016-09-01

    To what degree the cluster environment influences the sizes of protoplanetary disks surrounding young stars is still an open question. This is particularly true for the short-lived clusters typical for the solar neighborhood, in which the stellar density and therefore the influence of the cluster environment change considerably over the first 10 Myr. In previous studies, the effect of the gas on the cluster dynamics has often been neglected; this is remedied here. Using the code NBody6++, we study the stellar dynamics in different developmental phases—embedded, expulsion, and expansion—including the gas, and quantify the effect of fly-bys on the disk size. We concentrate on massive clusters (M {sub cl} ≥ 10{sup 3}–6 ∗ 10{sup 4} M {sub Sun}), which are representative for clusters like the Orion Nebula Cluster (ONC) or NGC 6611. We find that not only the stellar density but also the duration of the embedded phase matters. The densest clusters react fastest to the gas expulsion and drop quickly in density, here 98% of relevant encounters happen before gas expulsion. By contrast, disks in sparser clusters are initially less affected, but because these clusters expand more slowly, 13% of disks are truncated after gas expulsion. For ONC-like clusters, we find that disks larger than 500 au are usually affected by the environment, which corresponds to the observation that 200 au-sized disks are common. For NGC 6611-like clusters, disk sizes are cut-down on average to roughly 100 au. A testable hypothesis would be that the disks in the center of NGC 6611 should be on average ≈20 au and therefore considerably smaller than those in the ONC.

  15. Receptor assay

    Energy Technology Data Exchange (ETDEWEB)

    Kato, K; Ibayashi, H [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

    1975-05-01

    This paper summarized present status and problems of analysis of hormone receptor and a few considerations on clinical significance of receptor abnormalities. It was pointed that in future clinical field quantitative and qualitative analysis of receptor did not remain only in the etiological discussion, but that it was an epoch-making field of investigation which contained the possiblity of artificial change of sensitivity of living body on drugs and the development connected directly with treatment of various diseases.

  16. The 5-HT6 receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleep-wake architecture.

    Science.gov (United States)

    Amat-Foraster, Maria; Leiser, Steven C; Herrik, Kjartan F; Richard, Nelly; Agerskov, Claus; Bundgaard, Christoffer; Bastlund, Jesper F; de Jong, Inge E M

    2017-02-01

    The 5-HT 6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD). The high affinity and selective 5-HT 6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on cortical function using two in vivo electrophysiological methods. Neuronal network oscillations in the frontal cortex were measured during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and by an electroencephalogram (EEG) in the awake, freely moving rat. In conjunction with the EEG study, we investigated the effects of idalopirdine and donepezil on sleep-wake architecture using telemetric polysomnography. Idalopirdine (2 mg/kg i.v.) increased gamma power in the medial prefrontal cortex (mPFC) during nPO stimulation. Donepezil (0.3 and 1 mg/kg i.v.) also increased cortical gamma power and pretreatment with idalopirdine (2 mg/kg i.v.) potentiated and prolonged the effects of donepezil. Similarly, donepezil (1 and 3 mg/kg s.c.) dose-dependently increased frontal cortical gamma power in the freely moving rat and pretreatment with idalopirdine (10 mg/kg p.o.) augmented the effect of donepezil 1 mg/kg. Analysis of the sleep-wake architecture showed that donepezil (1 and 3 mg/kg s.c.) dose-dependently delayed sleep onset and decreased the time spent in both REM and non REM sleep stages. In contrast, idalopirdine (10 mg/kg p.o.) did not affect sleep-wake architecture nor the effects of donepezil. In summary, we show that idalopirdine potentiates the effects of donepezil on frontal cortical gamma oscillations, a pharmacodynamic biomarker associated with cognition, without modifying the effects of donepezil on sleep. The increased cortical excitability may contribute to the procognitive effects of idalopirdine in donepezil

  17. Cluster ion beam facilities

    International Nuclear Information System (INIS)

    Popok, V.N.; Prasalovich, S.V.; Odzhaev, V.B.; Campbell, E.E.B.

    2001-01-01

    A brief state-of-the-art review in the field of cluster-surface interactions is presented. Ionised cluster beams could become a powerful and versatile tool for the modification and processing of surfaces as an alternative to ion implantation and ion assisted deposition. The main effects of cluster-surface collisions and possible applications of cluster ion beams are discussed. The outlooks of the Cluster Implantation and Deposition Apparatus (CIDA) being developed in Guteborg University are shown

  18. The Evolution of Galaxies in Cluster Environment; HI Perspective

    NARCIS (Netherlands)

    Fujita, A.; van Gorkom, J.; van Kampen, E.

    1999-01-01

    We investigate the degree to which the environment affects the evolution of galaxies in clusters. One way is to study the fate of gas in cluster galaxies by deep HI synthesis imaging. We are interested in the correlation between HI deficiency of galaxies and the dynamical states of clusters/the

  19. PREFACE: Nuclear Cluster Conference; Cluster'07

    Science.gov (United States)

    Freer, Martin

    2008-05-01

    The Cluster Conference is a long-running conference series dating back to the 1960's, the first being initiated by Wildermuth in Bochum, Germany, in 1969. The most recent meeting was held in Nara, Japan, in 2003, and in 2007 the 9th Cluster Conference was held in Stratford-upon-Avon, UK. As the name suggests the town of Stratford lies upon the River Avon, and shortly before the conference, due to unprecedented rainfall in the area (approximately 10 cm within half a day), lay in the River Avon! Stratford is the birthplace of the `Bard of Avon' William Shakespeare, and this formed an intriguing conference backdrop. The meeting was attended by some 90 delegates and the programme contained 65 70 oral presentations, and was opened by a historical perspective presented by Professor Brink (Oxford) and closed by Professor Horiuchi (RCNP) with an overview of the conference and future perspectives. In between, the conference covered aspects of clustering in exotic nuclei (both neutron and proton-rich), molecular structures in which valence neutrons are exchanged between cluster cores, condensates in nuclei, neutron-clusters, superheavy nuclei, clusters in nuclear astrophysical processes and exotic cluster decays such as 2p and ternary cluster decay. The field of nuclear clustering has become strongly influenced by the physics of radioactive beam facilities (reflected in the programme), and by the excitement that clustering may have an important impact on the structure of nuclei at the neutron drip-line. It was clear that since Nara the field had progressed substantially and that new themes had emerged and others had crystallized. Two particular topics resonated strongly condensates and nuclear molecules. These topics are thus likely to be central in the next cluster conference which will be held in 2011 in the Hungarian city of Debrechen. Martin Freer Participants and Cluster'07

  20. How calcium makes endocytic receptors attractive

    DEFF Research Database (Denmark)

    Andersen, Christian B F; Moestrup, Søren K

    2014-01-01

    of the receptor. Endosomal acidification and calcium efflux lead to the essential ligand-receptor affinity switch and separation. Recent data, including crystal structures of receptor-ligand complexes, now reveal how calcium, in different types of domain scaffolds, functions in a common way as a removable...... 'lynchpin' that stabilizes favorable positioning of ligand-attractive receptor residues. In addition to explaining how calcium depletion can cause ligand-receptor dissociation, the new data add further insight into how acidification contributes to dissociation through structural changes that affect...... the receptor calcium sites....

  1. The CORE study protocol: a stepped wedge cluster randomised controlled trial to test a co-design technique to optimise psychosocial recovery outcomes for people affected by mental illness in the community mental health setting

    Science.gov (United States)

    Palmer, Victoria J; Chondros, Patty; Piper, Donella; Callander, Rosemary; Weavell, Wayne; Godbee, Kali; Potiriadis, Maria; Richard, Lauralie; Densely, Konstancja; Herrman, Helen; Furler, John; Pierce, David; Schuster, Tibor; Iedema, Rick; Gunn, Jane

    2015-01-01

    Introduction User engagement in mental health service design is heralded as integral to health systems quality and performance, but does engagement improve health outcomes? This article describes the CORE study protocol, a novel stepped wedge cluster randomised controlled trial (SWCRCT) to improve psychosocial recovery outcomes for people with severe mental illness. Methods An SWCRCT with a nested process evaluation will be conducted over nearly 4 years in Victoria, Australia. 11 teams from four mental health service providers will be randomly allocated to one of three dates 9 months apart to start the intervention. The intervention, a modified version of Mental Health Experience Co-Design (MH ECO), will be delivered to 30 service users, 30 carers and 10 staff in each cluster. Outcome data will be collected at baseline (6 months) and at completion of each intervention wave. The primary outcome is improvement in recovery score using the 24-item Revised Recovery Assessment Scale for service users. Secondary outcomes are improvements to user and carer mental health and well-being using the shortened 8-item version of the WHOQOL Quality of Life scale (EUROHIS), changes to staff attitudes using the 19-item Staff Attitudes to Recovery Scale and recovery orientation of services using the 36-item Recovery Self Assessment Scale (provider version). Intervention and usual care periods will be compared using a linear mixed effects model for continuous outcomes and a generalised linear mixed effects model for binary outcomes. Participants will be analysed in the group that the cluster was assigned to at each time point. Ethics and dissemination The University of Melbourne, Human Research Ethics Committee (1340299.3) and the Federal and State Departments of Health Committees (Project 20/2014) granted ethics approval. Baseline data results will be reported in 2015 and outcomes data in 2017. Trial registration number Australian and New Zealand Clinical Trials Registry ACTRN

  2. Management of cluster headache

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer C; Jensen, Rigmor H

    2012-01-01

    The prevalence of cluster headache is 0.1% and cluster headache is often not diagnosed or misdiagnosed as migraine or sinusitis. In cluster headache there is often a considerable diagnostic delay - an average of 7 years in a population-based survey. Cluster headache is characterized by very severe...... or severe orbital or periorbital pain with a duration of 15-180 minutes. The cluster headache attacks are accompanied by characteristic associated unilateral symptoms such as tearing, nasal congestion and/or rhinorrhoea, eyelid oedema, miosis and/or ptosis. In addition, there is a sense of restlessness...... and agitation. Patients may have up to eight attacks per day. Episodic cluster headache (ECH) occurs in clusters of weeks to months duration, whereas chronic cluster headache (CCH) attacks occur for more than 1 year without remissions. Management of cluster headache is divided into acute attack treatment...

  3. Symmetries of cluster configurations

    International Nuclear Information System (INIS)

    Kramer, P.

    1975-01-01

    A deeper understanding of clustering phenomena in nuclei must encompass at least two interrelated aspects of the subject: (A) Given a system of A nucleons with two-body interactions, what are the relevant and persistent modes of clustering involved. What is the nature of the correlated nucleon groups which form the clusters, and what is their mutual interaction. (B) Given the cluster modes and their interaction, what systematic patterns of nuclear structure and reactions emerge from it. Are there, for example, families of states which share the same ''cluster parents''. Which cluster modes are compatible or exclude each other. What quantum numbers could characterize cluster configurations. There is no doubt that we can learn a good deal from the experimentalists who have discovered many of the features relevant to aspect (B). Symmetries specific to cluster configurations which can throw some light on both aspects of clustering are discussed

  4. Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight.

    Science.gov (United States)

    Purohit, Rituraj

    2014-01-01

    KIT receptor is the prime target in gastrointestinal stromal tumor (GISTs) therapy. Second generation inhibitor, Sunitinib, binds to an inactivated conformation of KIT receptor and stabilizes it in order to prevent tumor formation. Here, we investigated the dynamic behavior of wild type and mutant D816H KIT receptor, and emphasized the extended A-loop (EAL) region (805-850) by conducting molecular dynamics simulation (∼100 ns). We analyzed different properties such as root mean square cutoff or deviation, root mean square fluctuation, radius of gyration, solvent-accessible surface area, hydrogen bonding network analysis, and essential dynamics. Apart from this, clustering and cross-correlation matrix approach was used to explore the conformational space of the wild type and mutant EAL region of KIT receptor. Molecular dynamics analysis indicated that mutation (D816H) was able to alter intramolecular hydrogen bonding pattern and affected the structural flexibility of EAL region. Moreover, flexible secondary elements, specially, coil and turns were dominated in EAL region of mutant KIT receptor during simulation. This phenomenon increased the movement of EAL region which in turn helped in shifting the equilibrium towards the active kinase conformation. Our atomic investigation of mutant KIT receptor which emphasized on EAL region provided a better insight into the understanding of Sunitinib resistance mechanism of KIT receptor and would help to discover new therapeutics for KIT-based resistant tumor cells in GIST therapy.

  5. Photo-antagonism of the GABAA receptor.

    Science.gov (United States)

    Mortensen, Martin; Iqbal, Favaad; Pandurangan, Arun P; Hannan, Saad; Huckvale, Rosemary; Topf, Maya; Baker, James R; Smart, Trevor G

    2014-07-29

    Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation.

  6. Red Maca (Lepidium meyenii) did not affect cell viability despite increased androgen receptor and prostate-specific antigen gene expression in the human prostate cancer cell line LNCaP.

    Science.gov (United States)

    Díaz, P; Cardenas, H; Orihuela, P A

    2016-10-01

    We examined whether aqueous extract of Lepidium meyenii (red Maca) could inhibit growth, potentiate apoptotic activity of two anticancer drugs Taxol and 2-methoxyestradiol (2ME) or change mRNA expression for the androgen target genes, androgen receptor (Ar) and prostate-specific antigen (Psa) in the human prostate cancer cell line LNCaP. Red Maca aqueous extract at 0, 10, 20, 40 or 80 μg/ml was added to LNCaP cells, and viability was evaluated by the MTS assay at 24 or 48 hr after treatment. Furthermore, LNCaP cells were treated with 80 μg/ml of red Maca plus Taxol or 2ME 5 μM and viability was assessed 48 hr later. Finally, LNCaP cells were treated with red Maca 0, 20, 40 or 80 μg/ml, and 12 hr later, mRNA level for Ar or Psa was assessed by real-time PCR. Treatment with red Maca did not affect viability of LNCaP cells. Apoptotic activity induced by Taxol and 2ME in LNCaP cells was not altered with red Maca treatment. Relative expression of the mRNA for Ar and Psa increased with red Maca 20 and 40 μg/ml, but not at 80 μg/ml. We conclude that red Maca aqueous extract does not have toxic effects, but stimulates androgen signalling in LNCaP cells. © 2016 Blackwell Verlag GmbH.

  7. Behavioral stress may increase the rewarding valence of cocaine-associated cues through a dynorphin/kappa-opioid receptor-mediated mechanism without affecting associative learning or memory retrieval mechanisms.

    Science.gov (United States)

    Schindler, Abigail G; Li, Shuang; Chavkin, Charles

    2010-08-01

    Stress exposure increases the risk of addictive drug use in human and animal models of drug addiction by mechanisms that are not completely understood. Mice subjected to repeated forced swim stress (FSS) before cocaine develop significantly greater conditioned place preference (CPP) for the drug-paired chamber than unstressed mice. Analysis of the dose dependency showed that FSS increased both the maximal CPP response and sensitivity to cocaine. To determine whether FSS potentiated CPP by enhancing associative learning mechanisms, mice were conditioned with cocaine in the absence of stress, then challenged after association was complete with the kappa-opioid receptor (KOR) agonist U50,488 or repeated FSS, before preference testing. Mice challenged with U50,488 60 min before CPP preference testing expressed significantly greater cocaine-CPP than saline-challenged mice. Potentiation by U50,488 was dose and time dependent and blocked by the KOR antagonist norbinaltorphimine (norBNI). Similarly, mice subjected to repeated FSS before the final preference test expressed significantly greater cocaine-CPP than unstressed controls, and FSS-induced potentiation was blocked by norBNI. Novel object recognition (NOR) performance was not affected by U50,488 given 60 min before assay, but was impaired when given 15 min before NOR assay, suggesting that KOR activation did not potentiate CPP by facilitating memory retrieval or expression. The results from this study show that the potentiation of cocaine-CPP by KOR activation does not result from an enhancement of associative learning mechanisms and that stress may instead enhance the rewarding valence of cocaine-associated cues by a dynorphin-dependent mechanism.

  8. Atomically precise cluster catalysis towards quantum controlled catalysts

    International Nuclear Information System (INIS)

    Watanabe, Yoshihide

    2014-01-01

    Catalysis of atomically precise clusters supported on a substrate is reviewed in relation to the type of reactions. The catalytic activity of supported clusters has generally been discussed in terms of electronic structure. Several lines of evidence have indicated that the electronic structure of clusters and the geometry of clusters on a support, including the accompanying cluster-support interaction, are strongly correlated with catalytic activity. The electronic states of small clusters would be easily affected by cluster–support interactions. Several studies have suggested that it is possible to tune the electronic structure through atomic control of the cluster size. It is promising to tune not only the number of cluster atoms, but also the hybridization between the electronic states of the adsorbed reactant molecules and clusters in order to realize a quantum-controlled catalyst. (review)

  9. Cluster Decline and Resilience

    DEFF Research Database (Denmark)

    Østergaard, Christian Richter; Park, Eun Kyung

    Most studies on regional clusters focus on identifying factors and processes that make clusters grow. However, sometimes technologies and market conditions suddenly shift, and clusters decline. This paper analyses the process of decline of the wireless communication cluster in Denmark, 1963......-2011. Our longitudinal study reveals that technological lock-in and exit of key firms have contributed to impairment of the cluster’s resilience in adapting to disruptions. Entrepreneurship has a positive effect on cluster resilience, while multinational companies have contradicting effects by bringing...... in new resources to the cluster but being quick to withdraw in times of crisis....

  10. Cluster-based global firms' use of local capabilities

    DEFF Research Database (Denmark)

    Andersen, Poul Houman; Bøllingtoft, Anne

    2011-01-01

    Purpose – Despite growing interest in clusters role for the global competitiveness of firms, there has been little research into how globalization affects cluster-based firms’ (CBFs) use of local knowledge resources and the combination of local and global knowledge used. Using the cluster......’s knowledge base as a mediating variable, the purpose of this paper is to examine how globalization affected the studied firms’ use of local cluster-based knowledge, integration of local and global knowledge, and networking capabilities. Design/methodology/approach – Qualitative case studies of nine firms...... in three clusters strongly affected by increasing global division of labour. Findings – The paper suggests that globalization has affected how firms use local resources and combine local and global knowledge. Unexpectedly, clustered firms with explicit procedures and established global fora for exchanging...

  11. Comprehensive cluster analysis with Transitivity Clustering.

    Science.gov (United States)

    Wittkop, Tobias; Emig, Dorothea; Truss, Anke; Albrecht, Mario; Böcker, Sebastian; Baumbach, Jan

    2011-03-01

    Transitivity Clustering is a method for the partitioning of biological data into groups of similar objects, such as genes, for instance. It provides integrated access to various functions addressing each step of a typical cluster analysis. To facilitate this, Transitivity Clustering is accessible online and offers three user-friendly interfaces: a powerful stand-alone version, a web interface, and a collection of Cytoscape plug-ins. In this paper, we describe three major workflows: (i) protein (super)family detection with Cytoscape, (ii) protein homology detection with incomplete gold standards and (iii) clustering of gene expression data. This protocol guides the user through the most important features of Transitivity Clustering and takes ∼1 h to complete.

  12. Root uptake and phytotoxicity of nanosized molybdenum octahedral clusters

    International Nuclear Information System (INIS)

    Aubert, Tangi; Burel, Agnès; Esnault, Marie-Andrée; Cordier, Stéphane; Grasset, Fabien; Cabello-Hurtado, Francisco

    2012-01-01

    Highlights: ► We investigated the effect of nanosized Mo 6 clusters on the growth of rapeseed plants. ► The aggregation state of the clusters depends on the dispersion medium. ► The concentration-dependant toxicity of the clusters depends on aggregation state. ► We took into account the possible contribution to toxicity of dissolved ionic species. ► The root uptake of the clusters was followed by NanoSIMS. - Abstract: Here are examined the root uptake and phytotoxicity of octahedral hexamolybdenum clusters on rapeseed plants using the solid state compound Cs 2 Mo 6 Br 14 as cluster precursor. [Mo 6 Br 14 ] 2− cluster units are nanosized entities offering a strong and stable emission in the near-infrared region with numerous applications in biotechnology. To investigate cluster toxicity on rapeseed plants, two different culture systems have been set up, using either a water-sorbing suspension of cluster aggregates or an ethanol-sorbing solution of dispersed nanosized clusters. Size, shape, surface area and state of clusters in both medium were analyzed by FE-SEM, BET and XPS. The potential contribution of cluster dissolution to phytotoxicity was evaluated by ICP-OES and toxicity analysis of Mo, Br and Cs. We showed that the clusters did not affect seed germination but greatly inhibited plant growth. This inhibition was much more important when plants were treated with nanosized entities than with microsized cluster aggregates. In addition, nanosized clusters affected the root morphology in a different manner than microsized cluster aggregates, as shown by FE-SEM observations. The root penetration of the clusters was followed by secondary ion mass spectroscopy with high spatial resolution (NanoSIMS) and was also found to be much more important for treatments with nanosized clusters.

  13. Root uptake and phytotoxicity of nanosized molybdenum octahedral clusters

    Energy Technology Data Exchange (ETDEWEB)

    Aubert, Tangi [Solid State Chemistry and Materials Group, UMR CNRS 6226 Sciences Chimiques de Rennes, University of Rennes 1, 263 av. du General Leclerc, Campus de Beaulieu, 35042 Rennes (France); Burel, Agnes [Electronic Microscopy Department, University of Rennes 1, 2 av. du Professeur Leon-Bernard, Campus de Villejean, 35043 Rennes (France); Esnault, Marie-Andree [Mechanisms at the Origin of Biodiversity Team, UMR CNRS 6553 Ecobio, University of Rennes 1, 263 av. du General Leclerc, Campus de Beaulieu, 35042 Rennes (France); Cordier, Stephane; Grasset, Fabien [Solid State Chemistry and Materials Group, UMR CNRS 6226 Sciences Chimiques de Rennes, University of Rennes 1, 263 av. du General Leclerc, Campus de Beaulieu, 35042 Rennes (France); Cabello-Hurtado, Francisco, E-mail: francisco.cabello@univ-rennes1.fr [Mechanisms at the Origin of Biodiversity Team, UMR CNRS 6553 Ecobio, University of Rennes 1, 263 av. du General Leclerc, Campus de Beaulieu, 35042 Rennes (France)

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer We investigated the effect of nanosized Mo{sub 6} clusters on the growth of rapeseed plants. Black-Right-Pointing-Pointer The aggregation state of the clusters depends on the dispersion medium. Black-Right-Pointing-Pointer The concentration-dependant toxicity of the clusters depends on aggregation state. Black-Right-Pointing-Pointer We took into account the possible contribution to toxicity of dissolved ionic species. Black-Right-Pointing-Pointer The root uptake of the clusters was followed by NanoSIMS. - Abstract: Here are examined the root uptake and phytotoxicity of octahedral hexamolybdenum clusters on rapeseed plants using the solid state compound Cs{sub 2}Mo{sub 6}Br{sub 14} as cluster precursor. [Mo{sub 6}Br{sub 14}]{sup 2-} cluster units are nanosized entities offering a strong and stable emission in the near-infrared region with numerous applications in biotechnology. To investigate cluster toxicity on rapeseed plants, two different culture systems have been set up, using either a water-sorbing suspension of cluster aggregates or an ethanol-sorbing solution of dispersed nanosized clusters. Size, shape, surface area and state of clusters in both medium were analyzed by FE-SEM, BET and XPS. The potential contribution of cluster dissolution to phytotoxicity was evaluated by ICP-OES and toxicity analysis of Mo, Br and Cs. We showed that the clusters did not affect seed germination but greatly inhibited plant growth. This inhibition was much more important when plants were treated with nanosized entities than with microsized cluster aggregates. In addition, nanosized clusters affected the root morphology in a different manner than microsized cluster aggregates, as shown by FE-SEM observations. The root penetration of the clusters was followed by secondary ion mass spectroscopy with high spatial resolution (NanoSIMS) and was also found to be much more important for treatments with nanosized clusters.

  14. The CORE study protocol: a stepped wedge cluster randomised controlled trial to test a co-design technique to optimise psychosocial recovery outcomes for people affected by mental illness in the community mental health setting.

    Science.gov (United States)

    Palmer, Victoria J; Chondros, Patty; Piper, Donella; Callander, Rosemary; Weavell, Wayne; Godbee, Kali; Potiriadis, Maria; Richard, Lauralie; Densely, Konstancja; Herrman, Helen; Furler, John; Pierce, David; Schuster, Tibor; Iedema, Rick; Gunn, Jane

    2015-03-24

    User engagement in mental health service design is heralded as integral to health systems quality and performance, but does engagement improve health outcomes? This article describes the CORE study protocol, a novel stepped wedge cluster randomised controlled trial (SWCRCT) to improve psychosocial recovery outcomes for people with severe mental illness. An SWCRCT with a nested process evaluation will be conducted over nearly 4 years in Victoria, Australia. 11 teams from four mental health service providers will be randomly allocated to one of three dates 9 months apart to start the intervention. The intervention, a modified version of Mental Health Experience Co-Design (MH ECO), will be delivered to 30 service users, 30 carers and 10 staff in each cluster. Outcome data will be collected at baseline (6 months) and at completion of each intervention wave. The primary outcome is improvement in recovery score using the 24-item Revised Recovery Assessment Scale for service users. Secondary outcomes are improvements to user and carer mental health and well-being using the shortened 8-item version of the WHOQOL Quality of Life scale (EUROHIS), changes to staff attitudes using the 19-item Staff Attitudes to Recovery Scale and recovery orientation of services using the 36-item Recovery Self Assessment Scale (provider version). Intervention and usual care periods will be compared using a linear mixed effects model for continuous outcomes and a generalised linear mixed effects model for binary outcomes. Participants will be analysed in the group that the cluster was assigned to at each time point. The University of Melbourne, Human Research Ethics Committee (1340299.3) and the Federal and State Departments of Health Committees (Project 20/2014) granted ethics approval. Baseline data results will be reported in 2015 and outcomes data in 2017. Australian and New Zealand Clinical Trials Registry ACTRN12614000457640. Published by the BMJ Publishing Group Limited. For

  15. Genetic diversity of canine olfactory receptors

    Directory of Open Access Journals (Sweden)

    Hitte Christophe

    2009-01-01

    Full Text Available Abstract Background Evolution has resulted in large repertoires of olfactory receptor (OR genes, forming the largest gene families in mammalian genomes. Knowledge of the genetic diversity of olfactory receptors is essential if we are to understand the differences in olfactory sensory capability between individuals. Canine breeds constitute an attractive model system for such investigations. Results We sequenced 109 OR genes considered representative of the whole OR canine repertoire, which consists of more than 800 genes, in a cohort of 48 dogs of six different breeds. SNP frequency showed the overall level of polymorphism to be high. However, the distribution of SNP was highly heterogeneous among OR genes. More than 50% of OR genes were found to harbour a large number of SNP, whereas the rest were devoid of SNP or only slightly polymorphic. Heterogeneity was also observed across breeds, with 25% of the SNP breed-specific. Linkage disequilibrium within OR genes and OR clusters suggested a gene conversion process, consistent with a mean level of polymorphism higher than that observed for introns and intergenic sequences. A large proportion (47% of SNP induced amino-acid changes and the Ka/Ks ratio calculated for all alleles with a complete ORF indicated a low selective constraint with respect to the high level of redundancy of the olfactory combinatory code and an ongoing pseudogenisation process, which affects dog breeds differently. Conclusion Our demonstration of a high overall level of polymorphism, likely to modify the ligand-binding capacity of receptors distributed differently within the six breeds tested, is the first step towards understanding why Labrador Retrievers and German Shepherd Dogs have a much greater potential for use as sniffer dogs than Pekingese dogs or Greyhounds. Furthermore, the heterogeneity in OR polymorphism observed raises questions as to why, in a context in which most OR genes are highly polymorphic, a subset of

  16. LMC clusters: young

    International Nuclear Information System (INIS)

    Freeman, K.C.

    1980-01-01

    The young globular clusters of the LMC have ages of 10 7 -10 8 y. Their masses and structure are similar to those of the smaller galactic globular clusters. Their stellar mass functions (in the mass range 6 solar masses to 1.2 solar masses) vary greatly from cluster to cluster, although the clusters are similar in total mass, age, structure and chemical composition. It would be very interesting to know why these clusters are forming now in the LMC and not in the Galaxy. The author considers the 'young globular' or 'blue populous' clusters of the LMC. The ages of these objects are 10 7 to 10 8 y, and their masses are 10 4 to 10 5 solar masses, so they are populous enough to be really useful for studying the evolution of massive stars. The author concentrates on the structure and stellar content of these young clusters. (Auth.)

  17. Star clusters and associations

    International Nuclear Information System (INIS)

    Ruprecht, J.; Palous, J.

    1983-01-01

    All 33 papers presented at the symposium were inputted to INIS. They dealt with open clusters, globular clusters, stellar associations and moving groups, and local kinematics and galactic structures. (E.S.)

  18. Cluster beam injection

    International Nuclear Information System (INIS)

    Bottiglioni, F.; Coutant, J.; Fois, M.

    1978-01-01

    Areas of possible applications of cluster injection are discussed. The deposition inside the plasma of molecules, issued from the dissociation of the injected clusters, has been computed. Some empirical scaling laws for the penetration are given

  19. Cluster analysis of obesity and asthma phenotypes.

    Directory of Open Access Journals (Sweden)

    E Rand Sutherland

    Full Text Available Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC. Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype.In a cohort of clinical trial participants (n = 250, minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCRα and induction of MAP kinase phosphatase-1 (MKP-1 expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m(2 and severity of asthma symptoms (AEQ score the most significant determinants of cluster membership (F = 57.1, p<0.0001 and F = 44.8, p<0.0001, respectively. Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ and control (ACQ, exhaled nitric oxide concentration (F(ENO and airway hyperresponsiveness (methacholine PC(20 but were similar with regard to measures of lung function (FEV(1 (% and FEV(1/FVC, airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP. Members of obese clusters demonstrated evidence of reduced expression of GCRα, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasoneObesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals

  20. Clustering at high redshifts

    International Nuclear Information System (INIS)

    Shaver, P.A.

    1986-01-01

    Evidence for clustering of and with high-redshift QSOs is discussed. QSOs of different redshifts show no clustering, but QSOs of similar redshifts appear to be clustered on a scale comparable to that of galaxies at the present epoch. In addition, spectroscopic studies of close pairs of QSOs indicate that QSOs are surrounded by a relatively high density of absorbing matter, possibly clusters of galaxies

  1. Structural Probing of Off-Target G Protein-Coupled Receptor Activities within a Series of Adenosine/Adenine Congeners

    Science.gov (United States)

    Paoletta, Silvia; Tosh, Dilip K.; Salvemini, Daniela; Jacobson, Kenneth A.

    2014-01-01

    We studied patterns of off-target receptor interactions, mostly at G protein-coupled receptors (GPCRs) in the µM range, of nucleoside derivatives that are highly engineered for nM interaction with adenosine receptors (ARs). Because of the considerable interest of using AR ligands for treating diseases of the CNS, we used the Psychoactive Drug Screening Program (PDSP) for probing promiscuity of these adenosine/adenine congeners at 41 diverse receptors, channels and a transporter. The step-wise truncation of rigidified, trisubstituted (at N6, C2, and 5′ positions) nucleosides revealed unanticipated interactions mainly with biogenic amine receptors, such as adrenergic receptors and serotonergic receptors, with affinities as high as 61 nM. The unmasking of consistent sets of structure activity relationship (SAR) at novel sites suggested similarities between receptor families in molecular recognition. Extensive molecular modeling of the GPCRs affected suggested binding modes of the ligands that supported the patterns of SAR at individual receptors. In some cases, the ligand docking mode closely resembled AR binding and in other cases the ligand assumed different orientations. The recognition patterns for different GPCRs were clustered according to which substituent groups were tolerated and explained in light of the complementarity with the receptor binding site. Thus, some likely off-target interactions, a concern for secondary drug effects, can be predicted for analogues of this set of substructures, aiding the design of additional structural analogues that either eliminate or accentuate certain off-target activities. Moreover, similar analyses could be performed for unrelated structural families for other GPCRs. PMID:24859150

  2. Cluster Physics with Merging Galaxy Clusters

    Directory of Open Access Journals (Sweden)

    Sandor M. Molnar

    2016-02-01

    Full Text Available Collisions between galaxy clusters provide a unique opportunity to study matter in a parameter space which cannot be explored in our laboratories on Earth. In the standard LCDM model, where the total density is dominated by the cosmological constant ($Lambda$ and the matter density by cold dark matter (CDM, structure formation is hierarchical, and clusters grow mostly by merging.Mergers of two massive clusters are the most energetic events in the universe after the Big Bang,hence they provide a unique laboratory to study cluster physics.The two main mass components in clusters behave differently during collisions:the dark matter is nearly collisionless, responding only to gravity, while the gas is subject to pressure forces and dissipation, and shocks and turbulenceare developed during collisions. In the present contribution we review the different methods used to derive the physical properties of merging clusters. Different physical processes leave their signatures on different wavelengths, thusour review is based on a multifrequency analysis. In principle, the best way to analyze multifrequency observations of merging clustersis to model them using N-body/HYDRO numerical simulations. We discuss the results of such detailed analyses.New high spatial and spectral resolution ground and space based telescopeswill come online in the near future. Motivated by these new opportunities,we briefly discuss methods which will be feasible in the near future in studying merging clusters.

  3. Size selected metal clusters

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. The Optical Absorption Spectra of Small Silver Clusters (5-11) ... Soft Landing and Fragmentation of Small Clusters Deposited in Noble-Gas Films. Harbich, W.; Fedrigo, S.; Buttet, J. Phys. Rev. B 1998, 58, 7428. CO combustion on supported gold clusters. Arenz M ...

  4. The Durban Auto Cluster

    DEFF Research Database (Denmark)

    Lorentzen, Jochen; Robbins, Glen; Barnes, Justin

    2004-01-01

    The paper describes the formation of the Durban Auto Cluster in the context of trade liberalization. It argues that the improvement of operational competitiveness of firms in the cluster is prominently due to joint action. It tests this proposition by comparing the gains from cluster activities...

  5. Marketing research cluster analysis

    Directory of Open Access Journals (Sweden)

    Marić Nebojša

    2002-01-01

    Full Text Available One area of applications of cluster analysis in marketing is identification of groups of cities and towns with similar demographic profiles. This paper considers main aspects of cluster analysis by an example of clustering 12 cities with the use of Minitab software.

  6. Marketing research cluster analysis

    OpenAIRE

    Marić Nebojša

    2002-01-01

    One area of applications of cluster analysis in marketing is identification of groups of cities and towns with similar demographic profiles. This paper considers main aspects of cluster analysis by an example of clustering 12 cities with the use of Minitab software.

  7. Minimalist's linux cluster

    International Nuclear Information System (INIS)

    Choi, Chang-Yeong; Kim, Jeong-Hyun; Kim, Seyong

    2004-01-01

    Using barebone PC components and NIC's, we construct a linux cluster which has 2-dimensional mesh structure. This cluster has smaller footprint, is less expensive, and use less power compared to conventional linux cluster. Here, we report our experience in building such a machine and discuss our current lattice project on the machine

  8. Range-clustering queries

    NARCIS (Netherlands)

    Abrahamsen, M.; de Berg, M.T.; Buchin, K.A.; Mehr, M.; Mehrabi, A.D.

    2017-01-01

    In a geometric k -clustering problem the goal is to partition a set of points in R d into k subsets such that a certain cost function of the clustering is minimized. We present data structures for orthogonal range-clustering queries on a point set S : given a query box Q and an integer k>2 , compute

  9. Cosmology with cluster surveys

    Indian Academy of Sciences (India)

    Abstract. Surveys of clusters of galaxies provide us with a powerful probe of the den- sity and nature of the dark energy. The red-shift distribution of detected clusters is highly sensitive to the dark energy equation of state parameter w. Upcoming Sunyaev–. Zel'dovich (SZ) surveys would provide us large yields of clusters to ...

  10. Impact of 4 Lactobacillus plantarum capsular polysaccharide clusters on surface glycan composition and host cell signaling

    Directory of Open Access Journals (Sweden)

    Remus Daniela M

    2012-11-01

    -J produced decreased levels of surface polysaccharides, whereas the molar mass and the composition of polysaccharides was not affected by these cluster mutations. In the quadruple mutant, the amount of surface polysaccharides was strongly reduced. The impact of the cps cluster mutations on toll-like receptor (TLR-mediated human nuclear factor (NF-κB activation in host cells was evaluated using a TLR2 reporter cell line. In comparison to a L. plantarum wild-type derivative, TLR2 activation remained unaffected by the Δcps1A-I and Δcps3A-J mutants but appeared slightly increased after stimulation with the Δcps2A-J and Δcps4A-J mutants, while the Δcps1A-3J and Δcps1A-3J, Δcps4A-J mutants elicited the strongest responses and clearly displayed enhanced TLR2 signaling. Conclusions Our study reveals that modulation of surface glycan characteristics in L. plantarum highlights the role of these molecules in shielding of cell envelope embedded host receptor ligands. Although the apparently complete cps clusters (cps2A-J and cps4A-J contributed individually to this shielding, the removal of all cps clusters led to the strongest signaling enhancement. Our findings provide new insights into cell surface glycan biosynthesis in L. plantarum, which bears relevance in the context of host-cell signaling by probiotic bacteria.

  11. Source-receptor relationships for speciated atmospheric mercury at the remote Experimental Lakes Area, northwestern Ontario, Canada

    Directory of Open Access Journals (Sweden)

    I. Cheng

    2012-02-01

    Full Text Available Source-receptor relationships for speciated atmospheric mercury measured at the Experimental Lakes Area (ELA, northwestern Ontario, Canada were investigated using various receptor-based approaches. The data used in this study include gaseous elemental mercury (GEM, mercury bound to fine airborne particles (<2.5 μm (PHg, reactive gaseous mercury (RGM, major inorganic ions, sulphur dioxide, nitric acid gas, ozone, and meteorological variables, all of which were measured between May 2005 and December 2006. The source origins identified were related to transport of industrial and combustion emissions (associated with elevated GEM, photochemical production of RGM (associated with elevated RGM, road-salt particles with absorption of gaseous Hg (associated with elevated PHg and RGM, crustal/soil emissions, and background pollution. Back trajectory modelling illustrated that a remote site, like ELA, is affected by distant Hg point sources in Canada and the United States. The sources identified from correlation analysis, principal components analysis and K-means cluster analysis were generally consistent. The discrepancies between the K-means and Hierarchical cluster analysis were the clusters related to transport of industrial/combustion emissions, photochemical production of RGM, and crustal/soil emissions. Although it was possible to assign the clusters to these source origins, the trajectory plots for the Hierarchical clusters were similar to some of the trajectories belonging to several K-means clusters. This likely occurred because the variables indicative of transport of industrial/combustion emissions were elevated in at least two or more of the clusters, which means this Hg source was well-represented in the data.

  12. Cu cluster shell structure at elevated temperatures

    DEFF Research Database (Denmark)

    Christensen, Ole Bøssing; Jacobsen, Karsten Wedel; Nørskov, Jens Kehlet

    1991-01-01

    Equilibrium structures of small (3–29)-atom Cu clusters are determined by simulated annealing, and finite-temperature ensembles are simulated by Monte Carlo techniques using the effective-medium theory for the energy calculation. Clusters with 8, 18, and 20 atoms are found to be particularly stable....... The equilibrium geometrical structures are determined and found to be determined by a Jahn-Teller distortion, which is found to affect the geometry also at high temperatures. The ‘‘magic’’ clusters retain their large stability even at elevated temperatures....

  13. Strontium clusters: electronic and geometry shell effects

    DEFF Research Database (Denmark)

    Lyalin, Andrey G.; Solov'yov, Ilia; Solov'yov, Andrey V.

    2008-01-01

    charged strontium clusters consisting of up to 14 atoms, average bonding distances, electronic shell closures, binding energies per atom, and spectra of the density of electronic states (DOS). It is demonstrated that the size-evolution of structural and electronic properties of strontium clusters...... is governed by an interplay of the electronic and geometry shell closures. Influence of the electronic shell effects on structural rearrangements can lead to violation of the icosahedral growth motif of strontium clusters. It is shown that the excessive charge essentially affects the optimized geometry...

  14. Cluster analysis for applications

    CERN Document Server

    Anderberg, Michael R

    1973-01-01

    Cluster Analysis for Applications deals with methods and various applications of cluster analysis. Topics covered range from variables and scales to measures of association among variables and among data units. Conceptual problems in cluster analysis are discussed, along with hierarchical and non-hierarchical clustering methods. The necessary elements of data analysis, statistics, cluster analysis, and computer implementation are integrated vertically to cover the complete path from raw data to a finished analysis.Comprised of 10 chapters, this book begins with an introduction to the subject o

  15. Clusters in nuclei

    CERN Document Server

    Following the pioneering discovery of alpha clustering and of molecular resonances, the field of nuclear clustering is today one of those domains of heavy-ion nuclear physics that faces the greatest challenges, yet also contains the greatest opportunities. After many summer schools and workshops, in particular over the last decade, the community of nuclear molecular physicists has decided to collaborate in producing a comprehensive collection of lectures and tutorial reviews covering the field. This third volume follows the successful Lect. Notes Phys. 818 (Vol. 1) and 848 (Vol. 2), and comprises six extensive lectures covering the following topics:  - Gamma Rays and Molecular Structure - Faddeev Equation Approach for Three Cluster Nuclear Reactions - Tomography of the Cluster Structure of Light Nuclei Via Relativistic Dissociation - Clustering Effects Within the Dinuclear Model : From Light to Hyper-heavy Molecules in Dynamical Mean-field Approach - Clusterization in Ternary Fission - Clusters in Light N...

  16. Spatial cluster modelling

    CERN Document Server

    Lawson, Andrew B

    2002-01-01

    Research has generated a number of advances in methods for spatial cluster modelling in recent years, particularly in the area of Bayesian cluster modelling. Along with these advances has come an explosion of interest in the potential applications of this work, especially in epidemiology and genome research. In one integrated volume, this book reviews the state-of-the-art in spatial clustering and spatial cluster modelling, bringing together research and applications previously scattered throughout the literature. It begins with an overview of the field, then presents a series of chapters that illuminate the nature and purpose of cluster modelling within different application areas, including astrophysics, epidemiology, ecology, and imaging. The focus then shifts to methods, with discussions on point and object process modelling, perfect sampling of cluster processes, partitioning in space and space-time, spatial and spatio-temporal process modelling, nonparametric methods for clustering, and spatio-temporal ...

  17. Clusters and how to make it work : Cluster Strategy Toolkit

    NARCIS (Netherlands)

    Manickam, Anu; van Berkel, Karel

    2014-01-01

    Clusters are the magic answer to regional economic development. Firms in clusters are more innovative; cluster policy dominates EU policy; ‘top-sectors’ and excellence are the choice of national policy makers; clusters are ‘in’. But, clusters are complex, clusters are ‘messy’; there is no clear

  18. Diversifying selection and functional analysis of interleukin-4 suggests antagonism-driven evolution at receptor-binding interfaces

    Directory of Open Access Journals (Sweden)

    Brown Scott

    2010-07-01

    Full Text Available Abstract Background Interleukin-4 (IL4 is a secreted immunoregulatory cytokine critically involved in host protection from parasitic helminths 1. Reasoning that helminths may have evolved mechanisms to antagonize IL4 to maximize their dispersal, we explored mammalian IL4 evolution. Results This analysis revealed evidence of diversifying selection at 15 residues, clustered in epitopes responsible for IL4 binding to its Type I and Type II receptors. Such a striking signature of selective pressure suggested either recurrent episodes of pathogen antagonism or ligand/receptor co-evolution. To test the latter possibility, we performed detailed functional analysis of IL4 allotypes expressed by Mus musculus musculus and Mus musculus castaneus, which happen to differ at 5 residues (including three at positively selected sites in and adjacent to the site 1 epitope that binds the IL4Rα subunit shared by the Type I and Type II IL4 receptors. We show that this intra-species variation affects the ability of IL4 neither to bind IL4 receptor alpha (IL4Rα nor to signal biological responses through its Type I receptor. Conclusions Our results -- reminiscent of clustered positively selected sites revealing functionally important residues at host-virus interaction interfaces -- are consistent with IL4 having evolved to avoid recurrent pathogen antagonism, while maintaining the capacity to bind and signal through its cognate receptor. This work exposes what may be a general feature of evolutionary conflicts fought by pathogen antagonists at host protein-protein interaction interfaces involved in immune signaling: the emergence of receptor-binding ligand epitopes capable of buffering amino acid variation.

  19. The growth of Fe clusters over graphene/Cu(111)

    International Nuclear Information System (INIS)

    Takahashi, Keisuke

    2015-01-01

    The growth of Fe clusters up to nine atoms over graphene/Cu(111) is investigated within the density functional theory. Graphene is weakly physisorbed on Cu(111) through van der Waals force. The structures of Fe clusters over graphene/Cu(111) grow differently compared to gas-phase Fe clusters where Fe clusters are predicted to form towards a pyramid-like structure on graphene/Cu(111). The graphene is negatively charged upon the adsorption of Fe clusters as a result of charge transfer from Fe to graphene. Despite the fact that the electronic structure of graphene is affected by Fe clusters, magnetic moment of Fe clusters over graphene/Cu(111) remains relatively high. This suggests that graphene can be a potential substrate for supporting Fe clusters towards applications in magnetism and catalysis. (paper)

  20. Agricultural Clusters in the Netherlands

    NARCIS (Netherlands)

    Schouten, M.A.; Heijman, W.J.M.

    2012-01-01

    Michael Porter was the first to use the term cluster in an economic context. He introduced the term in The Competitive Advantage of Nations (1990). The term cluster is also known as business cluster, industry cluster, competitive cluster or Porterian cluster. This article aims at determining and

  1. Open source clustering software.

    Science.gov (United States)

    de Hoon, M J L; Imoto, S; Nolan, J; Miyano, S

    2004-06-12

    We have implemented k-means clustering, hierarchical clustering and self-organizing maps in a single multipurpose open-source library of C routines, callable from other C and C++ programs. Using this library, we have created an improved version of Michael Eisen's well-known Cluster program for Windows, Mac OS X and Linux/Unix. In addition, we generated a Python and a Perl interface to the C Clustering Library, thereby combining the flexibility of a scripting language with the speed of C. The C Clustering Library and the corresponding Python C extension module Pycluster were released under the Python License, while the Perl module Algorithm::Cluster was released under the Artistic License. The GUI code Cluster 3.0 for Windows, Macintosh and Linux/Unix, as well as the corresponding command-line program, were released under the same license as the original Cluster code. The complete source code is available at http://bonsai.ims.u-tokyo.ac.jp/mdehoon/software/cluster. Alternatively, Algorithm::Cluster can be downloaded from CPAN, while Pycluster is also available as part of the Biopython distribution.

  2. Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH).

    Science.gov (United States)

    Koika, Vasiliki; Varnavas, Petros; Valavani, Helen; Sidis, Yisrael; Plummer, Lacey; Dwyer, Andrew; Quinton, Richard; Kanaka-Gantenbein, Christine; Pitteloud, Nelly; Sertedaki, Amalia; Dacou-Voutetakis, Catherine; Georgopoulos, Neoklis A

    2013-03-01

    FGFR1 mutations have been identified in both Kallmann syndrome and normosmic HH (nIHH). To date, few mutations in the FGFR1 gene have been structurally or functionally characterized in vitro to identify molecular mechanisms that contribute to the disease pathogenesis. We attempted to define the in vitro functionality of two FGFR1 mutants (R254W and R254Q), resulting from two different amino acid substitutions of the same residue, and to correlate the in vitro findings to the patient phenotypes. Two unrelated GnRH deficient probands were found to harbor mutations in FGFR1 (R254W and R254Q). Mutant signaling activity and expression levels were evaluated in vitro and compared to a wild type (WT) receptor. Signaling activity was determined by a FGF2/FGFR1 dependent transcription reporter assay. Receptor total expression levels were assessed by Western blot and cell surface expression was measured by a radiolabeled antibody binding assay. The R254W maximal receptor signaling capacity was reduced by 45% (p<0.01) while R254Q activity was not different from WT. However, both mutants displayed diminished total protein expression levels (40 and 30% reduction relative to WT, respectively), while protein maturation was unaffected. Accordingly, cell surface expression levels of the mutant receptors were also significantly reduced (35% p<0.01 and 15% p<0.05, respectively). The p.R254W and p.R254Q are both loss-of-function mutations as demonstrated by their reduced overall and cell surface expression levels suggesting a deleterious effect on receptor folding and stability. It appears that a tryptophan substitution at R254 is more disruptive to receptor structure than the more conserved glutamine substitution. No clear correlation between the severity of in vitro loss-of-function and phenotypic presentation could be assigned. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Electron: Cluster interactions

    International Nuclear Information System (INIS)

    Scheidemann, A.A.; Knight, W.D.

    1994-02-01

    Beam depletion spectroscopy has been used to measure absolute total inelastic electron-sodium cluster collision cross sections in the energy range from E ∼ 0.1 to E ∼ 6 eV. The investigation focused on the closed shell clusters Na 8 , Na 20 , Na 40 . The measured cross sections show an increase for the lowest collision energies where electron attachment is the primary scattering channel. The electron attachment cross section can be understood in terms of Langevin scattering, connecting this measurement with the polarizability of the cluster. For energies above the dissociation energy the measured electron-cluster cross section is energy independent, thus defining an electron-cluster interaction range. This interaction range increases with the cluster size

  4. Clustering high dimensional data

    DEFF Research Database (Denmark)

    Assent, Ira

    2012-01-01

    High-dimensional data, i.e., data described by a large number of attributes, pose specific challenges to clustering. The so-called ‘curse of dimensionality’, coined originally to describe the general increase in complexity of various computational problems as dimensionality increases, is known...... to render traditional clustering algorithms ineffective. The curse of dimensionality, among other effects, means that with increasing number of dimensions, a loss of meaningful differentiation between similar and dissimilar objects is observed. As high-dimensional objects appear almost alike, new approaches...... for clustering are required. Consequently, recent research has focused on developing techniques and clustering algorithms specifically for high-dimensional data. Still, open research issues remain. Clustering is a data mining task devoted to the automatic grouping of data based on mutual similarity. Each cluster...

  5. Charge exchange in galaxy clusters

    Science.gov (United States)

    Gu, Liyi; Mao, Junjie; de Plaa, Jelle; Raassen, A. J. J.; Shah, Chintan; Kaastra, Jelle S.

    2018-03-01

    Context. Though theoretically expected, the charge exchange emission from galaxy clusters has never been confidently detected. Accumulating hints were reported recently, including a rather marginal detection with the Hitomi data of the Perseus cluster. As previously suggested, a detection of charge exchange line emission from galaxy clusters would not only impact the interpretation of the newly discovered 3.5 keV line, but also open up a new research topic on the interaction between hot and cold matter in clusters. Aim. We aim to perform the most systematic search for the O VIII charge exchange line in cluster spectra using the RGS on board XMM-Newton. Methods: We introduce a sample of 21 clusters observed with the RGS. In order to search for O VIII charge exchange, the sample selection criterion is a >35σ detection of the O VIII Lyα line in the archival RGS spectra. The dominating thermal plasma emission is modeled and subtracted with a two-temperature thermal component, and the residuals are stacked for the line search. The systematic uncertainties in the fits are quantified by refitting the spectra with a varying continuum and line broadening. Results: By the residual stacking, we do find a hint of a line-like feature at 14.82 Å, the characteristic wavelength expected for oxygen charge exchange. This feature has a marginal significance of 2.8σ, and the average equivalent width is 2.5 × 10-4 keV. We further demonstrate that the putative feature can be barely affected by the systematic errors from continuum modeling and instrumental effects, or the atomic uncertainties of the neighboring thermal lines. Conclusions: Assuming a realistic temperature and abundance pattern, the physical model implied by the possible oxygen line agrees well with the theoretical model proposed previously to explain the reported 3.5 keV line. If the charge exchange source indeed exists, we expect that the oxygen abundance could have been overestimated by 8-22% in previous X

  6. Modulation of BCR Signaling by the Induced Dimerization of Receptor-Associated SYK

    Directory of Open Access Journals (Sweden)

    Mark L. Westbroek

    2017-12-01

    Full Text Available Clustering of the B cell antigen receptor (BCR by polyvalent antigens is transmitted through the SYK tyrosine kinase to the activation of multiple intracellular pathways that determine the physiological consequences of receptor engagement. To explore factors that modulate the quantity and quality of signals sent by the crosslinked BCR, we developed a novel chemical mediator of dimerization to induce clustering of receptor-associated SYK. To accomplish this, we fused SYK with E. coli dihydrofolate reductase (eDHFR, which binds the small molecule trimethoprim (TMP with high affinity and selectivity and synthesized a dimer of TMP with a flexible linker. The TMP dimer is able to induce the aggregation of eDHFR-linked SYK in live cells. The induced dimerization of SYK bound to the BCR differentially regulates the activation of downstream transcription factors, promoting the activation of Nuclear Factor of Activated T cells (NFAT without affecting the activation of NFκB. The dimerization of SYK enhances the duration but not the amplitude of calcium mobilization by enhancing the extent and duration of its interaction with the crosslinked BCR at the plasma membrane.

  7. Substructure in clusters of galaxies

    International Nuclear Information System (INIS)

    Fitchett, M.J.

    1988-01-01

    Optical observations suggesting the existence of substructure in clusters of galaxies are examined. Models of cluster formation and methods used to detect substructure in clusters are reviewed. Consideration is given to classification schemes based on a departure of bright cluster galaxies from a spherically symmetric distribution, evidence for statistically significant substructure, and various types of substructure, including velocity, spatial, and spatial-velocity substructure. The substructure observed in the galaxy distribution in clusters is discussed, focusing on observations from general cluster samples, the Virgo cluster, the Hydra cluster, Centaurus, the Coma cluster, and the Cancer cluster. 88 refs

  8. Nuclear cluster states

    International Nuclear Information System (INIS)

    Rae, W.D.M.; Merchant, A.C.

    1993-01-01

    We review clustering in light nuclei including molecular resonances in heavy ion reactions. In particular we study the systematics, paying special attention to the relationships between cluster states and superdeformed configurations. We emphasise the selection rules which govern the formation and decay of cluster states. We review some recent experimental results from Daresbury and elsewhere. In particular we report on the evidence for a 7-α chain state in 28 Si in experiments recently performed at the NSF, Daresbury. Finally we begin to address theoretically the important question of the lifetimes of cluster states as deduced from the experimental energy widths of the resonances. (Author)

  9. 15th Cluster workshop

    CERN Document Server

    Laakso, Harri; Escoubet, C. Philippe; The Cluster Active Archive : Studying the Earth’s Space Plasma Environment

    2010-01-01

    Since the year 2000 the ESA Cluster mission has been investigating the small-scale structures and processes of the Earth's plasma environment, such as those involved in the interaction between the solar wind and the magnetospheric plasma, in global magnetotail dynamics, in cross-tail currents, and in the formation and dynamics of the neutral line and of plasmoids. This book contains presentations made at the 15th Cluster workshop held in March 2008. It also presents several articles about the Cluster Active Archive and its datasets, a few overview papers on the Cluster mission, and articles reporting on scientific findings on the solar wind, the magnetosheath, the magnetopause and the magnetotail.

  10. Clusters in simple fluids

    International Nuclear Information System (INIS)

    Sator, N.

    2003-01-01

    This article concerns the correspondence between thermodynamics and the morphology of simple fluids in terms of clusters. Definitions of clusters providing a geometric interpretation of the liquid-gas phase transition are reviewed with an eye to establishing their physical relevance. The author emphasizes their main features and basic hypotheses, and shows how these definitions lead to a recent approach based on self-bound clusters. Although theoretical, this tutorial review is also addressed to readers interested in experimental aspects of clustering in simple fluids

  11. Membrane Trafficking of Death Receptors: Implications on Signalling

    Directory of Open Access Journals (Sweden)

    Wulf Schneider-Brachert

    2013-07-01

    Full Text Available Death receptors were initially recognised as potent inducers of apoptotic cell death and soon ambitious attempts were made to exploit selective ignition of controlled cellular suicide as therapeutic strategy in malignant diseases. However, the complexity of death receptor signalling has increased substantially during recent years. Beyond activation of the apoptotic cascade, involvement in a variety of cellular processes including inflammation, proliferation and immune response was recognised. Mechanistically, these findings raised the question how multipurpose receptors can ensure selective activation of a particular pathway. A growing body of evidence points to an elegant spatiotemporal regulation of composition and assembly of the receptor-associated signalling complex. Upon ligand binding, receptor recruitment in specialized membrane compartments, formation of receptor-ligand clusters and internalisation processes constitute key regulatory elements. In this review, we will summarise the current concepts of death receptor trafficking and its implications on receptor-associated signalling events.

  12. The complex lives of star clusters

    CERN Document Server

    Stevenson, David

    2015-01-01

    As with the author’s recent books Extreme Explosions and Under a Crimson Sun, the complex topic of star clusters is broken down and made accessible with clear links to other areas of astronomy in a language which the non-specialist can easily read and enjoy. The full range of a star cluster's lifespan is depicted, as both globular and open clusters are tracked from birth to eventual death. Why is it some are dense conglomerates of stars while others are looser associations? Are the young, brilliant clusters seen in neighboring galaxies such as the Large Magellanic Cloud, M33 or M82 analogous to the ancient globulars seen in the Milky Way? How will these clusters change as their stars wane and die? More interestingly, how does living in a dense star cluster affect the fates of the stars and any attendant planets that accompany them?   Star clusters form many of the most dazzling objects in the astronomers’ catalogs. Many amateur astronomers are interested in exploring how these objects are created and wh...

  13. Molecular vibration-activity relationship in the agonism of adenosine receptors.

    Science.gov (United States)

    Chee, Hyun Keun; Oh, S June

    2013-12-01

    The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands.

  14. Molecular Vibration-Activity Relationship in the Agonism of Adenosine Receptors

    Directory of Open Access Journals (Sweden)

    Hyun Keun Chee

    2013-12-01

    Full Text Available The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands.

  15. Lifting to cluster-tilting objects in higher cluster categories

    OpenAIRE

    Liu, Pin

    2008-01-01

    In this note, we consider the $d$-cluster-tilted algebras, the endomorphism algebras of $d$-cluster-tilting objects in $d$-cluster categories. We show that a tilting module over such an algebra lifts to a $d$-cluster-tilting object in this $d$-cluster category.

  16. Andrographolide regulates epidermal growth factor receptor and transferrin receptor trafficking in epidermoid carcinoma (A-431) cells

    Science.gov (United States)

    Tan, Y; Chiow, KH; Huang, D; Wong, SH

    2010-01-01

    Background and purpose: Andrographolide is the active component of Andrographis paniculata, a plant used in both Indian and Chinese traditional medicine, and it has been demonstrated to induce apoptosis in different cancer cell lines. However, not much is known about how it may affect the key receptors implicated in cancer. Knowledge of how andrographolide affects receptor trafficking will allow us to better understand new mechanisms by which andrographolide may cause death in cancer cells. Experimental approach: We utilized the well-characterized epidermal growth factor receptor (EGFR) and transferrin receptor (TfR) expressed in epidermoid carcinoma (A-431) cells as a model to study the effect of andrographolide on receptor trafficking. Receptor distribution, the total number of receptors and surface receptors were analysed by immunofluorescence, Western blot as well as flow-cytometry respectively. Key results: Andrographolide treatment inhibited cell growth, down-regulated EGFRs on the cell surface and affected the degradation of EGFRs and TfRs. The EGFR was internalized into the cell at an increased rate, and accumulated in a compartment that co-localizes with the lysosomal-associated membrane protein in the late endosomes. Conclusion and implications: This study sheds light on how andrographolide may affect receptor trafficking by inhibiting receptor movement from the late endosomes to lysosomes. The down-regulation of EGFR from the cell surface also indicates a new mechanism by which andrographolide may induce cancer cell death. PMID:20233216

  17. Genetics Home Reference: myopathy with deficiency of iron-sulfur cluster assembly enzyme

    Science.gov (United States)

    ... Myopathy with deficiency of iron-sulfur cluster assembly enzyme Printable PDF Open All Close All Enable Javascript ... Myopathy with deficiency of iron-sulfur cluster assembly enzyme is an inherited disorder that primarily affects muscles ...

  18. Childhood asthma clusters and response to therapy in clinical trials.

    Science.gov (United States)

    Chang, Timothy S; Lemanske, Robert F; Mauger, David T; Fitzpatrick, Anne M; Sorkness, Christine A; Szefler, Stanley J; Gangnon, Ronald E; Page, C David; Jackson, Daniel J

    2014-02-01

    Childhood asthma clusters, or subclasses, have been developed by computational methods without evaluation of clinical utility. To replicate and determine whether childhood asthma clusters previously identified computationally in the Severe Asthma Research Program (SARP) are associated with treatment responses in Childhood Asthma Research and Education (CARE) Network clinical trials. A cluster assignment model was determined by using SARP participant data. A total of 611 participants 6 to 18 years old from 3 CARE trials were assigned to SARP pediatric clusters. Primary and secondary outcomes were analyzed by cluster in each trial. CARE participants were assigned to SARP clusters with high accuracy. Baseline characteristics were similar between SARP and CARE children of the same cluster. Treatment response in CARE trials was generally similar across clusters. However, with the caveat of a smaller sample size, children in the early-onset/severe-lung function cluster had best response with fluticasone/salmeterol (64% vs 23% 2.5× fluticasone and 13% fluticasone/montelukast in the Best ADd-on Therapy Giving Effective Responses trial; P = .011) and children in the early-onset/comorbidity cluster had the least clinical efficacy to treatments (eg, -0.076% change in FEV1 in the Characterizing Response to Leukotriene Receptor Antagonist and Inhaled Corticosteroid trial). In this study, we replicated SARP pediatric asthma clusters by using a separate, large clinical trials network. Early-onset/severe-lung function and early-onset/comorbidity clusters were associated with differential and limited response to therapy, respectively. Further prospective study of therapeutic response by cluster could provide new insights into childhood asthma treatment. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  19. Failure of lysosome clustering and positioning in the juxtanuclear region in cells deficient in rapsyn

    Science.gov (United States)

    Aittaleb, Mohamed; Chen, Po-Ju; Akaaboune, Mohammed

    2015-01-01

    ABSTRACT Rapsyn, a scaffold protein, is required for the clustering of acetylcholine receptors (AChRs) at contacts between motor neurons and differentiating muscle cells. Rapsyn is also expressed in cells that do not express AChRs. However, its function in these cells remains unknown. Here, we show that rapsyn plays an AChR-independent role in organizing the distribution and mobility of lysosomes. In cells devoid of AChRs, rapsyn selectively induces the clustering of lysosomes at high density in the juxtanuclear region without affecting the distribution of other intracellular organelles. However, when the same cells overexpress AChRs, rapsyn is recruited away from lysosomes to colocalize with AChR clusters on the cell surface. In rapsyn-deficient (Rapsn−/−) myoblasts or cells overexpressing rapsyn mutants, lysosomes are scattered within the cell and highly dynamic. The increased mobility of lysosomes in Rapsn−/− cells is associated with a significant increase in lysosomal exocytosis, as evidenced by increased release of lysosomal enzymes and plasma membrane damage when cells were challenged with the bacterial pore-forming toxin streptolysin-O. These findings uncover a new link between rapsyn, lysosome positioning, exocytosis and plasma membrane integrity. PMID:26330529

  20. Neurostimulation in cluster headache

    DEFF Research Database (Denmark)

    Pedersen, Jeppe L; Barloese, Mads; Jensen, Rigmor H

    2013-01-01

    PURPOSE OF REVIEW: Neurostimulation has emerged as a viable treatment for intractable chronic cluster headache. Several therapeutic strategies are being investigated including stimulation of the hypothalamus, occipital nerves and sphenopalatine ganglion. The aim of this review is to provide...... effective strategy must be preferred as first-line therapy for intractable chronic cluster headache....

  1. Cauchy cluster process

    DEFF Research Database (Denmark)

    Ghorbani, Mohammad

    2013-01-01

    In this paper we introduce an instance of the well-know Neyman–Scott cluster process model with clusters having a long tail behaviour. In our model the offspring points are distributed around the parent points according to a circular Cauchy distribution. Using a modified Cramér-von Misses test...

  2. When Clusters become Networks

    NARCIS (Netherlands)

    S.M.W. Phlippen (Sandra); G.A. van der Knaap (Bert)

    2007-01-01

    textabstractPolicy makers spend large amounts of public resources on the foundation of science parks and other forms of geographically clustered business activities, in order to stimulate regional innovation. Underlying the relation between clusters and innovation is the assumption that co-located

  3. Mixed-Initiative Clustering

    Science.gov (United States)

    Huang, Yifen

    2010-01-01

    Mixed-initiative clustering is a task where a user and a machine work collaboratively to analyze a large set of documents. We hypothesize that a user and a machine can both learn better clustering models through enriched communication and interactive learning from each other. The first contribution or this thesis is providing a framework of…

  4. Coma cluster of galaxies

    Science.gov (United States)

    1999-01-01

    Atlas Image mosaic, covering 34' x 34' on the sky, of the Coma cluster, aka Abell 1656. This is a particularly rich cluster of individual galaxies (over 1000 members), most prominently the two giant ellipticals, NGC 4874 (right) and NGC 4889 (left). The remaining members are mostly smaller ellipticals, but spiral galaxies are also evident in the 2MASS image. The cluster is seen toward the constellation Coma Berenices, but is actually at a distance of about 100 Mpc (330 million light years, or a redshift of 0.023) from us. At this distance, the cluster is in what is known as the 'Hubble flow,' or the overall expansion of the Universe. As such, astronomers can measure the Hubble Constant, or the universal expansion rate, based on the distance to this cluster. Large, rich clusters, such as Coma, allow astronomers to measure the 'missing mass,' i.e., the matter in the cluster that we cannot see, since it gravitationally influences the motions of the member galaxies within the cluster. The near-infrared maps the overall luminous mass content of the member galaxies, since the light at these wavelengths is dominated by the more numerous older stellar populations. Galaxies, as seen by 2MASS, look fairly smooth and homogeneous, as can be seen from the Hubble 'tuning fork' diagram of near-infrared galaxy morphology. Image mosaic by S. Van Dyk (IPAC).

  5. Cluster growth kinetics

    International Nuclear Information System (INIS)

    Dubovik, V.M.; Gal'perin, A.G.; Rikhvitskij, V.S.; Lushnikov, A.A.

    2000-01-01

    Processes of some traffic blocking coming into existence are considered as probabilistic ones. We study analytic solutions for models for the dynamics of both cluster growth and cluster growth with fragmentation in the systems of finite number of objects. Assuming rates constancy of both coalescence and fragmentation, the models under consideration are linear on the probability functions

  6. Alpha clustering in nuclei

    International Nuclear Information System (INIS)

    Hodgson, P.E.

    1990-01-01

    The effects of nucleon clustering in nuclei are described, with reference to both nuclear structure and nuclear reactions, and the advantages of using the cluster formalism to describe a range of phenomena are discussed. It is shown that bound and scattering alpha-particle states can be described in a unified way using an energy-dependent alpha-nucleus potential. (author)

  7. Microarray-Based Determination of Estrogen Receptor, Progesterone Receptor, and HER2 Receptor Status in Breast Cancer

    NARCIS (Netherlands)

    Roepman, Paul; Horlings, Hugo M.; Krijgsman, Oscar; Kok, Marleen; Bueno-de-Mesquita, Jolien M.; Bender, Richard; Linn, Sabine C.; Glas, Annuska M.; van de Vijver, Marc J.

    2009-01-01

    Purpose: The level of estrogen receptor (ER), progesterone receptor (PR), and HER2 aids in the determination of prognosis and treatment of breast cancer. Immunohistochemistry is currently the predominant method for assessment, but differences in methods and interpretation can substantially affect

  8. Negotiating Cluster Boundaries

    DEFF Research Database (Denmark)

    Giacomin, Valeria

    2017-01-01

    Palm oil was introduced to Malay(si)a as an alternative to natural rubber, inheriting its cluster organizational structure. In the late 1960s, Malaysia became the world’s largest palm oil exporter. Based on archival material from British colonial institutions and agency houses, this paper focuses...... on the governance dynamics that drove institutional change within this cluster during decolonization. The analysis presents three main findings: (i) cluster boundaries are defined by continuous tug-of-war style negotiations between public and private actors; (ii) this interaction produces institutional change...... within the cluster, in the form of cumulative ‘institutional rounds’ – the correction or disruption of existing institutions or the creation of new ones; and (iii) this process leads to a broader inclusion of local actors in the original cluster configuration. The paper challenges the prevalent argument...

  9. Mathematical classification and clustering

    CERN Document Server

    Mirkin, Boris

    1996-01-01

    I am very happy to have this opportunity to present the work of Boris Mirkin, a distinguished Russian scholar in the areas of data analysis and decision making methodologies. The monograph is devoted entirely to clustering, a discipline dispersed through many theoretical and application areas, from mathematical statistics and combina­ torial optimization to biology, sociology and organizational structures. It compiles an immense amount of research done to date, including many original Russian de­ velopments never presented to the international community before (for instance, cluster-by-cluster versions of the K-Means method in Chapter 4 or uniform par­ titioning in Chapter 5). The author's approach, approximation clustering, allows him both to systematize a great part of the discipline and to develop many in­ novative methods in the framework of optimization problems. The optimization methods considered are proved to be meaningful in the contexts of data analysis and clustering. The material presented in ...

  10. Neutrosophic Hierarchical Clustering Algoritms

    Directory of Open Access Journals (Sweden)

    Rıdvan Şahin

    2014-03-01

    Full Text Available Interval neutrosophic set (INS is a generalization of interval valued intuitionistic fuzzy set (IVIFS, whose the membership and non-membership values of elements consist of fuzzy range, while single valued neutrosophic set (SVNS is regarded as extension of intuitionistic fuzzy set (IFS. In this paper, we extend the hierarchical clustering techniques proposed for IFSs and IVIFSs to SVNSs and INSs respectively. Based on the traditional hierarchical clustering procedure, the single valued neutrosophic aggregation operator, and the basic distance measures between SVNSs, we define a single valued neutrosophic hierarchical clustering algorithm for clustering SVNSs. Then we extend the algorithm to classify an interval neutrosophic data. Finally, we present some numerical examples in order to show the effectiveness and availability of the developed clustering algorithms.

  11. Stargazin Modulation of AMPA Receptors

    Directory of Open Access Journals (Sweden)

    Sana A. Shaikh

    2016-10-01

    Full Text Available Fast excitatory synaptic signaling in the mammalian brain is mediated by AMPA-type ionotropic glutamate receptors. In neurons, AMPA receptors co-assemble with auxiliary proteins, such as stargazin, which can markedly alter receptor trafficking and gating. Here, we used luminescence resonance energy transfer measurements to map distances between the full-length, functional AMPA receptor and stargazin expressed in HEK293 cells and to determine the ensemble structural changes in the receptor due to stargazin. In addition, we used single-molecule fluorescence resonance energy transfer to study the structural and conformational distribution of the receptor and how this distribution is affected by stargazin. Our nanopositioning data place stargazin below the AMPA receptor ligand-binding domain, where it is well poised to act as a scaffold to facilitate the long-range conformational selection observations seen in single-molecule experiments. These data support a model of stargazin acting to stabilize or select conformational states that favor activation.

  12. OX1 and OX2 orexin/hypocretin receptor pharmacogenetics

    Directory of Open Access Journals (Sweden)

    Miles Douglas Thompson

    2014-05-01

    Full Text Available Orexin/hypocretin peptide mutations are rare in humans. Even though human narcolepsy is associated with orexin deficiency, this is only extremely rarely due to mutations in the gene coding prepro-orexin, the precursor for both orexin peptides. In contrast, coding and non-coding variants of the OX1 and OX2 orexin receptors have been identified in many human populations; sometimes, these have been associated with disease phenotype, although most confer a relatively low risk. In most cases, these studies have been based on a candidate gene hypothesis that predicts involvement of orexins in the relevant pathophysiological processes. In the current review, the known human OX1/HCRTR1 and OX2/HCRTR2 genetic variants/polymorphisms as well as studies concerning their involvement in disorders such as narcolepsy, excessive daytime sleepiness, cluster headache, polydipsia-hyponatremia in schizophrenia, and affective disorders are presented. In most cases, the functional cellular or pharmacological correlates of orexin variants have not been investigated  with the exception of the possible impact of an amino acid 10 Pro/Ser variant of OX2 on orexin potency  leaving conclusions on the nature of the receptor variant effects speculative. Nevertheless, we present perspectives that could shape the basis for further studies. The pharmacology and other properties of the orexin receptor variants are discussed in the context of GPCR signaling. Since orexinergic therapeutics are emerging, the impact of receptor variants on the affinity or potency of ligands deserves consideration. This perspective (pharmacogenetics is also discussed in the review.

  13. Herd Clustering: A synergistic data clustering approach using collective intelligence

    KAUST Repository

    Wong, Kachun; Peng, Chengbin; Li, Yue; Chan, Takming

    2014-01-01

    , this principle is used to develop a new clustering algorithm. Inspired by herd behavior, the clustering method is a synergistic approach using collective intelligence called Herd Clustering (HC). The novel part is laid in its first stage where data instances

  14. The selective antagonism of P2X7 and P2Y1 receptors prevents synaptic failure and affects cell proliferation induced by oxygen and glucose deprivation in rat dentate gyrus.

    Directory of Open Access Journals (Sweden)

    Giovanna Maraula

    Full Text Available Purinergic P2X and P2Y receptors are broadly expressed on both neurons and glial cells in the central nervous system (CNS, including dentate gyrus (DG. The aim of this research was to determine the synaptic and proliferative response of the DG to severe oxygen and glucose deprivation (OGD in acute rat hippocampal slices and to investigate the contribution of P2X7 and P2Y1 receptor antagonism to recovery of synaptic activity after OGD. Extracellular field excitatory post-synaptic potentials (fEPSPs in granule cells of the DG were recorded from rat hippocampal slices. Nine-min OGD elicited an irreversible loss of fEPSP and was invariably followed by the appearance of anoxic depolarization (AD. Application of MRS2179 (selective antagonist of P2Y1 receptor and BBG (selective antagonist of P2X7 receptor, before and during OGD, prevented AD appearance and allowed a significant recovery of neurotransmission after 9-min OGD. The effects of 9-min OGD on proliferation and maturation of cells localized in the subgranular zone (SGZ of slices prepared from rats treated with 5-Bromo-2'-deoxyuridine (BrdU were investigated. Slices were further incubated with an immature neuron marker, doublecortin (DCX. The number of BrdU+ cells in the SGZ was significantly decreased 6 hours after OGD. This effect was antagonized by BBG, but not by MRS2179. Twenty-four hours after 9-min OGD, the number of BrdU+ cells returned to control values and a significant increase of DCX immunofluorescence was observed. This phenomenon was still evident when BBG, but not MRS2179, was applied during OGD. Furthermore, the P2Y1 antagonist reduced the number of BrdU+ cells at this time. The data demonstrate that P2X7 and P2Y1 activation contributes to early damage induced by OGD in the DG. At later stages after the insult, P2Y1 receptors might play an additional and different role in promoting cell proliferation and maturation in the DG.

  15. Document clustering methods, document cluster label disambiguation methods, document clustering apparatuses, and articles of manufacture

    Science.gov (United States)

    Sanfilippo, Antonio [Richland, WA; Calapristi, Augustin J [West Richland, WA; Crow, Vernon L [Richland, WA; Hetzler, Elizabeth G [Kennewick, WA; Turner, Alan E [Kennewick, WA

    2009-12-22

    Document clustering methods, document cluster label disambiguation methods, document clustering apparatuses, and articles of manufacture are described. In one aspect, a document clustering method includes providing a document set comprising a plurality of documents, providing a cluster comprising a subset of the documents of the document set, using a plurality of terms of the documents, providing a cluster label indicative of subject matter content of the documents of the cluster, wherein the cluster label comprises a plurality of word senses, and selecting one of the word senses of the cluster label.

  16. Cluster-cluster correlations and constraints on the correlation hierarchy

    Science.gov (United States)

    Hamilton, A. J. S.; Gott, J. R., III

    1988-01-01

    The hypothesis that galaxies cluster around clusters at least as strongly as they cluster around galaxies imposes constraints on the hierarchy of correlation amplitudes in hierachical clustering models. The distributions which saturate these constraints are the Rayleigh-Levy random walk fractals proposed by Mandelbrot; for these fractal distributions cluster-cluster correlations are all identically equal to galaxy-galaxy correlations. If correlation amplitudes exceed the constraints, as is observed, then cluster-cluster correlations must exceed galaxy-galaxy correlations, as is observed.

  17. Formation of stable products from cluster-cluster collisions

    International Nuclear Information System (INIS)

    Alamanova, Denitsa; Grigoryan, Valeri G; Springborg, Michael

    2007-01-01

    The formation of stable products from copper cluster-cluster collisions is investigated by using classical molecular-dynamics simulations in combination with an embedded-atom potential. The dependence of the product clusters on impact energy, relative orientation of the clusters, and size of the clusters is studied. The structures and total energies of the product clusters are analysed and compared with those of the colliding clusters before impact. These results, together with the internal temperature, are used in obtaining an increased understanding of cluster fusion processes

  18. Simulating star clusters with the AMUSE software framework. I. Dependence of cluster lifetimes on model assumptions and cluster dissolution modes

    International Nuclear Information System (INIS)

    Whitehead, Alfred J.; McMillan, Stephen L. W.; Vesperini, Enrico; Portegies Zwart, Simon

    2013-01-01

    We perform a series of simulations of evolving star clusters using the Astrophysical Multipurpose Software Environment (AMUSE), a new community-based multi-physics simulation package, and compare our results to existing work. These simulations model a star cluster beginning with a King model distribution and a selection of power-law initial mass functions and contain a tidal cutoff. They are evolved using collisional stellar dynamics and include mass loss due to stellar evolution. After studying and understanding that the differences between AMUSE results and results from previous studies are understood, we explored the variation in cluster lifetimes due to the random realization noise introduced by transforming a King model to specific initial conditions. This random realization noise can affect the lifetime of a simulated star cluster by up to 30%. Two modes of star cluster dissolution were identified: a mass evolution curve that contains a runaway cluster dissolution with a sudden loss of mass, and a dissolution mode that does not contain this feature. We refer to these dissolution modes as 'dynamical' and 'relaxation' dominated, respectively. For Salpeter-like initial mass functions, we determined the boundary between these two modes in terms of the dynamical and relaxation timescales.

  19. Tune Your Brown Clustering, Please

    DEFF Research Database (Denmark)

    Derczynski, Leon; Chester, Sean; Bøgh, Kenneth Sejdenfaden

    2015-01-01

    Brown clustering, an unsupervised hierarchical clustering technique based on ngram mutual information, has proven useful in many NLP applications. However, most uses of Brown clustering employ the same default configuration; the appropriateness of this configuration has gone predominantly...

  20. Cluster Management Institutionalization

    DEFF Research Database (Denmark)

    Normann, Leo; Agger Nielsen, Jeppe

    2015-01-01

    of how it was legitimized as a “ready-to-use” management model. Further, our account reveals how cluster management translated into considerably different local variants as it travelled into specific organizations. However, these processes have not occurred sequentially with cluster management first...... legitimized at the field level, then spread, and finally translated into action in the adopting organizations. Instead, we observed entangled field and organizational-level processes. Accordingly, we argue that cluster management institutionalization is most readily understood by simultaneously investigating...

  1. The concept of cluster

    DEFF Research Database (Denmark)

    Laursen, Lea Louise Holst; Møller, Jørgen

    2013-01-01

    villages in order to secure their future. This paper will address the concept of cluster-villages as a possible approach to strengthen the conditions of contemporary Danish villages. Cluster-villages is a concept that gather a number of villages in a network-structure where the villages both work together...... to forskellige positioner ser vi en ny mulighed for landsbyudvikling, som vi kalder Clustervillages. In order to investigate the potentials and possibilities of the cluster-village concept the paper will seek to unfold the concept strategically; looking into the benefits of such concept. Further, the paper seeks...

  2. Raspberry Pi super cluster

    CERN Document Server

    Dennis, Andrew K

    2013-01-01

    This book follows a step-by-step, tutorial-based approach which will teach you how to develop your own super cluster using Raspberry Pi computers quickly and efficiently.Raspberry Pi Super Cluster is an introductory guide for those interested in experimenting with parallel computing at home. Aimed at Raspberry Pi enthusiasts, this book is a primer for getting your first cluster up and running.Basic knowledge of C or Java would be helpful but no prior knowledge of parallel computing is necessary.

  3. Introduction to cluster dynamics

    CERN Document Server

    Reinhard, Paul-Gerhard

    2008-01-01

    Clusters as mesoscopic particles represent an intermediate state of matter between single atoms and solid material. The tendency to miniaturise technical objects requires knowledge about systems which contain a ""small"" number of atoms or molecules only. This is all the more true for dynamical aspects, particularly in relation to the qick development of laser technology and femtosecond spectroscopy. Here, for the first time is a highly qualitative introduction to cluster physics. With its emphasis on cluster dynamics, this will be vital to everyone involved in this interdisciplinary subje

  4. Contextualizing the Cluster

    DEFF Research Database (Denmark)

    Giacomin, Valeria

    This dissertation examines the case of the palm oil cluster in Malaysia and Indonesia, today one of the largest agricultural clusters in the world. My analysis focuses on the evolution of the cluster from the 1880s to the 1970s in order to understand how it helped these two countries to integrate...... into the global economy in both colonial and post-colonial times. The study is based on empirical material drawn from five UK archives and background research using secondary sources, interviews, and archive visits to Malaysia and Singapore. The dissertation comprises three articles, each discussing a major under...

  5. Atomic cluster collisions

    Science.gov (United States)

    Korol, Andrey V.; Solov'yov, Andrey

    2013-01-01

    Atomic cluster collisions are a field of rapidly emerging research interest by both experimentalists and theorists. The international symposium on atomic cluster collisions (ISSAC) is the premier forum to present cutting-edge research in this field. It was established in 2003 and the most recent conference was held in Berlin, Germany in July of 2011. This Topical Issue presents original research results from some of the participants, who attended this conference. This issues specifically focuses on two research areas, namely Clusters and Fullerenes in External Fields and Nanoscale Insights in Radiation Biodamage.

  6. Combining cluster number counts and galaxy clustering

    Energy Technology Data Exchange (ETDEWEB)

    Lacasa, Fabien; Rosenfeld, Rogerio, E-mail: fabien@ift.unesp.br, E-mail: rosenfel@ift.unesp.br [ICTP South American Institute for Fundamental Research, Instituto de Física Teórica, Universidade Estadual Paulista, São Paulo (Brazil)

    2016-08-01

    The abundance of clusters and the clustering of galaxies are two of the important cosmological probes for current and future large scale surveys of galaxies, such as the Dark Energy Survey. In order to combine them one has to account for the fact that they are not independent quantities, since they probe the same density field. It is important to develop a good understanding of their correlation in order to extract parameter constraints. We present a detailed modelling of the joint covariance matrix between cluster number counts and the galaxy angular power spectrum. We employ the framework of the halo model complemented by a Halo Occupation Distribution model (HOD). We demonstrate the importance of accounting for non-Gaussianity to produce accurate covariance predictions. Indeed, we show that the non-Gaussian covariance becomes dominant at small scales, low redshifts or high cluster masses. We discuss in particular the case of the super-sample covariance (SSC), including the effects of galaxy shot-noise, halo second order bias and non-local bias. We demonstrate that the SSC obeys mathematical inequalities and positivity. Using the joint covariance matrix and a Fisher matrix methodology, we examine the prospects of combining these two probes to constrain cosmological and HOD parameters. We find that the combination indeed results in noticeably better constraints, with improvements of order 20% on cosmological parameters compared to the best single probe, and even greater improvement on HOD parameters, with reduction of error bars by a factor 1.4-4.8. This happens in particular because the cross-covariance introduces a synergy between the probes on small scales. We conclude that accounting for non-Gaussian effects is required for the joint analysis of these observables in galaxy surveys.

  7. Low-energy irradiation effects of gas cluster ion beams

    International Nuclear Information System (INIS)

    Houzumi, Shingo; Takeshima, Keigo; Mochiji, Kozo; Toyoda, Noriaki; Yamada, Isao

    2007-01-01

    A cluster-ion irradiation system with cluster-size selection has been developed to study the effects of the cluster size for surface processes using cluster ions. A permanent magnet with a magnetic field of 1.2 T is installed for size separation of large cluster ions. Trace formations at HOPG surface by the irradiation with size-selected Ar-cluster ions under acceleration energy of 30 keV were investigated by a scanning tunneling microscopy. Generation behavior of the crater-like traces is strongly affected by the number of constituent atoms (cluster size) of the irradiating cluster ion. When the incident cluster ion is composed of 100-3000 atoms, crater-like traces are observed on the irradiated surfaces. In contrast, such traces are not observed at all with the irradiation of the cluster-ions composed of over 5000 atoms. Such the behavior is discussed on the basis of the kinetic energy per constituent atom of the cluster ion. To study GCIB irradiation effects against macromolecule, GCIB was irradiated on DNA molecules absorbed on graphite surface. By the GCIB irradiation, much more DNA molecules was sputtered away as compared with the monomer-ion irradiation. (author)

  8. Lipid raft localization of TLR2 and its co-receptors is independent of membrane lipid composition

    Directory of Open Access Journals (Sweden)

    Christine Hellwing

    2018-01-01

    Full Text Available Background Toll like receptors (TLRs are an important and evolutionary conserved class of pattern recognition receptors associated with innate immunity. The recognition of Gram-positive cell wall constituents strongly depends on TLR2. In order to be functional, TLR2 predominantly forms a heterodimer with TLR1 or TLR6 within specialized membrane microdomains, the lipid rafts. The membrane lipid composition and the physicochemical properties of lipid rafts are subject to modification by exogenous fatty acids. Previous investigations of our group provide evidence that macrophage enrichment with polyunsaturated fatty acids (PUFA induces a reordering of lipid rafts and non-rafts based on the incorporation of supplemented PUFA as well as their elongation and desaturation products. Methods In the present study we investigated potential constraining effects of membrane microdomain reorganization on the clustering of TLR2 with its co-receptors TLR1 and TLR6 within lipid rafts. To this end, RAW264.7 macrophages were supplemented with either docosahexaenoic acid (DHA or arachidonic acid (AA and analyzed for receptor expression and microdomain localization in context of TLR stimulation. Results and Conclusions Our analyses showed that receptor levels and microdomain localization were unchanged by PUFA supplementation. The TLR2 pathway, in contrast to the TLR4 signaling cascade, is not affected by exogenous PUFA at the membrane level.

  9. The insecticide fipronil and its metabolite fipronil sulphone inhibit the rat α1β2γ2L GABAA receptor

    Science.gov (United States)

    Li, P; Akk, G

    2008-01-01

    Background and purpose: Fipronil is the active ingredient in a number of widely used insecticides. Human exposure to fipronil leads to symptoms (headache, nausea and seizures) typically associated with the antagonism of GABAA receptors in the brain. In this study, we have examined the modulation of the common brain GABAA receptor subtype by fipronil and its major metabolite, fipronil sulphone. Experimental approach: Whole-cell and single-channel recordings were made from HEK 293 cells transiently expressing rat α1β2γ2L GABAA receptors. Key results: The major effect of fipronil was to increase the rate of current decay in macroscopic recordings. In single-channel recordings, the presence of fipronil resulted in shorter cluster durations without affecting the intracluster open and closed time distributions or the single-channel conductance. The α1V256S mutation, previously shown alleviate channel inhibition by inhibitory steroids and several insecticides, had a relatively small effect on channel block by fipronil. The mode of action of fipronil sulphone was similar to that of its parent compound but the metabolite was less potent at inhibiting the α1β2γ2L receptor. Conclusions and implications: We conclude that exposure to fipronil induces accumulation of receptors in a novel, long-lived blocked state. This process proceeds in parallel with and independently of, channel desensitization. The lower potency of fipronil sulphone indicates that the conversion serves as a detoxifying process in mammalian brain. PMID:18660823

  10. Metal cluster compounds - chemistry and importance; clusters containing isolated main group element atoms, large metal cluster compounds, cluster fluxionality

    International Nuclear Information System (INIS)

    Walther, B.

    1988-01-01

    This part of the review on metal cluster compounds deals with clusters containing isolated main group element atoms, with high nuclearity clusters and metal cluster fluxionality. It will be obvious that main group element atoms strongly influence the geometry, stability and reactivity of the clusters. High nuclearity clusters are of interest in there own due to the diversity of the structures adopted, but their intermediate position between molecules and the metallic state makes them a fascinating research object too. These both sites of the metal cluster chemistry as well as the frequently observed ligand and core fluxionality are related to the cluster metal and surface analogy. (author)

  11. Disentangling Porterian Clusters

    DEFF Research Database (Denmark)

    Jagtfelt, Tue

    , contested theory become so widely disseminated and applied as a normative and prescriptive strategy for economic development? The dissertation traces the introduction of the cluster notion into the EU’s Lisbon Strategy and demonstrates how its inclusion originates from Porter’s colleagues: Professor Örjan...... to his membership on the Commission on Industrial Competitiveness, and that the cluster notion found in his influential book, Nations, represents a significant shift in his conception of cluster compared with his early conceptions. This shift, it is argued, is a deliberate attempt by Porter to create...... a paradigmatic textbook that follows Kuhn’s blueprint for scientific revolutions by instilling Nations with circular references and thus creating a local linguistic holism conceptualized through an encompassing notion of cluster. The dissertation concludes that the two research questions are philosophically...

  12. Remarks on stellar clusters

    International Nuclear Information System (INIS)

    Teller, E.

    1985-01-01

    In the following, a few simple remarks on the evolution and properties of stellar clusters will be collected. In particular, globular clusters will be considered. Though details of such clusters are often not known, a few questions can be clarified with the help of primitive arguments. These are:- why are spherical clusters spherical, why do they have high densities, why do they consist of approximately a million stars, how may a black hole of great mass form within them, may they be the origin of gamma-ray bursts, may their invisible remnants account for the missing mass of our galaxy. The available data do not warrant a detailed evaluation. However, it is remarkable that exceedingly simple models can shed some light on the questions enumerated above. (author)

  13. From collisions to clusters

    DEFF Research Database (Denmark)

    Loukonen, Ville; Bork, Nicolai; Vehkamaki, Hanna

    2014-01-01

    -principles molecular dynamics collision simulations of (sulphuric acid)1(water)0, 1 + (dimethylamine) → (sulphuric acid)1(dimethylamine)1(water)0, 1 cluster formation processes. The simulations indicate that the sticking factor in the collisions is unity: the interaction between the molecules is strong enough...... control. As a consequence, the clusters show very dynamic ion pair structure, which differs from both the static structure optimisation calculations and the equilibrium first-principles molecular dynamics simulations. In some of the simulation runs, water mediates the proton transfer by acting as a proton...... to overcome the possible initial non-optimal collision orientations. No post-collisional cluster break up is observed. The reasons for the efficient clustering are (i) the proton transfer reaction which takes place in each of the collision simulations and (ii) the subsequent competition over the proton...

  14. Clustering of Emerging Flux

    Science.gov (United States)

    Ruzmaikin, A.

    1997-01-01

    Observations show that newly emerging flux tends to appear on the Solar surface at sites where there is flux already. This results in clustering of solar activity. Standard dynamo theories do not predict this effect.

  15. How Clusters Work

    Science.gov (United States)

    Technology innovation clusters are geographic concentrations of interconnected companies, universities, and other organizations with a focus on environmental technology. They play a key role in addressing the nation’s pressing environmental problems.

  16. Evolution of clustered storage

    CERN Multimedia

    CERN. Geneva; Van de Vyvre, Pierre

    2007-01-01

    The session actually featured two presentations: * Evolution of clustered storage by Lance Hukill, Quantum Corporation * ALICE DAQ - Usage of a Cluster-File System: Quantum StorNext by Pierre Vande Vyvre, CERN-PH the second one prepared at short notice by Pierre (thanks!) to present how the Quantum technologies are being used in the ALICE experiment. The abstract to Mr Hukill's follows. Clustered Storage is a technology that is driven by business and mission applications. The evolution of Clustered Storage solutions starts first at the alignment between End-users needs and Industry trends: * Push-and-Pull between managing for today versus planning for tomorrow * Breaking down the real business problems to the core applications * Commoditization of clients, servers, and target devices * Interchangeability, Interoperability, Remote Access, Centralized control * Oh, and yes, there is a budget and the "real world" to deal with This presentation will talk through these needs and trends, and then ask the question, ...

  17. Galaxy clusters and cosmology

    CERN Document Server

    White, S

    1994-01-01

    Galaxy clusters are the largest coherent objects in Universe. It has been known since 1933 that their dynamical properties require either a modification of the theory of gravity, or the presence of a dominant component of unseen material of unknown nature. Clusters still provide the best laboratories for studying the amount and distribution of this dark matter relative to the material which can be observed directly -- the galaxies themselves and the hot,X-ray-emitting gas which lies between them.Imaging and spectroscopy of clusters by satellite-borne X -ray telescopes has greatly improved our knowledge of the structure and composition of this intergalactic medium. The results permit a number of new approaches to some fundamental cosmological questions,but current indications from the data are contradictory. The observed irregularity of real clusters seems to imply recent formation epochs which would require a universe with approximately the critical density. On the other hand, the large baryon fraction observ...

  18. Applications of Clustering

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Applications of Clustering. Biology – medical imaging, bioinformatics, ecology, phylogenies problems etc. Market research. Data Mining. Social Networks. Any problem measuring similarity/correlation. (dimensions represent different parameters)

  19. Clustering Game Behavior Data

    DEFF Research Database (Denmark)

    Bauckhage, C.; Drachen, Anders; Sifa, Rafet

    2015-01-01

    of the causes, the proliferation of behavioral data poses the problem of how to derive insights therefrom. Behavioral data sets can be large, time-dependent and high-dimensional. Clustering offers a way to explore such data and to discover patterns that can reduce the overall complexity of the data. Clustering...... and other techniques for player profiling and play style analysis have, therefore, become popular in the nascent field of game analytics. However, the proper use of clustering techniques requires expertise and an understanding of games is essential to evaluate results. With this paper, we address game data...... scientists and present a review and tutorial focusing on the application of clustering techniques to mine behavioral game data. Several algorithms are reviewed and examples of their application shown. Key topics such as feature normalization are discussed and open problems in the context of game analytics...

  20. Clustering on Membranes

    DEFF Research Database (Denmark)

    Johannes, Ludger; Pezeshkian, Weria; Ipsen, John H

    2018-01-01

    Clustering of extracellular ligands and proteins on the plasma membrane is required to perform specific cellular functions, such as signaling and endocytosis. Attractive forces that originate in perturbations of the membrane's physical properties contribute to this clustering, in addition to direct...... protein-protein interactions. However, these membrane-mediated forces have not all been equally considered, despite their importance. In this review, we describe how line tension, lipid depletion, and membrane curvature contribute to membrane-mediated clustering. Additional attractive forces that arise...... from protein-induced perturbation of a membrane's fluctuations are also described. This review aims to provide a survey of the current understanding of membrane-mediated clustering and how this supports precise biological functions....

  1. Air void clustering.

    Science.gov (United States)

    2015-06-01

    Air void clustering around coarse aggregate in concrete has been identified as a potential source of : low strengths in concrete mixes by several Departments of Transportation around the country. Research was : carried out to (1) develop a quantitati...

  2. Speaker segmentation and clustering

    OpenAIRE

    Kotti, M; Moschou, V; Kotropoulos, C

    2008-01-01

    07.08.13 KB. Ok to add the accepted version to Spiral, Elsevier says ok whlile mandate not enforced. This survey focuses on two challenging speech processing topics, namely: speaker segmentation and speaker clustering. Speaker segmentation aims at finding speaker change points in an audio stream, whereas speaker clustering aims at grouping speech segments based on speaker characteristics. Model-based, metric-based, and hybrid speaker segmentation algorithms are reviewed. Concerning speaker...

  3. Fermion cluster algorithms

    International Nuclear Information System (INIS)

    Chandrasekharan, Shailesh

    2000-01-01

    Cluster algorithms have been recently used to eliminate sign problems that plague Monte-Carlo methods in a variety of systems. In particular such algorithms can also be used to solve sign problems associated with the permutation of fermion world lines. This solution leads to the possibility of designing fermion cluster algorithms in certain cases. Using the example of free non-relativistic fermions we discuss the ideas underlying the algorithm

  4. BUILDING e-CLUSTERS

    OpenAIRE

    Milan Davidovic

    2013-01-01

    E-clusters are strategic alliance in TIMES technology sector (Telecommunication, Information technology, Multimedia, Entertainment, Security) where products and processes are digitalized. They enable horizontal and vertical integration of small and medium companies and establish new added value e-chains. E-clusters also build supply chains based on cooperation relationship, innovation, organizational knowledge and compliance of intellectual properties. As an innovative approach for economic p...

  5. Clusters and exotic processes

    International Nuclear Information System (INIS)

    Schiffer, J.P.

    1975-01-01

    An attempt is made to present some data which may be construed as indicating that perhaps clusters play a role in high energy and exotic pion or kaon interactions with complex (A much greater than 16) nuclei. Also an attempt is made to summarize some very recent experimental work on pion interactions with nuclei which may or may not in the end support a picture in which clusters play an important role. (U.S.)

  6. Characteristics in Molecular Vibrational Frequency Patterns between Agonists and Antagonists of Histamine Receptors

    Directory of Open Access Journals (Sweden)

    S. June Oh

    2012-06-01

    Full Text Available To learn the differences between the structure-activity relationship and molecular vibration-activity relationship in the ligand-receptor interaction of the histamine receptor, 47 ligands of the histamine receptor were analyzed by structural similarity and molecular vibrational frequency patterns. The radial tree that was produced by clustering analysis of molecular vibrational frequency patterns shows its potential for the functional classification of histamine receptor ligands.

  7. Robust continuous clustering.

    Science.gov (United States)

    Shah, Sohil Atul; Koltun, Vladlen

    2017-09-12

    Clustering is a fundamental procedure in the analysis of scientific data. It is used ubiquitously across the sciences. Despite decades of research, existing clustering algorithms have limited effectiveness in high dimensions and often require tuning parameters for different domains and datasets. We present a clustering algorithm that achieves high accuracy across multiple domains and scales efficiently to high dimensions and large datasets. The presented algorithm optimizes a smooth continuous objective, which is based on robust statistics and allows heavily mixed clusters to be untangled. The continuous nature of the objective also allows clustering to be integrated as a module in end-to-end feature learning pipelines. We demonstrate this by extending the algorithm to perform joint clustering and dimensionality reduction by efficiently optimizing a continuous global objective. The presented approach is evaluated on large datasets of faces, hand-written digits, objects, newswire articles, sensor readings from the Space Shuttle, and protein expression levels. Our method achieves high accuracy across all datasets, outperforming the best prior algorithm by a factor of 3 in average rank.

  8. Cluster bomb ocular injuries.

    Science.gov (United States)

    Mansour, Ahmad M; Hamade, Haya; Ghaddar, Ayman; Mokadem, Ahmad Samih; El Hajj Ali, Mohamad; Awwad, Shady

    2012-01-01

    To present the visual outcomes and ocular sequelae of victims of cluster bombs. This retrospective, multicenter case series of ocular injury due to cluster bombs was conducted for 3 years after the war in South Lebanon (July 2006). Data were gathered from the reports to the Information Management System for Mine Action. There were 308 victims of clusters bombs; 36 individuals were killed, of which 2 received ocular lacerations and; 272 individuals were injured with 18 receiving ocular injury. These 18 surviving individuals were assessed by the authors. Ocular injury occurred in 6.5% (20/308) of cluster bomb victims. Trauma to multiple organs occurred in 12 of 18 cases (67%) with ocular injury. Ocular findings included corneal or scleral lacerations (16 eyes), corneal foreign bodies (9 eyes), corneal decompensation (2 eyes), ruptured cataract (6 eyes), and intravitreal foreign bodies (10 eyes). The corneas of one patient had extreme attenuation of the endothelium. Ocular injury occurred in 6.5% of cluster bomb victims and 67% of the patients with ocular injury sustained trauma to multiple organs. Visual morbidity in civilians is an additional reason for a global ban on the use of cluster bombs.

  9. Clustering aspects in nuclear structure functions

    International Nuclear Information System (INIS)

    Hirai, M.; Saito, K.; Watanabe, T.; Kumano, S.

    2011-01-01

    For understanding an anomalous nuclear effect experimentally observed for the beryllium-9 nucleus at the Thomas Jefferson National Accelerator Facility, clustering aspects are studied in structure functions of deep inelastic lepton-nucleus scattering by using momentum distributions calculated in antisymmetrized (or fermionic) molecular dynamics (AMD) and also in a simple shell model for comparison. According to AMD, the 9 Be nucleus consists of two α-like clusters with a surrounding neutron. The clustering produces high-momentum components in nuclear wave functions, which affects nuclear modifications of the structure functions. We investigated whether clustering features could appear in the structure function F 2 of 9 Be along with studies for other light nuclei. We found that nuclear modifications of F 2 are similar in both AMD and shell models within our simple convolution description although there are slight differences in 9 Be. It indicates that the anomalous 9 Be result should be explained by a different mechanism from the nuclear binding and Fermi motion. If nuclear-modification slopes d(F 2 A /F 2 D )/dx are shown by the maximum local densities, the 9 Be anomaly can be explained by the AMD picture, namely by the clustering structure, whereas it certainly cannot be described in the simple shell model. This fact suggests that the large nuclear modification in 9 Be should be explained by large densities in the clusters. For example, internal nucleon structure could be modified in the high-density clusters. The clustering aspect of nuclear structure functions is an unexplored topic which is interesting for future investigations.

  10. MPA-capped CdTe quantum dots exposure causes neurotoxic effects in nematode Caenorhabditis elegans by affecting the transporters and receptors of glutamate, serotonin and dopamine at the genetic level, or by increasing ROS, or both

    Science.gov (United States)

    Wu, Tianshu; He, Keyu; Zhan, Qinglin; Ang, Shengjun; Ying, Jiali; Zhang, Shihan; Zhang, Ting; Xue, Yuying; Tang, Meng

    2015-12-01

    As quantum dots (QDs) are widely used in biomedical applications, the number of studies focusing on their biological properties is increasing. While several studies have attempted to evaluate the toxicity of QDs towards neural cells, the in vivo toxic effects on the nervous system and the molecular mechanisms are unclear. The aim of the present study was to investigate the neurotoxic effects and the underlying mechanisms of water-soluble cadmium telluride (CdTe) QDs capped with 3-mercaptopropionic acid (MPA) in Caenorhabditis elegans (C. elegans). Our results showed that exposure to MPA-capped CdTe QDs induced behavioral defects, including alterations to body bending, head thrashing, pharyngeal pumping and defecation intervals, as well as impaired learning and memory behavior plasticity, based on chemotaxis or thermotaxis, in a dose-, time- and size-dependent manner. Further investigations suggested that MPA-capped CdTe QDs exposure inhibited the transporters and receptors of glutamate, serotonin and dopamine in C. elegans at the genetic level within 24 h, while opposite results were observed after 72 h. Additionally, excessive reactive oxygen species (ROS) generation was observed in the CdTe QD-treated worms, which confirmed the common nanotoxicity mechanism of oxidative stress damage, and might overcome the increased gene expression of neurotransmitter transporters and receptors in C. elegans induced by long-term QD exposure, resulting in more severe behavioral impairments.

  11. Cluster ion-surface interactions: from meV to MeV energies

    Energy Technology Data Exchange (ETDEWEB)

    Nordlund, Kai; Meinander, Kristoffer; Jaervi, Tommi T.; Peltola, Jarkko; Samela, Juha [Accelerator Laboratory, University of Helsinki (Finland)

    2008-07-01

    The nature of cluster ion-surface interactions changes dramatically with the kinetic energy of the incoming cluster species. In this talk I review some of our recent work on the nature of cluster-surface interactions spanning an energy range from a few MeV/cluster to about 1 MeV/cluster and cluster sizes in the range of 10 - 1000 atoms/cluster. In the energy range of a few MeV/cluster ion, the kinetic energy of the incoming ion is insignificant compared to the energy gained when the surface potential energy at the cluster-surface interface is released and partly translated into kinetic energy. Even in this energy regime I show that surprisingly drastic effects can occur. When the energy of the incoming cluster is raised to a few eV/atom, the kinetic energy of the incoming cluster starts to affect the deposition. It will cause the cluster to entirely reform on impact. When the energy is raised to the range of keV's/cluster, the clusters start to penetrate the sample, fairly similar to conventional ion implantation. However, in dense targets the cluster ions may stick close to each other long enough to cause a significant enhancement of the heat spike in the material. Finally, I show that at kinetic energies around 1 MeV/cluster the cluster enhancement of the heat spike may lead to dramatic surface effects.

  12. 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.

  13. Identifying subgroups of CERME affect research papers

    OpenAIRE

    Hannula, Markku S.; Garcia Moreno-Esteva, Enrique

    2017-01-01

    Research in mathematics related affect uses a variety of theoretical frameworks. Three different dimensions have been suggested as significant to characterize concepts in this area: (1) emotional, motivational, and cognitive aspects of affect, (2) state and trait aspects of affect, and (3) physiological, psychological, and sociological level of theorizing affect. In this study, we used the information in reference lists and graph theory to identify Graph Communities (coherent clusters) of res...

  14. Determination of atomic cluster structure with cluster fusion algorithm

    DEFF Research Database (Denmark)

    Obolensky, Oleg I.; Solov'yov, Ilia; Solov'yov, Andrey V.

    2005-01-01

    We report an efficient scheme of global optimization, called cluster fusion algorithm, which has proved its reliability and high efficiency in determination of the structure of various atomic clusters.......We report an efficient scheme of global optimization, called cluster fusion algorithm, which has proved its reliability and high efficiency in determination of the structure of various atomic clusters....

  15. Study on distributed re-clustering algorithm for moblie wireless sensor networks

    Directory of Open Access Journals (Sweden)

    XU Chaojie

    2016-04-01

    Full Text Available In mobile wireless sensor networks,node mobility influences the topology of the hierarchically clustered network,thus affects packet delivery ratio and energy consumption of communications in clusters.To reduce the influence of node mobility,a distributed re-clustering algorithm is proposed in this paper.In this algorithm,basing on the clustered network,nodes estimate their current locations with particle algorithm and predict the most possible locations of next time basing on the mobility model.Each boundary node of a cluster periodically estimates the need for re-clustering and re-cluster itself to the optimal cluster through communicating with the cluster headers when needed.The simulation results indicate that,with small re-clustering periods,the proposed algorithm can be effective to keep appropriate communication distance and outperforms existing schemes on packet delivery ratio and energy consumption.

  16. Cluster dynamics at different cluster size and incident laser wavelengths

    International Nuclear Information System (INIS)

    Desai, Tara; Bernardinello, Andrea

    2002-01-01

    X-ray emission spectra from aluminum clusters of diameter -0.4 μm and gold clusters of dia. ∼1.25 μm are experimentally studied by irradiating the cluster foil targets with 1.06 μm laser, 10 ns (FWHM) at an intensity ∼10 12 W/cm 2 . Aluminum clusters show a different spectra compared to bulk material whereas gold cluster evolve towards bulk gold. Experimental data are analyzed on the basis of cluster dimension, laser wavelength and pulse duration. PIC simulations are performed to study the behavior of clusters at higher intensity I≥10 17 W/cm 2 for different size of the clusters irradiated at different laser wavelengths. Results indicate the dependence of cluster dynamics on cluster size and incident laser wavelength

  17. Cluster fusion algorithm: application to Lennard-Jones clusters

    DEFF Research Database (Denmark)

    Solov'yov, Ilia; Solov'yov, Andrey V.; Greiner, Walter

    2006-01-01

    paths up to the cluster size of 150 atoms. We demonstrate that in this way all known global minima structures of the Lennard-Jones clusters can be found. Our method provides an efficient tool for the calculation and analysis of atomic cluster structure. With its use we justify the magic number sequence......We present a new general theoretical framework for modelling the cluster structure and apply it to description of the Lennard-Jones clusters. Starting from the initial tetrahedral cluster configuration, adding new atoms to the system and absorbing its energy at each step, we find cluster growing...... for the clusters of noble gas atoms and compare it with experimental observations. We report the striking correspondence of the peaks in the dependence of the second derivative of the binding energy per atom on cluster size calculated for the chain of the Lennard-Jones clusters based on the icosahedral symmetry...

  18. Cluster fusion algorithm: application to Lennard-Jones clusters

    DEFF Research Database (Denmark)

    Solov'yov, Ilia; Solov'yov, Andrey V.; Greiner, Walter

    2008-01-01

    paths up to the cluster size of 150 atoms. We demonstrate that in this way all known global minima structures of the Lennard-Jones clusters can be found. Our method provides an efficient tool for the calculation and analysis of atomic cluster structure. With its use we justify the magic number sequence......We present a new general theoretical framework for modelling the cluster structure and apply it to description of the Lennard-Jones clusters. Starting from the initial tetrahedral cluster configuration, adding new atoms to the system and absorbing its energy at each step, we find cluster growing...... for the clusters of noble gas atoms and compare it with experimental observations. We report the striking correspondence of the peaks in the dependence of the second derivative of the binding energy per atom on cluster size calculated for the chain of the Lennard-Jones clusters based on the icosahedral symmetry...

  19. 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.

  20. GibbsCluster: unsupervised clustering and alignment of peptide sequences

    DEFF Research Database (Denmark)

    Andreatta, Massimo; Alvarez, Bruno; Nielsen, Morten

    2017-01-01

    motif characterizing each cluster. Several parameters are available to customize cluster analysis, including adjustable penalties for small clusters and overlapping groups and a trash cluster to remove outliers. As an example application, we used the server to deconvolute multiple specificities in large......-scale peptidome data generated by mass spectrometry. The server is available at http://www.cbs.dtu.dk/services/GibbsCluster-2.0....

  1. Affective Urbanism

    DEFF Research Database (Denmark)

    Samson, Kristine

    Urban design and architecture are increasingly used as material and affective strategies for setting the scene, for manipulation and the production of urban life: The orchestration of atmospheres, the framing and staging of urban actions, the programming for contemplation, involvement, play......, experience and consumption are all strategic design tools applied by planners and architects. Whereas urban design in former modernist planning served merely functional or political means, urban design has increasingly become an aesthetical mediator of ideologies embedded in the urban field of life forces....... Under these circumstances affective aesthetics operate strategically within the urban field of interests, capital flows and desires of the social. This ‘affective urbanism’ (Anderson & Holden 2008) is linked to a society influenced by new kinds of information flows, where culture is mediated and enacted...

  2. Clustering of affective categories in Scandinavian and Romance languages

    DEFF Research Database (Denmark)

    Sauciuc, Gabriela-Alina

    and Rusell's prototype approach to emotions are analyzed from a perspective that goes beyond the interpretation of prototype theory and aligns with the theory-based approaches to categorization (cfr. the seminal paper by Murphy and Medin, 1985). Due to space limitations, only a short overview of the data...... obtained with the help of a supplemented version of the traditional free-listing task (a ranking and a definitional-inferential task being added) will be considered here. 10 different sets combining quantitative and qualitative data have been collected, corresponding to the various relevant superordinate...

  3. Cluster Implantation and Deposition Apparatus

    DEFF Research Database (Denmark)

    Hanif, Muhammad; Popok, Vladimir

    2015-01-01

    In the current report, a design and capabilities of a cluster implantation and deposition apparatus (CIDA) involving two different cluster sources are described. The clusters produced from gas precursors (Ar, N etc.) by PuCluS-2 can be used to study cluster ion implantation in order to develop...

  4. Subspace K-means clustering

    NARCIS (Netherlands)

    Timmerman, Marieke E.; Ceulemans, Eva; De Roover, Kim; Van Leeuwen, Karla

    2013-01-01

    To achieve an insightful clustering of multivariate data, we propose subspace K-means. Its central idea is to model the centroids and cluster residuals in reduced spaces, which allows for dealing with a wide range of cluster types and yields rich interpretations of the clusters. We review the

  5. Lack of TNF-alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression.

    Science.gov (United States)

    Tortarolo, Massimo; Vallarola, Antonio; Lidonnici, Dario; Battaglia, Elisa; Gensano, Francesco; Spaltro, Gabriella; Fiordaliso, Fabio; Corbelli, Alessandro; Garetto, Stefano; Martini, Elisa; Pasetto, Laura; Kallikourdis, Marinos; Bonetto, Valentina; Bendotti, Caterina

    2015-10-01

    Changes in the homeostasis of tumor necrosis factor α (TNFα) have been demonstrated in patients and experimental models of amyotrophic lateral sclerosis (ALS). However, the contribution of TNFα to the development of ALS is still debated. TNFα is expressed by glia and neurons and acts through the membrane receptors TNFR1 and TNFR2, which may have opposite effects in neurodegeneration. We investigated the role of TNFα and its receptors in the selective motor neuron death in ALS in vitro and in vivo. TNFR2 expressed by astrocytes and neurons, but not TNFR1, was implicated in motor neuron loss in primary SOD1-G93A co-cultures. Deleting TNFR2 from SOD1-G93A mice, there was partial but significant protection of spinal motor neurons, sciatic nerves, and tibialis muscles. However, no improvement of motor impairment or survival was observed. Since the sciatic nerves of SOD1-G93A/TNFR2-/- mice showed high phospho-TAR DNA-binding protein 43 (TDP-43) accumulation and low levels of acetyl-tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons. These results indicate the interaction between TNFR2 and membrane-bound TNFα as an innovative pathway involved in motor neuron death. Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology. We show evidence of the involvement of neuronal and astroglial TNFR2 in the motor neuron degeneration in ALS. Both concur to cause motor neuron death in primary astrocyte/spinal neuron co-cultures. TNFR2 deletion partially protects motor neurons and sciatic nerves in SOD1-G93A mice but does not improve their symptoms and survival. However, TNFR2 could be a new target for multi-intervention therapies. © 2015 International Society for Neurochemistry.

  6. Projected coupled cluster theory.

    Science.gov (United States)

    Qiu, Yiheng; Henderson, Thomas M; Zhao, Jinmo; Scuseria, Gustavo E

    2017-08-14

    Coupled cluster theory is the method of choice for weakly correlated systems. But in the strongly correlated regime, it faces a symmetry dilemma, where it either completely fails to describe the system or has to artificially break certain symmetries. On the other hand, projected Hartree-Fock theory captures the essential physics of many kinds of strong correlations via symmetry breaking and restoration. In this work, we combine and try to retain the merits of these two methods by applying symmetry projection to broken symmetry coupled cluster wave functions. The non-orthogonal nature of states resulting from the application of symmetry projection operators furnishes particle-hole excitations to all orders, thus creating an obstacle for the exact evaluation of overlaps. Here we provide a solution via a disentanglement framework theory that can be approximated rigorously and systematically. Results of projected coupled cluster theory are presented for molecules and the Hubbard model, showing that spin projection significantly improves unrestricted coupled cluster theory while restoring good quantum numbers. The energy of projected coupled cluster theory reduces to the unprojected one in the thermodynamic limit, albeit at a much slower rate than projected Hartree-Fock.

  7. Globular Clusters - Guides to Galaxies

    CERN Document Server

    Richtler, Tom; Joint ESO-FONDAP Workshop on Globular Clusters

    2009-01-01

    The principal question of whether and how globular clusters can contribute to a better understanding of galaxy formation and evolution is perhaps the main driving force behind the overall endeavour of studying globular cluster systems. Naturally, this splits up into many individual problems. The objective of the Joint ESO-FONDAP Workshop on Globular Clusters - Guides to Galaxies was to bring together researchers, both observational and theoretical, to present and discuss the most recent results. Topics covered in these proceedings are: internal dynamics of globular clusters and interaction with host galaxies (tidal tails, evolution of cluster masses), accretion of globular clusters, detailed descriptions of nearby cluster systems, ultracompact dwarfs, formations of massive clusters in mergers and elsewhere, the ACS Virgo survey, galaxy formation and globular clusters, dynamics and kinematics of globular cluster systems and dark matter-related problems. With its wide coverage of the topic, this book constitute...

  8. Reproducibility of Cognitive Profiles in Psychosis Using Cluster Analysis.

    Science.gov (United States)

    Lewandowski, Kathryn E; Baker, Justin T; McCarthy, Julie M; Norris, Lesley A; Öngür, Dost

    2018-04-01

    Cognitive dysfunction is a core symptom dimension that cuts across the psychoses. Recent findings support classification of patients along the cognitive dimension using cluster analysis; however, data-derived groupings may be highly determined by sampling characteristics and the measures used to derive the clusters, and so their interpretability must be established. We examined cognitive clusters in a cross-diagnostic sample of patients with psychosis and associations with clinical and functional outcomes. We then compared our findings to a previous report of cognitive clusters in a separate sample using a different cognitive battery. Participants with affective or non-affective psychosis (n=120) and healthy controls (n=31) were administered the MATRICS Consensus Cognitive Battery, and clinical and community functioning assessments. Cluster analyses were performed on cognitive variables, and clusters were compared on demographic, cognitive, and clinical measures. Results were compared to findings from our previous report. A four-cluster solution provided a good fit to the data; profiles included a neuropsychologically normal cluster, a globally impaired cluster, and two clusters of mixed profiles. Cognitive burden was associated with symptom severity and poorer community functioning. The patterns of cognitive performance by cluster were highly consistent with our previous findings. We found evidence of four cognitive subgroups of patients with psychosis, with cognitive profiles that map closely to those produced in our previous work. Clusters were associated with clinical and community variables and a measure of premorbid functioning, suggesting that they reflect meaningful groupings: replicable, and related to clinical presentation and functional outcomes. (JINS, 2018, 24, 382-390).

  9. Neurobiology and sleep disorders in cluster headache

    DEFF Research Database (Denmark)

    Barloese, Mads Christian Johannes

    2015-01-01

    of daylight, substantially poorer sleep quality in patients compared to controls which was present not only inside the clusters but also outside, affected REM-sleep in patients without a particular temporal connection to nocturnal attacks, equal prevalence of sleep apnea in both patient and control groups......Cluster headache is characterized by unilateral attacks of severe pain accompanied by cranial autonomic features. Apart from these there are also sleep-related complaints and strong chronobiological features. The interaction between sleep and headache is complex at any level and evidence suggests...... that it may be of critical importance in our understanding of primary headache disorders. In cluster headache several interactions between sleep and the severe pain attacks have already been proposed. Supported by endocrinological and radiological findings as well as the chronobiological features, predominant...

  10. Insight into pattern of codon biasness and nucleotide base usage in serotonin receptor gene family from different mammalian species.

    Science.gov (United States)

    Dass, J Febin Prabhu; Sudandiradoss, C

    2012-07-15

    5-HT (5-Hydroxy-tryptamine) or serotonin receptors are found both in central and peripheral nervous system as well as in non-neuronal tissues. In the animal and human nervous system, serotonin produces various functional effects through a variety of membrane bound receptors. In this study, we focus on 5-HT receptor family from different mammals and examined the factors that account for codon and nucleotide usage variation. A total of 110 homologous coding sequences from 11 different mammalian species were analyzed using relative synonymous codon usage (RSCU), correspondence analysis (COA) and hierarchical cluster analysis together with nucleotide base usage frequency of chemically similar amino acid codons. The mean effective number of codon (ENc) value of 37.06 for 5-HT(6) shows very high codon bias within the family and may be due to high selective translational efficiency. The COA and Spearman's rank correlation reveals that the nucleotide compositional mutation bias as the major factors influencing the codon usage in serotonin receptor genes. The hierarchical cluster analysis suggests that gene function is another dominant factor that affects the codon usage bias, while species is a minor factor. Nucleotide base usage was reported using Goldman, Engelman, Stietz (GES) scale reveals the presence of high uracil (>45%) content at functionally important hydrophobic regions. Our in silico approach will certainly help for further investigations on critical inference on evolution, structure, function and gene expression aspects of 5-HT receptors family which are potential antipsychotic drug targets. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. The LDL receptor.

    Science.gov (United States)

    Goldstein, Joseph L; Brown, Michael S

    2009-04-01

    In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

  12. Therapeutic actions of an insulin receptor activator and a novel peroxisome proliferator-activated receptor gamma agonist in the spontaneously hypertensive obese rat model of metabolic syndrome X.

    Science.gov (United States)

    Velliquette, Rodney A; Friedman, Jacob E; Shao, J; Zhang, Bei B; Ernsberger, Paul

    2005-07-01

    Insulin resistance clusters with hyperlipidemia, impaired glucose tolerance, and hypertension as metabolic syndrome X. We tested a low molecular weight insulin receptor activator, demethylasterriquinone B-1 (DMAQ-B1), and a novel indole peroxisome proliferator-activated receptor gamma agonist, 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (PPEIA), in spontaneously hypertensive obese rats (SHROB), a genetic model of syndrome X. Agents were given orally for 19 days. SHROB showed fasting normoglycemia but impaired glucose tolerance after an oral load, as shown by increased glucose area under the curve (AUC) [20,700 mg x min/ml versus 8100 in lean spontaneously hypertensive rats (SHR)]. Insulin resistance was indicated by 20-fold excess fasting insulin and increased insulin AUC (6300 ng x min/ml versus 990 in SHR). DMAQ-B1 did not affect glucose tolerance (glucose AUC = 21,300) but reduced fasting insulin 2-fold and insulin AUC (insulin AUC = 4300). PPEIA normalized glucose tolerance (glucose AUC = 9100) and reduced insulin AUC (to 3180) without affecting fasting insulin. PPEIA also increased food intake, fat mass, and body weight gain (81 +/- 12 versus 45 +/- 8 g in untreated controls), whereas DMAQ-B1 had no effect on body weight but reduced subscapular fat mass. PPEIA but not DMAQ-B1 reduced blood pressure. In skeletal muscle, insulin-stimulated phosphorylation of the insulin receptor and insulin receptor substrate protein 1-associated phosphatidylinositol 3-kinase activity were decreased by 40 to 55% in SHROB relative to lean SHR. PPEIA, but not DMAQ-B1, enhanced both insulin actions. SHROB also showed severe hypertriglyceridemia (355 +/- 42 mg/dl versus 65 +/- 3 in SHR) attenuated by both agents (DMAQ-B1, 228 +/- 18; PPEIA, 79 +/- 3). Both these novel antidiabetic agents attenuate insulin resistance and hypertriglyceridemia associated with metabolic syndrome but via distinct mechanisms.

  13. Affect Regulation

    DEFF Research Database (Denmark)

    Pedersen, Signe Holm; Poulsen, Stig Bernt; Lunn, Susanne

    2014-01-01

    Gergely and colleagues’ state that their Social Biofeedback Theory of Parental Affect Mirroring” can be seen as a kind of operationalization of the classical psychoanalytic concepts of holding, containing and mirroring. This article examines to what extent the social biofeedback theory of parenta...

  14. Spanning Tree Based Attribute Clustering

    DEFF Research Database (Denmark)

    Zeng, Yifeng; Jorge, Cordero Hernandez

    2009-01-01

    Attribute clustering has been previously employed to detect statistical dependence between subsets of variables. We propose a novel attribute clustering algorithm motivated by research of complex networks, called the Star Discovery algorithm. The algorithm partitions and indirectly discards...... inconsistent edges from a maximum spanning tree by starting appropriate initial modes, therefore generating stable clusters. It discovers sound clusters through simple graph operations and achieves significant computational savings. We compare the Star Discovery algorithm against earlier attribute clustering...

  15. Spatial cluster detection using dynamic programming

    Directory of Open Access Journals (Sweden)

    Sverchkov Yuriy

    2012-03-01

    Full Text Available Abstract Background The task of spatial cluster detection involves finding spatial regions where some property deviates from the norm or the expected value. In a probabilistic setting this task can be expressed as finding a region where some event is significantly more likely than usual. Spatial cluster detection is of interest in fields such as biosurveillance, mining of astronomical data, military surveillance, and analysis of fMRI images. In almost all such applications we are interested both in the question of whether a cluster exists in the data, and if it exists, we are interested in finding the most accurate characterization of the cluster. Methods We present a general dynamic programming algorithm for grid-based spatial cluster detection. The algorithm can be used for both Bayesian maximum a-posteriori (MAP estimation of the most likely spatial distribution of clusters and Bayesian model averaging over a large space of spatial cluster distributions to compute the posterior probability of an unusual spatial clustering. The algorithm is explained and evaluated in the context of a biosurveillance application, specifically the detection and identification of Influenza outbreaks based on emergency department visits. A relatively simple underlying model is constructed for the purpose of evaluating the algorithm, and the algorithm is evaluated using the model and semi-synthetic test data. Results When compared to baseline methods, tests indicate that the new algorithm can improve MAP estimates under certain conditions: the greedy algorithm we compared our method to was found to be more sensitive to smaller outbreaks, while as the size of the outbreaks increases, in terms of area affected and proportion of individuals affected, our method overtakes the greedy algorithm in spatial precision and recall. The new algorithm performs on-par with baseline methods in the task of Bayesian model averaging. Conclusions We conclude that the dynamic

  16. Exotic cluster structures on

    CERN Document Server

    Gekhtman, M; Vainshtein, A

    2017-01-01

    This is the second paper in the series of papers dedicated to the study of natural cluster structures in the rings of regular functions on simple complex Lie groups and Poisson-Lie structures compatible with these cluster structures. According to our main conjecture, each class in the Belavin-Drinfeld classification of Poisson-Lie structures on \\mathcal{G} corresponds to a cluster structure in \\mathcal{O}(\\mathcal{G}). The authors have shown before that this conjecture holds for any \\mathcal{G} in the case of the standard Poisson-Lie structure and for all Belavin-Drinfeld classes in SL_n, n<5. In this paper the authors establish it for the Cremmer-Gervais Poisson-Lie structure on SL_n, which is the least similar to the standard one.

  17. From superdeformation to clusters

    Energy Technology Data Exchange (ETDEWEB)

    Betts, R R [Argonne National Lab., IL (United States). Physics Div.

    1992-08-01

    Much of the discussion at the conference centred on superdeformed states and their study by precise gamma spectrometry. The author suggests that the study of superdeformation by fission fragments and by auto-scattering is of importance, and may become more important. He concludes that there exists clear evidence of shell effects at extreme deformation in light nuclei studied by fission or cluster decay. The connection between the deformed shell model and the multi-center shell model can be exploited to give give insight into the cluster structure of these extremely deformed states, and also gives hope of a spectroscopy based on selection rules for cluster decay. A clear disadvantage at this stage is inability to make this spectroscopy more quantitative through calculation of the decay widths. The introduction of a new generation of high segmentation, high resolution, particle arrays has and will have a major impact on this aspect of the study of highly deformed nuclei. 20 refs., 16 figs.

  18. Knowledge between communities of practice and firms in clusters

    DEFF Research Database (Denmark)

    Reinau, Kristian Hegner

    . This paper presents a case study in which theory about knowledge, communities of practice and networks is used to understand how knowledge is developed in high-tech companies placed in a cluster. The case study illuminates how internal and external relations and factors affect the knowledge development...... which factors that affect the knowledge development process in communities in the case companies. By analysing the interplay between formal and informal relations utilized by the companies, the knowledge embedded in the persons constituting the communities as well as knowledge embedded in objects used......Currently there is growing focus on how cluster internal and cluster external relations affect the creation of knowledge in companies placed in clusters. However, the current theories on this topic are too simple and the interplay between internal and external relations is relatively unknown...

  19. Clustering evolving proteins into homologous families.

    Science.gov (United States)

    Chan, Cheong Xin; Mahbob, Maisarah; Ragan, Mark A

    2013-04-08

    Clustering sequences into groups of putative homologs (families) is a critical first step in many areas of comparative biology and bioinformatics. The performance of clustering approaches in delineating biologically meaningful families depends strongly on characteristics of the data, including content bias and degree of divergence. New, highly scalable methods have recently been introduced to cluster the very large datasets being generated by next-generation sequencing technologies. However, there has been little systematic investigation of how characteristics of the data impact the performance of these approaches. Using clusters from a manually curated dataset as reference, we examined the performance of a widely used graph-based Markov clustering algorithm (MCL) and a greedy heuristic approach (UCLUST) in delineating protein families coded by three sets of bacterial genomes of different G+C content. Both MCL and UCLUST generated clusters that are comparable to the reference sets at specific parameter settings, although UCLUST tends to under-cluster compositionally biased sequences (G+C content 33% and 66%). Using simulated data, we sought to assess the individual effects of sequence divergence, rate heterogeneity, and underlying G+C content. Performance decreased with increasing sequence divergence, decreasing among-site rate variation, and increasing G+C bias. Two MCL-based methods recovered the simulated families more accurately than did UCLUST. MCL using local alignment distances is more robust across the investigated range of sequence features than are greedy heuristics using distances based on global alignment. Our results demonstrate that sequence divergence, rate heterogeneity and content bias can individually and in combination affect the accuracy with which MCL and UCLUST can recover homologous protein families. For application to data that are more divergent, and exhibit higher among-site rate variation and/or content bias, MCL may often be the better

  20. Refractory chronic cluster headache

    DEFF Research Database (Denmark)

    Mitsikostas, Dimos D; Edvinsson, Lars; Jensen, Rigmor H

    2014-01-01

    Chronic cluster headache (CCH) often resists to prophylactic pharmaceutical treatments resulting in patients' life damage. In this rare but pragmatic situation escalation to invasive management is needed but framing criteria are lacking. We aimed to reach a consensus for refractory CCH definition...... for clinical and research use. The preparation of the final consensus followed three stages. Internal between authors, a larger between all European Headache Federation members and finally an international one among all investigators that have published clinical studies on cluster headache the last five years...

  1. I Cluster geografici

    Directory of Open Access Journals (Sweden)

    Maurizio Rosina

    2010-03-01

    Full Text Available Geographic ClustersOver the past decade, public alphanumeric database have been growing at exceptional rate. Most of data can be georeferenced, so that is possible gaining new knowledge from such databases. The contribution of this paper is two-fold. We first present a model of geographic clusters, which uses only geographic and functionally data properties. The model is useful to process huge amount of public/government data, even daily upgrading. After that, we merge the model into the framework GEOPOI (GEOcoding Points Of Interest, and show some graphic map results.

  2. I Cluster geografici

    Directory of Open Access Journals (Sweden)

    Maurizio Rosina

    2010-03-01

    Full Text Available Geographic Clusters Over the past decade, public alphanumeric database have been growing at exceptional rate. Most of data can be georeferenced, so that is possible gaining new knowledge from such databases. The contribution of this paper is two-fold. We first present a model of geographic clusters, which uses only geographic and functionally data properties. The model is useful to process huge amount of public/government data, even daily upgrading. After that, we merge the model into the framework GEOPOI (GEOcoding Points Of Interest, and show some graphic map results.

  3. Clustering via Kernel Decomposition

    DEFF Research Database (Denmark)

    Have, Anna Szynkowiak; Girolami, Mark A.; Larsen, Jan

    2006-01-01

    Methods for spectral clustering have been proposed recently which rely on the eigenvalue decomposition of an affinity matrix. In this work it is proposed that the affinity matrix is created based on the elements of a non-parametric density estimator. This matrix is then decomposed to obtain...... posterior probabilities of class membership using an appropriate form of nonnegative matrix factorization. The troublesome selection of hyperparameters such as kernel width and number of clusters can be obtained using standard cross-validation methods as is demonstrated on a number of diverse data sets....

  4. Triangular clustering in document networks

    Energy Technology Data Exchange (ETDEWEB)

    Cheng Xueqi; Ren Fuxin [Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190 (China); Zhou Shi [Department of Computer Science, University College London, Malet Place, London WC1E 6BT (United Kingdom); Hu Maobin [School of Engineering Science, University of Science and Technology of China, Hefei 230026 (China)], E-mail: cxq@ict.ac.cn, E-mail: renfuxin@software.ict.ac.cn, E-mail: s.zhou@adastral.ucl.ac.uk, E-mail: humaobin@ustc.edu.cn

    2009-03-15

    Document networks have the characteristic that a document node, e.g. a webpage or an article, carries meaningful content. Properties of document networks are not only affected by topological connectivity between nodes, but are also strongly influenced by the semantic relation between the content of the nodes. We observed that document networks have a large number of triangles and a high value clustering coefficient. Also there is a strong correlation between the probability of formation of a triangle and the content similarity among the three nodes involved. We propose the degree-similarity product (DSP) model, which well reproduces these properties. The model achieves this by using a preferential attachment mechanism that favours the linkage between nodes that are both popular and similar. This work is a step forward towards a better understanding of the structure and evolution of document networks.

  5. Phylogenetic Inference of HIV Transmission Clusters

    Directory of Open Access Journals (Sweden)

    Vlad Novitsky

    2017-10-01

    Full Text Available Better understanding the structure and dynamics of HIV transmission networks is essential for designing the most efficient interventions to prevent new HIV transmissions, and ultimately for gaining control of the HIV epidemic. The inference of phylogenetic relationships and the interpretation of results rely on the definition of the HIV transmission cluster. The definition of the HIV cluster is complex and dependent on multiple factors, including the design of sampling, accuracy of sequencing, precision of sequence alignment, evolutionary models, the phylogenetic method of inference, and specified thresholds for cluster support. While the majority of studies focus on clusters, non-clustered cases could also be highly informative. A new dimension in the analysis of the global and local HIV epidemics is the concept of phylogenetically distinct HIV sub-epidemics. The identification of active HIV sub-epidemics reveals spreading viral lineages and may help in the design of targeted interventions.HIVclustering can also be affected by sampling density. Obtaining a proper sampling density may increase statistical power and reduce sampling bias, so sampling density should be taken into account in study design and in interpretation of phylogenetic results. Finally, recent advances in long-range genotyping may enable more accurate inference of HIV transmission networks. If performed in real time, it could both inform public-health strategies and be clinically relevant (e.g., drug-resistance testing.

  6. β-Adrenergic receptor-mediated suppression of interleukin 2 receptors in human lymphocytes

    International Nuclear Information System (INIS)

    Feldman, R.D.; Hunninghake, G.W.; McArdle, W.L.

    1987-01-01

    Adrenergic receptor agonists are know to attenuate the proliferative response of human lymphocytes after activation; however, their mechanism of action is unknown. Since expression of interleukin 2 (IL-2) receptors is a prerequisite for proliferation, the effect of β-adrenergic receptor agonists on lymphocyte IL-2 receptors was studied on both mitogen-stimulated lymphocytes and IL-2-dependent T lymphocyte cell lines. In both cell types the β-adrenergic receptor agonist isoproterenol blocked the expression of IL-2 receptors, as determined with the IL-2 receptor anti-TAC antibody. To determine the effect of β-adrenergic agonists on expression of the high affinity IL-2 receptors, [ 125 I]IL-2 binding studies were performed at concentrations selective for high affinity sites. No significant effect of β-adrenergic agonists on high affinity IL-2 receptor sites could be detected. The data demonstrate that β-adrenergic receptor agonists down-regulate IL-2 receptors primarily affecting low affinity sites

  7. Donor Interventions and SME Networking in Industrial Clusters in Punjab Province, Pakistan

    DEFF Research Database (Denmark)

    Fayyaz, Anjum

    . Thus, the author seeks to answer two interrelated questions in this thesis: a) How did the IDA interventions affect SME networks in the Lahore garments and Sialkot football clusters in Pakistan? b) Why did the IDA-supported SME networks in these clusters continue or discontinue after the IDA withdrew...... the IDA’s interventions affected the long-term sustainability of SME networks present in both clusters. In the case of the Lahore garments cluster, the IDA supported two networks in the cluster. One was known as the Lahore Garments Consortium and the other was named the Lahore Fashion Apparel Network...

  8. N-glycosylation of the β2 adrenergic receptor regulates receptor function by modulating dimerization.

    Science.gov (United States)

    Li, Xiaona; Zhou, Mang; Huang, Wei; Yang, Huaiyu

    2017-07-01

    N-glycosylation is a common post-translational modification of G-protein-coupled receptors (GPCRs). However, it remains unknown how N-glycosylation affects GPCR signaling. β 2 adrenergic receptor (β 2 AR) has three N-glycosylation sites: Asn6, Asn15 at the N-terminus, and Asn187 at the second extracellular loop (ECL2). Here, we show that deletion of the N-glycan did not affect receptor expression and ligand binding. Deletion of the N-glycan at the N-terminus rather than Asn187 showed decreased effects on isoproterenol-promoted G-protein-dependent signaling, β-arrestin2 recruitment, and receptor internalization. Both N6Q and N15Q showed decreased receptor dimerization, while N187Q did not influence receptor dimerization. As decreased β 2 AR homodimer accompanied with reduced efficiency for receptor function, we proposed that the N-glycosylation of β 2 AR regulated receptor function by influencing receptor dimerization. To verify this hypothesis, we further paid attention to the residues at the dimerization interface. Studies of Lys60 and Glu338, two residues at the receptor dimerization interface, exhibited that the K60A/E338A showed decreased β 2 AR dimerization and its effects on receptor signaling were similar to N6Q and N15Q, which further supported the importance of receptor dimerization for receptor function. This work provides new insights into the relationship among glycosylation, dimerization, and function of GPCRs. Peptide-N-glycosidase F (PNGase F, EC 3.2.2.11); endo-β-N-acetylglucosaminidase A (Endo-A, EC 3.2.1.96). © 2017 Federation of European Biochemical Societies.

  9. Multi-Optimisation Consensus Clustering

    Science.gov (United States)

    Li, Jian; Swift, Stephen; Liu, Xiaohui

    Ensemble Clustering has been developed to provide an alternative way of obtaining more stable and accurate clustering results. It aims to avoid the biases of individual clustering algorithms. However, it is still a challenge to develop an efficient and robust method for Ensemble Clustering. Based on an existing ensemble clustering method, Consensus Clustering (CC), this paper introduces an advanced Consensus Clustering algorithm called Multi-Optimisation Consensus Clustering (MOCC), which utilises an optimised Agreement Separation criterion and a Multi-Optimisation framework to improve the performance of CC. Fifteen different data sets are used for evaluating the performance of MOCC. The results reveal that MOCC can generate more accurate clustering results than the original CC algorithm.

  10. Photochemistry in rare gas clusters

    International Nuclear Information System (INIS)

    Moeller, T.; Haeften, K. von; Pietrowski, R. von

    1999-01-01

    In this contribution photochemical processes in pure rare gas clusters will be discussed. The relaxation dynamics of electronically excited He clusters is investigated with luminescence spectroscopy. After electronic excitation of He clusters many sharp lines are observed in the visible and infrared spectral range which can be attributed to He atoms and molecules desorbing from the cluster. It turns out that the desorption of electronically excited He atoms and molecules is an important decay channel. The findings for He clusters are compared with results for Ar clusters. While desorption of electronically excited He atoms is observed for all clusters containing up to several thousand atoms a corresponding process in Ar clusters is only observed for very small clusters (N<10). (orig.)

  11. Photochemistry in rare gas clusters

    Energy Technology Data Exchange (ETDEWEB)

    Moeller, T.; Haeften, K. von; Pietrowski, R. von [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Hamburger Synchrotronstrahlungslabor; Laarman, T. [Universitaet Hamburg, II. Institut fuer Experimentalphysik, Luruper Chaussee 149, D-22761 Hamburg (Germany)

    1999-12-01

    In this contribution photochemical processes in pure rare gas clusters will be discussed. The relaxation dynamics of electronically excited He clusters is investigated with luminescence spectroscopy. After electronic excitation of He clusters many sharp lines are observed in the visible and infrared spectral range which can be attributed to He atoms and molecules desorbing from the cluster. It turns out that the desorption of electronically excited He atoms and molecules is an important decay channel. The findings for He clusters are compared with results for Ar clusters. While desorption of electronically excited He atoms is observed for all clusters containing up to several thousand atoms a corresponding process in Ar clusters is only observed for very small clusters (N<10). (orig.)

  12. Globular clusters, old and young

    International Nuclear Information System (INIS)

    Samus', N.N.

    1984-01-01

    The problem of similarity of and difference in the globular and scattered star clusters is considered. Star clusters in astronomy are related either to globular or to scattered ones according to the structure of Hertzsprung-Russell diagram constructed for star clusters, but not according to the appearance. The qlobular clusters in the Galaxy are composed of giants and subgiants, which testifies to the old age of the globular clusters. The Globular clusters in the Magellanic clouds are classified into ''red'' ones - similar to the globular clusters of the Galaxy, and ''blue'' ones - similar to them in appearance but differing extremely by the star composition and so by the age. The old star clusters are suggested to be called globular ones, while another name (''populous'', for example) is suggested to be used for other clusters similar to globular ones only in appearance

  13. Globular clusters and galaxy halos

    International Nuclear Information System (INIS)

    Van Den Bergh, S.

    1984-01-01

    Using semipartial correlation coefficients and bootstrap techniques, a study is made of the important features of globular clusters with respect to the total number of galaxy clusters and dependence of specific galaxy cluster on parent galaxy type, cluster radii, luminosity functions and cluster ellipticity. It is shown that the ellipticity of LMC clusters correlates significantly with cluster luminosity functions, but not with cluster age. The cluter luminosity value above which globulars are noticeably flattened may differ by a factor of about 100 from galaxy to galaxy. Both in the Galaxy and in M31 globulars with small core radii have a Gaussian distribution over luminosity, whereas clusters with large core radii do not. In the cluster systems surrounding the Galaxy, M31 and NGC 5128 the mean radii of globular clusters was found to increase with the distance from the nucleus. Central galaxies in rich clusters have much higher values for specific globular cluster frequency than do other cluster ellipticals, suggesting that such central galaxies must already have been different from normal ellipticals at the time they were formed

  14. Clustering of resting state networks.

    Directory of Open Access Journals (Sweden)

    Megan H Lee

    Full Text Available The goal of the study was to demonstrate a hierarchical structure of resting state activity in the healthy brain using a data-driven clustering algorithm.The fuzzy-c-means clustering algorithm was applied to resting state fMRI data in cortical and subcortical gray matter from two groups acquired separately, one of 17 healthy individuals and the second of 21 healthy individuals. Different numbers of clusters and different starting conditions were used. A cluster dispersion measure determined the optimal numbers of clusters. An inner product metric provided a measure of similarity between different clusters. The two cluster result found the task-negative and task-positive systems. The cluster dispersion measure was minimized with seven and eleven clusters. Each of the clusters in the seven and eleven cluster result was associated with either the task-negative or task-positive system. Applying the algorithm to find seven clusters recovered previously described resting state networks, including the default mode network, frontoparietal control network, ventral and dorsal attention networks, somatomotor, visual, and language networks. The language and ventral attention networks had significant subcortical involvement. This parcellation was consistently found in a large majority of algorithm runs under different conditions and was robust to different methods of initialization.The clustering of resting state activity using different optimal numbers of clusters identified resting state networks comparable to previously obtained results. This work reinforces the observation that resting state networks are hierarchically organized.

  15. Clustering in Ethiopia

    African Journals Online (AJOL)

    Background: The importance of local variations in patterns of health and disease are increasingly recognised, but, particularly in the case of tropical infections, available methods and resources for characterising disease clusters in time and space are limited. Whilst the Global Positioning System. (GPS) allows accurate and ...

  16. Hardness of Clustering

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Hardness of Clustering. Both k-means and k-medians intractable (when n and d are both inputs even for k =2). The best known deterministic algorithms. are based on Voronoi partitioning that. takes about time. Need for approximation – “close” to optimal.

  17. On small clusters

    International Nuclear Information System (INIS)

    Bernardes, N.

    1984-01-01

    A discussion is presented of zero-point motion effects on the binding energy of a small cluster of identical particles interacting through short range attractive-repulsive forces. The model is appropriate to a discussion of both Van der Waals as well as nuclear forces. (Author) [pt

  18. Emergence of regional clusters

    DEFF Research Database (Denmark)

    Dahl, Michael S.; Østergaard, Christian Richter; Dalum, Bent

    2010-01-01

    The literature on regional clusters has increased considerably during the last decade. The emergence and growth patterns are usually explained by such factors as unique local culture, regional capabilities, tacit knowledge or the existence of location-specific externalities (knowledge spillovers...

  19. Supersonic copper clusters

    International Nuclear Information System (INIS)

    Powers, D.E.; Hansen, S.G.; Geusic, M.E.; Michalopoulos, D.L.; Smalley, R.E.

    1983-01-01

    Copper clusters ranging in size from 1 to 29 atoms have been prepared in a supersonic beam by laser vaporization of a rotating copper target rod within the throat of a pulsed supersonic nozzle using helium for the carrier gas. The clusters were cooled extensively in the supersonic expansion [T(translational) 1 to 4 K, T(rotational) = 4 K, T(vibrational) = 20 to 70 K]. These clusters were detected in the supersonic beam by laser photoionization with time-of-flight mass analysis. Using a number of fixed frequency outputs of an exciplex laser, the threshold behavior of the photoionization cross section was monitored as a function of cluster size.nce two-photon ionization (R2PI) with mass selective detection allowed the detection of five new electronic band systems in the region between 2690 and 3200 A, for each of the three naturally occurring isotopic forms of Cu 2 . In the process of scanning the R2PI spectrum of these new electronic states, the ionization potential of the copper dimer was determined to be 7.894 +- 0.015 eV

  20. Greedy subspace clustering.

    Science.gov (United States)

    2016-09-01

    We consider the problem of subspace clustering: given points that lie on or near the union of many low-dimensional linear subspaces, recover the subspaces. To this end, one first identifies sets of points close to the same subspace and uses the sets ...

  1. Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors.

    Science.gov (United States)

    Pediaditakis, Iosif; Iliopoulos, Ioannis; Theologidis, Ioannis; Delivanoglou, Nickoleta; Margioris, Andrew N; Charalampopoulos, Ioannis; Gravanis, Achille

    2015-01-01

    Dehydroepiandosterone (DHEA), the most abundant steroid in humans, affects multiple cellular functions of the endocrine, immune, and nervous systems. However, up to quite recently, no receptor has been described specifically for it, whereas most of its physiological actions have been attributed to its conversion to either androgens or estrogens. DHEA interacts and modulate a variety of membrane and intracellular neurotransmitter and steroid receptors. We have recently reported that DHEA protects neuronal cells against apoptosis, interacting with TrkA, the high-affinity prosurvival receptor of the neurotrophin, nerve growth factor. Intrigued by its pleiotropic effects in the nervous system of a variety of species, we have investigated the ability of DHEA to interact with the other two mammalian neurotrophin receptors, ie, the TrkB and TrkC, as well as their invertebrate counterparts (orthologs) in mollusks Lymnaea and Aplysia and in cephalochordate fish Amphioxus. Amazingly, DHEA binds to all Trk receptors, although with lower affinity by 2 orders of magnitude compared with that of the polypeptidic neurotrophins. DHEA effectively induced the first step of the TrkA and TrkC receptors activation (phosphorylation at tyrosine residues), including the vertebrate neurotrophin nonresponding invertebrate Lymnaea and Aplysia receptors. Based on our data, we hypothesize that early in evolution, DHEA may have acted as a nonspecific neurotrophic factor promoting neuronal survival. The interaction of DHEA with all types of neurotrophin receptors offers new insights into the largely unidentified mechanisms of its actions on multiple tissues and organs known to express neurotrophin receptors.

  2. Data clustering algorithms and applications

    CERN Document Server

    Aggarwal, Charu C

    2013-01-01

    Research on the problem of clustering tends to be fragmented across the pattern recognition, database, data mining, and machine learning communities. Addressing this problem in a unified way, Data Clustering: Algorithms and Applications provides complete coverage of the entire area of clustering, from basic methods to more refined and complex data clustering approaches. It pays special attention to recent issues in graphs, social networks, and other domains.The book focuses on three primary aspects of data clustering: Methods, describing key techniques commonly used for clustering, such as fea

  3. Cluster structures in light nuclei

    International Nuclear Information System (INIS)

    Horiuchi, H.

    2000-01-01

    Complete text of publication follows. Clustering in neutron-rich nuclei is discussed. To understand the novel features (1,2,3) of the clustering in neutron-rich nuclei, the basic features of the clustering in stable nuclei (4) are briefly reviewed. In neutron-rich nuclei, the requirement of the stability of clusters is questioned and the threshold rule is no more obeyed. Examples of clustering in Be and B isotopes (4,5) are discussed in some detail. Possible existence of novel type of clustering near neutron dripline is suggested (1). (author)

  4. Cluster model of the nucleus

    International Nuclear Information System (INIS)

    Horiuchi, H.; Ikeda, K.

    1986-01-01

    This article reviews the development of the cluster model study. The stress is put on two points; one is how the cluster structure has come to be regarded as a fundamental structure in light nuclei together with the shell-model structure, and the other is how at present the cluster model is extended to and connected with the studies of the various subjects many of which are in the neighbouring fields. The authors the present the main theme with detailed explanations of the fundamentals of the microscopic cluster model which have promoted the development of the cluster mode. Examples of the microscopic cluster model study of light nuclear structure are given

  5. Affective Maps

    DEFF Research Database (Denmark)

    Salovaara-Moring, Inka

    . In particular, mapping environmental damage, endangered species, and human made disasters has become one of the focal point of affective knowledge production. These ‘more-than-humangeographies’ practices include notions of species, space and territory, and movement towards a new political ecology. This type...... of digital cartographies has been highlighted as the ‘processual turn’ in critical cartography, whereas in related computational journalism it can be seen as an interactive and iterative process of mapping complex and fragile ecological developments. This paper looks at computer-assisted cartography as part...

  6. Simulating the Birth of Massive Star Clusters: Is Destruction Inevitable?

    Science.gov (United States)

    Rosen, Anna

    2013-10-01

    Very early in its operation, the Hubble Space Telescope {HST} opened an entirely new frontier: study of the demographics and properties of star clusters far beyond the Milky Way. However, interpretation of HST's observations has proven difficult, and has led to the development of two conflicting models. One view is that most massive star clusters are disrupted during their infancy by feedback from newly formed stars {i.e., "infant mortality"}, independent of cluster mass or environment. The other model is that most star clusters survive their infancy and are disrupted later by mass-dependent dynamical processes. Since observations at present have failed to discriminate between these views, we propose a theoretical investigation to provide new insight. We will perform radiation-hydrodynamic simulations of the formation of massive star clusters, including for the first time a realistic treatment of the most important stellar feedback processes. These simulations will elucidate the physics of stellar feedback, and allow us to determine whether cluster disruption is mass-dependent or -independent. We will also use our simulations to search for observational diagnostics that can distinguish bound from unbound clusters, and to predict how cluster disruption affects the cluster luminosity function in a variety of galactic environments.

  7. TreeCluster: Massively scalable transmission clustering using phylogenetic trees

    OpenAIRE

    Moshiri, Alexander

    2018-01-01

    Background: The ability to infer transmission clusters from molecular data is critical to designing and evaluating viral control strategies. Viral sequencing datasets are growing rapidly, but standard methods of transmission cluster inference do not scale well beyond thousands of sequences. Results: I present TreeCluster, a cross-platform tool that performs transmission cluster inference on a given phylogenetic tree orders of magnitude faster than existing inference methods and supports multi...

  8. The rotation of galaxy clusters

    International Nuclear Information System (INIS)

    Tovmassian, H.M.

    2015-01-01

    The method for detection of the galaxy cluster rotation based on the study of distribution of member galaxies with velocities lower and higher of the cluster mean velocity over the cluster image is proposed. The search for rotation is made for flat clusters with a/b> 1.8 and BMI type clusters which are expected to be rotating. For comparison there were studied also round clusters and clusters of NBMI type, the second by brightness galaxy in which does not differ significantly from the cluster cD galaxy. Seventeen out of studied 65 clusters are found to be rotating. It was found that the detection rate is sufficiently high for flat clusters, over 60 per cent, and clusters of BMI type with dominant cD galaxy, ≈ 35 per cent. The obtained results show that clusters were formed from the huge primordial gas clouds and preserved the rotation of the primordial clouds, unless they did not have mergings with other clusters and groups of galaxies, in the result of which the rotation has been prevented

  9. Rapid, directed transport of DC-SIGN clusters in the plasma membrane.

    Science.gov (United States)

    Liu, Ping; Weinreb, Violetta; Ridilla, Marc; Betts, Laurie; Patel, Pratik; de Silva, Aravinda M; Thompson, Nancy L; Jacobson, Ken

    2017-11-01

    C-type lectins, including dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), are all-purpose pathogen receptors that exist in nanoclusters in plasma membranes of dendritic cells. A small fraction of these clusters, obvious from the videos, can undergo rapid, directed transport in the plane of the plasma membrane at average speeds of more than 1 μm/s in both dendritic cells and MX DC-SIGN murine fibroblasts ectopically expressing DC-SIGN. Surprisingly, instantaneous speeds can be considerably greater. In MX DC-SIGN cells, many cluster trajectories are colinear with microtubules that reside close to the ventral membrane, and the microtubule-depolymerizing drug, nocodazole, markedly reduced the areal density of directed movement trajectories, suggesting a microtubule motor-driven transport mechanism; by contrast, latrunculin A, which affects the actin network, did not depress this movement. Rapid, retrograde movement of DC-SIGN may be an efficient mechanism for bringing bound pathogen on the leading edge and projections of dendritic cells to the perinuclear region for internalization and processing. Dengue virus bound to DC-SIGN on dendritic projections was rapidly transported toward the cell center. The existence of this movement within the plasma membrane points to an unexpected lateral transport mechanism in mammalian cells and challenges our current concepts of cortex-membrane interactions.

  10. Investigation of Gamma-aminobutyric acid (GABA A receptors genes and migraine susceptibility

    Directory of Open Access Journals (Sweden)

    Ciccodicola Alfredo

    2008-12-01

    Full Text Available Abstract Background Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24–28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ, which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24–28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type ε (GABRE and type θ (GABRQ genes and their involvement in migraine. Methods We have performed an association analysis in a large population of case-controls (275 unrelated Caucasian migraineurs versus 275 controls examining a set of 3 single nucleotide polymorphisms (SNPs in the coding region (exons 3, 5 and 9 of the GABRE gene and also the I478F coding variant of the GABRQ gene. Results Our study did not show any association between the examined SNPs in our test population (P > 0.05. Conclusion Although these particular GABA receptor genes did not show positive association, further studies are necessary to consider the role of other GABA receptor genes in migraine susceptibility.

  11. Single-cluster dynamics for the random-cluster model

    NARCIS (Netherlands)

    Deng, Y.; Qian, X.; Blöte, H.W.J.

    2009-01-01

    We formulate a single-cluster Monte Carlo algorithm for the simulation of the random-cluster model. This algorithm is a generalization of the Wolff single-cluster method for the q-state Potts model to noninteger values q>1. Its results for static quantities are in a satisfactory agreement with those

  12. Choosing the Number of Clusters in K-Means Clustering

    Science.gov (United States)

    Steinley, Douglas; Brusco, Michael J.

    2011-01-01

    Steinley (2007) provided a lower bound for the sum-of-squares error criterion function used in K-means clustering. In this article, on the basis of the lower bound, the authors propose a method to distinguish between 1 cluster (i.e., a single distribution) versus more than 1 cluster. Additionally, conditional on indicating there are multiple…

  13. Androgen insensitivity syndrome: gonadal androgen receptor activity

    International Nuclear Information System (INIS)

    Coulam, C.B.; Graham, M.L.; Spelsberg, T.C.

    1984-01-01

    To determine whether abnormalities of the androgen receptor previously observed in skin fibroblasts from patients with androgen insensitivity syndrome also occur in the gonads of affected individuals, androgen receptor activity in the gonads of a patient with testicular feminization syndrome was investigated. Using conditions for optimal recovery of androgen receptor from human testes established by previous studies, we detected the presence of a high-affinity (dissociation constant . 3.2 X 10(-10) mol/L), low-capacity (4.2 X 10(-12) mol/mg DNA), androgen-binding protein when tritium-labeled R1881 was incubated at 4 degrees C with nuclear extracts from the gonads of control patients or from a patient with testicular feminization syndrome but not when incubated at 37 degrees C. Thus this patient has an androgen receptor with a temperature lability similar to that of receptors from normal persons

  14. Heavy hitters via cluster-preserving clustering

    DEFF Research Database (Denmark)

    Larsen, Kasper Green; Nelson, Jelani; Nguyen, Huy L.

    2016-01-01

    In the turnstile lp heavy hitters problem with parameter ε, one must maintain a high-dimensional vector xεRn subject to updates of the form update (i,Δ) causing the change xi≤ ← xi + Δ, where iε[n], ΔεR. Upon receiving a query, the goal is to report every "heavy hitter" iε[n] with |xi| ≥ε......|x|p as part of a list L⊆[n] of size O(1/εp), i.e. proportional to the maximum possible number of heavy hitters. For any pε(0,2] the COUNTSKETCH of [CCFC04] solves lp heavy hitters using O(ε-plog n) words of space with O(log n) update time, O(nlog n) query time to output L, and whose output after any query......, providing correctness whp. In fact, a simpler version of our algorithm for p = 1 in the strict turnstile model answers queries even faster than the "dyadic trick" by roughly a log n factor, dominating it in all regards. Our main innovation is an efficient reduction from the heavy hitters to a clustering...

  15. Evolution of the spherical clusters

    International Nuclear Information System (INIS)

    Surdin, V.G.

    1978-01-01

    The possible processes of the Galaxy spherical clusters formation and evolution are described on a popular level. The orbits of spherical cluster motion and their spatial velocities are determined. Given are the distrbutions of spherical cluster stars according to their velocities and the observed distribution of spherical clusters in the area of the Galaxy slow evolution. The dissipation and dynamic friction processes destructing clusters with the mass less than 10 4 of solar mass and bringing about the reduction of clusters in the Galaxy are considered. The paradox of forming mainly X-ray sources in spherical clusters is explained. The schematic image of possible ways of forming X-ray sources in spherical clusters is given

  16. Clusters in nuclei. Vol. 1

    International Nuclear Information System (INIS)

    Beck, Christian

    2010-01-01

    Following the pioneering discovery of alpha clustering and of molecular resonances, the field of nuclear clustering is presently one of the domains of heavy-ion nuclear physics facing both the greatest challenges and opportunities. After many summer schools and workshops, in particular over the last decade, the community of nuclear molecular physics decided to team up in producing a comprehensive collection of lectures and tutorial reviews covering the field. This first volume, gathering seven extensive lectures, covers the follow topics: - Cluster Radioactivity - Cluster States and Mean Field Theories - Alpha Clustering and Alpha Condensates - Clustering in Neutron-rich Nuclei - Di-neutron Clustering - Collective Clusterization in Nuclei - Giant Nuclear Molecules By promoting new ideas and developments while retaining a pedagogical nature of presentation throughout, these lectures will both serve as a reference and as advanced teaching material for future courses and schools in the fields of nuclear physics and nuclear astrophysics. (orig.)

  17. Structure and bonding in clusters

    International Nuclear Information System (INIS)

    Kumar, V.

    1991-10-01

    We review here the recent progress made in the understanding of the electronic and atomic structure of small clusters of s-p bonded materials using the density functional molecular dynamics technique within the local density approximation. Starting with a brief description of the method, results are presented for alkali metal clusters, clusters of divalent metals such as Mg and Be which show a transition from van der Waals or weak chemical bonding to metallic behaviour as the cluster size grows and clusters of Al, Sn and Sb. In the case of semiconductors, we discuss results for Si, Ge and GaAs clusters. Clusters of other materials such as P, C, S, and Se are also briefly discussed. From these and other available results we suggest the possibility of unique structures for the magic clusters. (author). 69 refs, 7 figs, 1 tab

  18. Random matrix improved subspace clustering

    KAUST Repository

    Couillet, Romain; Kammoun, Abla

    2017-01-01

    This article introduces a spectral method for statistical subspace clustering. The method is built upon standard kernel spectral clustering techniques, however carefully tuned by theoretical understanding arising from random matrix findings. We show

  19. Eclipsing binaries in open clusters

    DEFF Research Database (Denmark)

    Southworth, John; Clausen, J.V.

    2006-01-01

    Stars: fundamental parameters - Stars : binaries : eclipsing - Stars: Binaries: spectroscopic - Open clusters and ass. : general Udgivelsesdato: 5 August......Stars: fundamental parameters - Stars : binaries : eclipsing - Stars: Binaries: spectroscopic - Open clusters and ass. : general Udgivelsesdato: 5 August...

  20. A search for presynaptic inhibitory histamine receptors in guinea-pig tissues: Further H3 receptors but no evidence for H4 receptors.

    Science.gov (United States)

    Petri, Doris; Schlicker, Eberhard

    2016-07-01

    The histamine H4 receptor is coupled to Gi/o proteins and expressed on inflammatory cells and lymphoid tissues; it was suggested that this receptor also occurs in the brain or on peripheral neurones. Since many Gi/o protein-coupled receptors, including the H3 receptor, serve as presynaptic inhibitory receptors, we studied whether the sympathetic neurones supplying four peripheral tissues and the cholinergic neurones in the hippocampus from the guinea-pig are equipped with release-modulating H4 and H3 receptors. For this purpose, we preincubated tissue pieces from the aorta, atrium, renal cortex and vas deferens with (3)H-noradrenaline and hippocampal slices with (3)H-choline and determined the electrically evoked tritium overflow. The stimulation-evoked overflow in the five superfused tissues was inhibited by the muscarinic receptor agonist oxotremorine, which served as a positive control, but not affected by the H4 receptor agonist 4-methylhistamine. The H3 receptor agonist R-α-methylhistamine inhibited noradrenaline release in the peripheral tissues without affecting acetylcholine release in the hippocampal slices. Thioperamide shifted the concentration-response curve of histamine in the aorta and the renal cortex to the right, yielding apparent pA2 values of 8.0 and 8.1, respectively, which are close to its affinity at other H3 receptors but higher by one log unit than its pKi at the H4 receptor of the guinea-pig. In conclusion, histamine H4 receptors could not be identified in five experimental models of the guinea-pig that are suited for the detection of presynaptic inhibitory receptors whereas H3 receptors could be shown in the peripheral tissues but not in the hippocampus. This article is part of the Special Issue entitled 'Histamine Receptors'. Copyright © 2015 Elsevier Ltd. All rights reserved.