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Sample records for h4 receptor antagonism

  1. Effects of a histamine H4 receptor antagonist on cisplatin-induced anorexia in mice.

    Science.gov (United States)

    Yamamoto, Kouichi; Okui, Rikuya; Yamatodani, Atsushi

    2018-04-12

    Cancer chemotherapy often induces gastrointestinal symptoms such as anorexia, nausea, and vomiting. Antiemetic agents are effective in inhibiting nausea and vomiting, but patients still experience anorexia. We previously reported that chemotherapeutic agent-induced anorexia is associated with an increase of inflammatory cytokines. Other studies also reported that antagonism of the histamine H 4 receptor is anti-inflammatory. In this study, we investigated the involvement of the H 4 receptor in the development of chemotherapy-induced anorexia in mice. Cisplatin-induced anorexia occurred within 24 h of its administration and continued for 3 days. The early phase (day 1), but not the delayed phase (days 2 and 3), of anorexia was inhibited by the daily injection of a 5-HT 3 receptor antagonist (granisetron). However, a corticosteroid (dexamethasone) or selective H 4 receptor antagonist (JNJ7777120) abolished the delayed phases of anorexia. Cisplatin significantly increased TNF-α mRNA expression in the hypothalamus and spleen, and the period of expression increase paralleled the onset period of anorexia. In addition, pretreatment with JNJ7777120 completely inhibited the increased expression. These results suggest that TNF-α mRNA expression via H 4 receptors may contribute to the development of cisplatin-induced anorexia, and that H 4 receptor antagonists are potentially useful treatments. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Ophthalmic antihistamines and H1-H4 receptors.

    Science.gov (United States)

    Wade, Laurie; Bielory, Leonard; Rudner, Shara

    2012-10-01

    Antihistamines exert pharmacologic effects by binding to four histamine receptors (H1-H4) at different affinities, producing variable effects depending on the receptor they predominantly bind to. This review's purpose is to determine the relative potency of antihistamines by comparing their binding affinities to these receptors. Studies on binding affinities of antihistamines to histamine receptors were reviewed and the dissociation constant for inhibitor binding (Ki) analyzed to determine the most and least potent antihistamine for each receptor. We retrieved the binding affinities for nineteen antihistamines. For H1 receptors, pyrilamine exhibited the highest affinity (Ki = 0.8 nM), and thioperamide the lowest (Ki = 280, 000 nM). For H2 receptors, ranitidine exhibited the highest affinity (Ki = 187 nM), and olopatadine the lowest (Ki = 100 ,000 nM). For the recently discovered H3 and H4 receptors, thioperamide exhibited the highest affinity (Ki = 1.1 nM), and olopatadine exhibited the lowest (Ki = 79 ,400 nM), to H3. Data on binding affinities to the H4 receptor exist for: ketotifen, pheniramine, ranitidine, cimetidine and thioperamide. Of these, thioperamide exhibited the highest affinity (Ki = 27 nM), whereas cimetidine and ranitidine exhibited the lowest affinity (Ki = >10, 000 nM) for H4 receptors. This review summarizes the relative potency of antihistamines based on their binding affinities to the four histamine receptors. Although data on binding affinities of antihistamines to the H4 receptor are sparse, it is apparent that further research on these histamine subtypes may open new venues for more direct treatment with a higher therapeutic efficacy on allergic disorders including those affecting the ocular surface.

  3. Histamine H4 receptor in oral lichen planus.

    Science.gov (United States)

    Salem, A; Al-Samadi, A; Stegajev, V; Stark, H; Häyrinen-Immonen, R; Ainola, M; Hietanen, J; Konttinen, Y T

    2015-04-01

    Oral lichen planus (OLP) is an autoimmune disease characterized by a band-like T-cell infiltrate below the apoptotic epithelial cells and degenerated basement membrane. We tested the hypothesis that the high-affinity histamine H4 receptors (H4 Rs) are downregulated in OLP by high histamine concentrations and proinflammatory T-cell cytokines. Immunohistochemistry and immunofluorescence staining, image analysis and quantitative real-time polymerase chain reaction of tissue samples and cytokine-stimulated cultured SCC-25 and primary human oral keratinocytes. H4 R immunoreactivity was weak in OLP and characterized by mast cell (MC) hyperplasia and degranulation. In contrast to controls, H4 R immunostaining and MC counts were negatively correlated in OLP (P = 0.003). H4 R agonist at nanomolar levels led to a rapid internalization of H4 Rs, whereas high histamine concentration and interferon-γ decreased HRH4 -gene transcripts. Healthy oral epithelial cells are equipped with H4 R, which displays a uniform staining pattern in a MC-independent fashion. In contrast, in OLP, increased numbers of activated MCs associate with increasing loss of epithelial H4 R. Cell culture experiments suggest a rapid H4 R stimulation-dependent receptor internalization and a slow cytokine-driven decrease in H4 R synthesis. H4 R may be involved in the maintenance of healthy oral mucosa. In OLP, this maintenance might be impaired by MC degranulation and inflammatory cytokines. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. The Histamine H4 Receptor: From Orphan to the Clinic

    Directory of Open Access Journals (Sweden)

    Robin L. Thurmond

    2015-03-01

    Full Text Available The histamine H4 receptor (H4R was first noted as a sequence in genomic databases that had features of a G-protein coupled receptor. This putative receptor was found to bind histamine consistent with its homology to other histamine receptors and thus became the fourth member of the histamine receptor family. Due to the previous success of drugs that target the H1 and H2 receptors, an effort was made to understand the function of this receptor and determine if it represented a drug target. Taking advantage of the vast literature on histamine, a search for histamine activity that did not appear to be mediated by the other three histamine receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antihistamines that target the H1 and H2 receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. Antihistamines that target the H1 receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists to the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel receptor and the translation of this into

  5. Identification and mechanism of ABA receptor antagonism

    KAUST Repository

    Melcher, Karsten; Xu, Yong; Ng, Ley-Moy; Zhou, X. Edward; Soon, Fen-Fen; Chinnusamy, Viswanathan; Suino-Powell, Kelly M.; Kovach, Amanda; Tham, Fook S.; Cutler, Sean R.; Li, Jun; Yong, Eu-Leong; Zhu, Jian-Kang; Xu, H. Eric

    2010-01-01

    The phytohormone abscisic acid (ABA) functions through a family of fourteen PYR/PYL receptors, which were identified by resistance to pyrabactin, a synthetic inhibitor of seed germination. ABA activates these receptors to inhibit type 2C protein phosphatases, such as ABI1, yet it remains unclear whether these receptors can be antagonized. Here we demonstrate that pyrabactin is an agonist of PYR1 and PYL1 but is unexpectedly an antagonist of PYL2. Crystal structures of the PYL2-pyrabactin and PYL1-pyrabactin-ABI1 complexes reveal the mechanism responsible for receptor-selective activation and inhibition, which enables us to design mutations that convert PYL1 to a pyrabactin-inhibited receptor and PYL2 to a pyrabactin-activated receptor and to identify new pyrabactin-based ABA receptor agonists. Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands. © 2010 Nature America, Inc. All rights reserved.

  6. Identification and mechanism of ABA receptor antagonism

    KAUST Repository

    Melcher, Karsten

    2010-08-22

    The phytohormone abscisic acid (ABA) functions through a family of fourteen PYR/PYL receptors, which were identified by resistance to pyrabactin, a synthetic inhibitor of seed germination. ABA activates these receptors to inhibit type 2C protein phosphatases, such as ABI1, yet it remains unclear whether these receptors can be antagonized. Here we demonstrate that pyrabactin is an agonist of PYR1 and PYL1 but is unexpectedly an antagonist of PYL2. Crystal structures of the PYL2-pyrabactin and PYL1-pyrabactin-ABI1 complexes reveal the mechanism responsible for receptor-selective activation and inhibition, which enables us to design mutations that convert PYL1 to a pyrabactin-inhibited receptor and PYL2 to a pyrabactin-activated receptor and to identify new pyrabactin-based ABA receptor agonists. Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands. © 2010 Nature America, Inc. All rights reserved.

  7. Uncompetitive antagonism of AMPA receptors

    DEFF Research Database (Denmark)

    Andersen, Trine F; Tikhonov, Denis B; Bølcho, Ulrik

    2006-01-01

    Philanthotoxins are uncompetitive antagonists of Ca2+-permeable AMPA receptors presumed to bind to the pore-forming region, but a detailed molecular mechanism for this interaction is missing. Here a small library of novel philanthotoxins was designed and synthesized using a solid-phase strategy. ...

  8. Agonism and antagonism at the insulin receptor

    DEFF Research Database (Denmark)

    Knudsen, Louise; Hansen, Bo Falck; Jensen, Pia

    2012-01-01

    Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new...... insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been...... shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B'29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR...

  9. Sequential application of ligand and structure based modeling approaches to index chemicals for their hH4R antagonism.

    Directory of Open Access Journals (Sweden)

    Matteo Pappalardo

    Full Text Available The human histamine H4 receptor (hH4R, a member of the G-protein coupled receptors (GPCR family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH4R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH4R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE and Iterative Stochastic Elimination (ISE approach, were used to index chemicals for their hH4R bioactivity. An application of the prediction model on external test set composed of more than 160 hH4R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ∼ 4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH4R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH4R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and

  10. Sequential application of ligand and structure based modeling approaches to index chemicals for their hH4R antagonism.

    Science.gov (United States)

    Pappalardo, Matteo; Shachaf, Nir; Basile, Livia; Milardi, Danilo; Zeidan, Mouhammed; Raiyn, Jamal; Guccione, Salvatore; Rayan, Anwar

    2014-01-01

    The human histamine H4 receptor (hH4R), a member of the G-protein coupled receptors (GPCR) family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH4R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH4R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE) and Iterative Stochastic Elimination (ISE) approach, were used to index chemicals for their hH4R bioactivity. An application of the prediction model on external test set composed of more than 160 hH4R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ∼ 4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH4R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH4R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and increase the

  11. 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.

  12. Prostaglandins and prostaglandin receptor antagonism in migraine

    DEFF Research Database (Denmark)

    Antonova, Maria

    2013-01-01

    Human models of headache may contribute to understanding of prostaglandins' role in migraine pathogenesis. The current thesis investigated the migraine triggering effect of prostaglandin E2 (PGE2) in migraine patients without aura, the efficacy of a novel EP4 receptor antagonist, BGC20....... The infusion of PGE2 caused the immediate migraine-like attacks and vasodilatation of the middle cerebral artery in migraine patients without aura. The highly specific and potent EP4 receptor antagonist, BGC20-1531, was not able to attenuate PGE2-induced headache and vasodilatation of both intra- and extra......-cerebral arteries. The intravenous infusion of PGF2α did not induce headache or statistically significant vasoconstriction of cerebral arteries in healthy volunteers. Novel data on PGE2-provoked immediate migraine-like attacks suggest that PGE2 may be one of the important final products in the pathogenesis...

  13. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

    Science.gov (United States)

    Hubers, Scott A.; Brown, Nancy J.

    2016-01-01

    Heart failure affects approximately 5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the FDA approved the first of a new class of drugs for the treatment of heart failure; valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses two of the pathophysiologic mechanisms of heart failure - activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared to enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacologic properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension. PMID:26976916

  14. The extracellular loop 2 (ECL2 of the human histamine H4 receptor substantially contributes to ligand binding and constitutive activity.

    Directory of Open Access Journals (Sweden)

    David Wifling

    Full Text Available In contrast to the corresponding mouse and rat orthologs, the human histamine H4 receptor (hH4R shows extraordinarily high constitutive activity. In the extracellular loop (ECL, replacement of F169 by V as in the mouse H4R significantly reduced constitutive activity. Stabilization of the inactive state was even more pronounced for a double mutant, in which, in addition to F169V, S179 in the ligand binding site was replaced by M. To study the role of the FF motif in ECL2, we generated the hH4R-F168A mutant. The receptor was co-expressed in Sf9 insect cells with the G-protein subunits Gαi2 and Gβ1γ2, and the membranes were studied in [3H]histamine binding and functional [35S]GTPγS assays. The potency of various ligands at the hH4R-F168A mutant decreased compared to the wild-type hH4R, for example by 30- and more than 100-fold in case of the H4R agonist UR-PI376 and histamine, respectively. The high constitutive activity of the hH4R was completely lost in the hH4R-F168A mutant, as reflected by neutral antagonism of thioperamide, a full inverse agonist at the wild-type hH4R. By analogy, JNJ7777120 was a partial inverse agonist at the hH4R, but a partial agonist at the hH4R-F168A mutant, again demonstrating the decrease in constitutive activity due to F168A mutation. Thus, F168 was proven to play a key role not only in ligand binding and potency, but also in the high constitutive activity of the hH4R.

  15. TRPV1 and PLC Participate in Histamine H4 Receptor-Induced Itch.

    Science.gov (United States)

    Jian, Tunyu; Yang, Niuniu; Yang, Yan; Zhu, Chan; Yuan, Xiaolin; Yu, Guang; Wang, Changming; Wang, Zhongli; Shi, Hao; Tang, Min; He, Qian; Lan, Lei; Wu, Guanyi; Tang, Zongxiang

    2016-01-01

    Histamine H4 receptor has been confirmed to play a role in evoking peripheral pruritus. However, the ionic and intracellular signaling mechanism of activation of H4 receptor on the dorsal root ganglion (DRG) neurons is still unknown. By using cell culture and calcium imaging, we studied the underlying mechanism of activation of H4 receptor on the DRG neuron. Immepip dihydrobromide (immepip)-a histamine H4 receptor special agonist under cutaneous injection-obviously induced itch behavior of mice. Immepip-induced scratching behavior could be blocked by TRPV1 antagonist AMG9810 and PLC pathway inhibitor U73122. Application of immepip (8.3-50 μM) could also induce a dose-dependent increase in intracellular Ca(2+) ([Ca(2+)]i) of DRG neurons. We found that 77.8% of the immepip-sensitized DRG neurons respond to the TRPV1 selective agonist capsaicin. U73122 could inhibit immepip-induced Ca(2+) responses. In addition, immepip-induced [Ca(2+)]i increase could be blocked by ruthenium red, capsazepine, and AMG9810; however it could not be blocked by TRPA1 antagonist HC-030031. These results indicate that TRPV1 but not TRPA1 is the important ion channel to induce the DRG neurons' responses in the downstream signaling pathway of histamine H4 receptor and suggest that TRPV1 may be involved in the mechanism of histamine-induced itch response by H4 receptor activation.

  16. TRPV1 and PLC Participate in Histamine H4 Receptor-Induced Itch

    Directory of Open Access Journals (Sweden)

    Tunyu Jian

    2016-01-01

    Full Text Available Histamine H4 receptor has been confirmed to play a role in evoking peripheral pruritus. However, the ionic and intracellular signaling mechanism of activation of H4 receptor on the dorsal root ganglion (DRG neurons is still unknown. By using cell culture and calcium imaging, we studied the underlying mechanism of activation of H4 receptor on the DRG neuron. Immepip dihydrobromide (immepip—a histamine H4 receptor special agonist under cutaneous injection—obviously induced itch behavior of mice. Immepip-induced scratching behavior could be blocked by TRPV1 antagonist AMG9810 and PLC pathway inhibitor U73122. Application of immepip (8.3–50 μM could also induce a dose-dependent increase in intracellular Ca2+ (Ca2+i of DRG neurons. We found that 77.8% of the immepip-sensitized DRG neurons respond to the TRPV1 selective agonist capsaicin. U73122 could inhibit immepip-induced Ca2+ responses. In addition, immepip-induced Ca2+i increase could be blocked by ruthenium red, capsazepine, and AMG9810; however it could not be blocked by TRPA1 antagonist HC-030031. These results indicate that TRPV1 but not TRPA1 is the important ion channel to induce the DRG neurons’ responses in the downstream signaling pathway of histamine H4 receptor and suggest that TRPV1 may be involved in the mechanism of histamine-induced itch response by H4 receptor activation.

  17. Human eosinophils - potential pharmacological model applied in human histamine H4 receptor research.

    Science.gov (United States)

    Grosicki, Marek; Kieć-Kononowicz, Katarzyna

    2015-01-01

    Histamine and histamine receptors are well known for their immunomodulatory role in inflammation. In this review we describe the role of histamine and histamine H4 receptor on human eosinophils. In the first part of article we provide short summary of histamine and histamine receptors role in physiology and histamine related therapeutics used in clinics. We briefly describe the human histamine receptor H4 and its ligands, as well as human eosinophils. In the second part of the review we provide detailed description of known histamine effects on eosinophils including: intracellular calcium concentration flux, actin polymerization, cellular shape change, upregulation of adhesion proteins and cellular chemotaxis. We provide proofs that these effects are mainly connected with the activation of histamine H4 receptor. When examining experimental data we discuss the controversial results and limitations of the studies performed on isolated eosinophils. In conclusion we believe that studies on histamine H4 receptor on human eosinophils can provide interesting new biomarkers that can be used in clinical studies of histamine receptors, that in future might result in the development of new strategies in the treatment of chronic inflammatory conditions like asthma or allergy, in which eosinophils are involved.

  18. Major advances in the development of histamine H4 receptor ligands.

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    Smits, Rogier A; Leurs, Rob; de Esch, Iwan J P

    2009-08-01

    The search for new and potent histamine H4 receptor ligands is leading to a steadily increasing number of scientific publications and patent applications. Several interesting and structurally diverse compounds have been found, but fierce IP competition for a preferred 2-aminopyrimidine scaffold is becoming apparent. Recent investigations into the role of the histamine H(4)R in (patho)physiology and the use of H4R ligands in in vivo disease models reveal enormous potential in the field of inflammation and allergy, among others. The development of ligands that display activity at two or more histamine receptor (HR) subtypes is another clinical opportunity that is currently being explored. Taken together, the histamine H4R field is gearing up for clinical studies and has the potential to deliver another generation of blockbuster drugs.

  19. In silico modeling techniques for predicting the tertiary structure of human H4 receptor.

    Science.gov (United States)

    Zaid, Hilal; Raiyn, Jamal; Osman, Midhat; Falah, Mizied; Srouji, Samer; Rayan, Anwar

    2016-01-01

    First cloned in 2000, the human Histamine H4 Receptor (hH4R) is the last member of the histamine receptors family discovered so far, it belongs to the GPCR super-family and is involved in a wide variety of immunological and inflammatory responses. Potential hH4R antagonists are proposed to have therapeutic potential for the treatment of allergies, inflammation, asthma and colitis. So far, no hH4R ligands have been successfully introduced to the pharmaceutical market, which creates a strong demand for new selective ligands to be developed. in silico techniques and structural based modeling are likely to facilitate the achievement of this goal. In this review paper we attempt to cover the fundamental concepts of hH4R structure modeling and its implementations in drug discovery and development, especially those that have been experimentally tested and to highlight some ideas that are currently being discussed on the dynamic nature of hH4R and GPCRs, in regards to computerized techniques for 3-D structure modeling.

  20. Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone.

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    Stephen R Morairty

    Full Text Available The hypocretin (orexin system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1 and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867 and HCRTR2 (EMPA antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM and non-REM (NR sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg, almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4-6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking "drive".

  1. 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.

  2. A new generation of anti-histamines : Histamine H4 receptor antagonists on their way to the clinic

    NARCIS (Netherlands)

    Engelhardt, Harald; Smits, Rogier A; Leurs, Rob; Haaksma, Eric E J; de Esch, Iwan J P

    At the turn of the millennium, the DNA sequence encoding the histamine H4 receptor (H4R) was identified in data from human genome databases. Considering the clinical importance of H1R and H2R ligands, and the clinical trials that are ongoing for H3R ligands, the latest addition to the histamine

  3. Histone H4 Lys 20 methyltransferase SET8 promotes androgen receptor-mediated transcription activation in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Lushuai [Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Li, Yanyan; Du, Fengxia [Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); Han, Xiao [Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Li, Xiaohua [Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); Niu, Yuanjie [Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, Tianjin Medical University, Tianjin 300070 (China); Ren, Shancheng, E-mail: renshancheng@gmail.com [Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Sun, Yingli, E-mail: sunyl@big.ac.cn [Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China)

    2014-07-18

    Highlights: • Dihydrotestosterone stimulates H4K20me1 enrichment at the PSA promoter. • SET8 promotes AR-mediated transcription activation. • SET8 interacts with AR and promotes cell proliferation. - Abstract: Histone methylation status in different lysine residues has an important role in transcription regulation. The effect of H4K20 monomethylation (H4K20me1) on androgen receptor (AR)-mediated gene transcription remains unclear. Here we show that AR agonist stimulates the enrichment of H4K20me1 and SET8 at the promoter of AR target gene PSA in an AR dependent manner. Furthermore, SET8 is crucial for the transcription activation of PSA. Co-immunoprecipitation analyses demonstrate that SET8 interacts with AR. Therefore, we conclude that SET8 is involved in AR-mediated transcription activation, possibly through its interaction with AR and H4K20me1 modification.

  4. Distinct signalling pathways of murine histamine H1- and H4-receptors expressed at comparable levels in HEK293 cells.

    Directory of Open Access Journals (Sweden)

    Silke Beermann

    Full Text Available Histamine (HA is recognized by its target cells via four G-protein-coupled receptors, referred to as histamine H1-receptor (H1R, H2R, H3R, and H4R. Both H1R and H4R exert pro-inflammatory functions. However, their signal transduction pathways have never been analyzed in a directly comparable manner side by side. Moreover, the analysis of pharmacological properties of the murine orthologs, representing the main targets of pre-clinical research, is very important. Therefore, we engineered recombinant HEK293 cells expressing either mouse (mH1R or mH4R at similar levels and analyzed HA-induced signalling in these cells. HA induced intracellular calcium mobilization via both mH1R and mH4R, with the mH1R being much more effective. Whereas cAMP accumulation was potentiated via the mH1R, it was reduced via the mH4R. The regulation of both second messengers via the H4R, but not the H1R, was sensitive to pertussis toxin (PTX. The mitogen-activated protein kinases (MAPKs ERK 1/2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA-induced EGR-1 gene expression. The p38 MAPK was moderately activated via both receptors as well, but was functionally involved in HA-induced EGR-1 gene expression only in H4R-expressing cells. Surprisingly, in this system p38 MAPK activity reduced the HA-induced gene expression. In summary, using this system which allows a direct comparison of mH1R- and mH4R-induced signalling, qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident.

  5. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

    NARCIS (Netherlands)

    Kroon, Jan; Kroon, Jan; Puhr, M.; Buijs, J.T.; van der Horst, G.; Hemmer, D.M.; Marijt, K.A.; Hwang, M.S.; Masood, M.; Grimm, S.; Storm, Gerrit; Metselaar, Josbert Maarten; Meijer, O.C.; Culig, Z.; van der Pluijm, M.

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance.

  6. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

    NARCIS (Netherlands)

    Kroon, Jan; Puhr, Martin; Buijs, Jeroen T.; Van Der Horst, Geertje; Lemhemmer, Daniël; Marijt, Koen A.; Hwang, Ming S.; Masood, Motasim; Grimm, Stefan; Storm, Gert; Metselaar, Josbert M.|info:eu-repo/dai/nl/244207690; Meijer, Onno C.; Culig, Zoran; Van Der Pluijm, Gabri

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCA). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance.

  7. H4 histamine receptors mediate cell cycle arrest in growth factor-induced murine and human hematopoietic progenitor cells.

    Directory of Open Access Journals (Sweden)

    Anne-France Petit-Bertron

    Full Text Available The most recently characterized H4 histamine receptor (H4R is expressed preferentially in the bone marrow, raising the question of its role during hematopoiesis. Here we show that both murine and human progenitor cell populations express this receptor subtype on transcriptional and protein levels and respond to its agonists by reduced growth factor-induced cell cycle progression that leads to decreased myeloid, erythroid and lymphoid colony formation. H4R activation prevents the induction of cell cycle genes through a cAMP/PKA-dependent pathway that is not associated with apoptosis. It is mediated specifically through H4R signaling since gene silencing or treatment with selective antagonists restores normal cell cycle progression. The arrest of growth factor-induced G1/S transition protects murine and human progenitor cells from the toxicity of the cell cycle-dependent anticancer drug Ara-C in vitro and reduces aplasia in a murine model of chemotherapy. This first evidence for functional H4R expression in hematopoietic progenitors opens new therapeutic perspectives for alleviating hematotoxic side effects of antineoplastic drugs.

  8. Complement C5a receptor antagonism by protamine and poly-L-Arg on human leukocytes.

    Science.gov (United States)

    Olsen, U B; Selmer, J; Kahl, J U

    1988-01-01

    It is shown that protamine selectively and dose-dependently inhibits complement C5a-induced leukocyte responses such as histamine release from basophils, chemiluminescence and beta-glucuronidase release from neutrophils. Protamine produces parallel rightward displacements of the C5a dose-response curves. The inhibitory capacity of the polypeptide is reversible and disappears following repeated washing of exposed cells. In neutrophils poly-L-Arg similarly and specifically antagonizes C5a-induced chemiluminescence and enzyme release. This polymer alone, however, degranulates basophils and neutrophils, leading to histamine and enzyme release, respectively. It is concluded that on human neutrophils the arginine-rich polycations protamine and poly-L-Arg exhibit a competitive C5a receptor antagonism. In addition, protamine inhibits the C5a receptors on basophils. It is hypothesized that molecular conformations of the arginine-rich polycations might bind reversibly to, and block negatively charged groups at the C5a-receptor sites.

  9. What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

    Energy Technology Data Exchange (ETDEWEB)

    Kufareva, Irina; Gustavsson, Martin; Zheng, Yi; Stephens, Bryan S.; Handel, Tracy M. (UCSD)

    2017-05-22

    Chemokines and their cell surface G protein–coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs. In parallel, chemokine receptor structures with small molecules reveal the complicated and diverse structural foundations of small molecule antagonism and allostery, highlight the inherent physicochemical challenges of receptor:chemokine interfaces, and suggest novel epitopes that can be exploited to overcome these challenges. The structures and models promote unique understanding of chemokine receptor biology, including the interpretation of two decades of experimental studies, and will undoubtedly assist future drug discovery endeavors.

  10. Antagonism of presynaptic dopamine receptors by phenothiazine drug metabolites

    International Nuclear Information System (INIS)

    Nowak, J.Z.; Arbilla, S.; Langer, S.Z.; Dahl, S.G.

    1990-01-01

    Electrically evoked release of dopamine from the caudate nucleus is reduced by the dopamine receptor agonists, apomorphine and bromocriptine, and facilitated by neuroleptic drugs, which act as dopamine autoreceptor antagonists. The potencies of chlorpromazine, fluphenazine, levomepromazine and their hydroxy-metabolites in modulating electrically evoked release of dopamine were examined by superfusion of rabbit caudate nucleus slices pre-incubated with 3 H-dopamine. O-Desmethyl levomepromazine, 3-hydroxy- and 7-hydroxy metabolites of chlorpromazine and levomepromazine facilitated electrically evoked release of 3 H-dopamine, having potencies similar to that of the parent compounds. 7-Hydroxy fluphenazine was less active than fluphenazine in this system. These results indicate that phenolic metabolites of chlorpromazine and levomepromazine, but not of fluphenazine, may contribute to effects of the drugs mediated by presynaptic dopamine receptors

  11. ANTAGONISM OF PROGESTERONE RECEPTOR SUPPRESSES CAROTID BODY RESPONSES TO HYPOXIA AND NICOTINE IN RAT PUPS

    OpenAIRE

    JOSEPH, V.; NIANE, L. M.; BAIRAM, A.

    2012-01-01

    We tested the hypothesis that antagonism of progesterone receptor (PR) in newborn rats alters carotid body and respiratory responses to hypoxia and nicotinic receptor agonists. Rats were treated with the PR antagonist mifepristone (daily oral gavage 40 μg/g/d) or vehicle between post-natal days 3 and 15. In 11–14-day-old rats, we used in vitro carotid body/carotid sinus nerve preparation and whole body plethysmography to assess the carotid body and ventilatory responses to hypoxia (65 mmHg in...

  12. An effector of the Irish potato famine pathogen antagonizes a host autophagy cargo receptor

    Science.gov (United States)

    Dagdas, Yasin F; Belhaj, Khaoula; Maqbool, Abbas; Chaparro-Garcia, Angela; Pandey, Pooja; Petre, Benjamin; Tabassum, Nadra; Cruz-Mireles, Neftaly; Hughes, Richard K; Sklenar, Jan; Win, Joe; Menke, Frank; Findlay, Kim; Banfield, Mark J; Kamoun, Sophien; Bozkurt, Tolga O

    2016-01-01

    Plants use autophagy to safeguard against infectious diseases. However, how plant pathogens interfere with autophagy-related processes is unknown. Here, we show that PexRD54, an effector from the Irish potato famine pathogen Phytophthora infestans, binds host autophagy protein ATG8CL to stimulate autophagosome formation. PexRD54 depletes the autophagy cargo receptor Joka2 out of ATG8CL complexes and interferes with Joka2's positive effect on pathogen defense. Thus, a plant pathogen effector has evolved to antagonize a host autophagy cargo receptor to counteract host defenses. DOI: http://dx.doi.org/10.7554/eLife.10856.001 PMID:26765567

  13. Neuropeptide Y Y5 receptor antagonism attenuates cocaine-induced effects in mice

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Jensen, Morten; Weikop, Pia

    2012-01-01

    Rationale Several studies suggest a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. However, the NPY receptors mediating addiction-related effects remain to be determined. Objectives To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural...... effects. Methods The Y5 antagonist L-152,804 and Y5-knockout (Y5-KO) mice were tested in two models of cocaine addiction-related behaviour: acute self-administration and cocaine-induced hyperactivity. We also studied effects of Y5 receptor antagonism on cocaine-induced c-fos expression and extracellular...... effects, suggesting that Y5 receptors could be a potential therapeutic target in cocaine addiction....

  14. Arctigenin antagonizes mineralocorticoid receptor to inhibit the transcription of Na/K-ATPase.

    Science.gov (United States)

    Cheng, Ye; Zhou, Meili; Wang, Yan

    2016-01-01

    Hypertension is one of the most important risk factors in cardiovascular disease and is the most common chronic disease. Mineralocorticoid receptor (MR) antagonists have been successfully used in clinic for the treatment of hypertension. Our study aims to investigate whether Arctigenin can antagonize MR and inhibit the transcription of Na/K-ATPase. The yeast two-hybrid assay was used to screen natural products and Arctigenin was identified as an MR antagonist. The direct binding of Arctigenin to MR was determined using assays based on surface plasmon resonance, differential scanning calorimetry and fluorescence quenching. Furthermore, results from mammalian one-hybrid and transcriptional activation experiments also confirmed that Arctigenin can potently antagonize MR in cells. We demonstrated that Arctigenin can decrease the level of Na/K-ATPase mRNA by antagonizing MR in HK-2 cells. Our findings show that Arctigenin can effectively decrease Na/K-ATPase transcription; thus highlight its potential as an anti-hypertensive drug lead compound. Our current findings demonstrate that Arctigenin is an antagonist of MR and effectively decreases the Na/K-ATPase 1 gene expression. Our work provides a hint for the drug discovery against cardiovascular disease.

  15. Preliminary study of histamine H4 receptor expressed on human CD4+ T cells and its immunomodulatory potency in the IL-17 pathway of psoriasis.

    Science.gov (United States)

    Han, Song Hee; Hur, Min Seok; Kim, Min Jung; Kim, Bo Mi; Kim, Kyoung Woon; Kim, Hae Rim; Choe, Yong Beom; Ahn, Kyu Joong; Lee, Yang Won

    2017-10-01

    Previous studies have shown the expression of histamine H 4 receptor (H4R) on CD4 + T cells, especially human CD4 + T h 2-polarized T cells. This study aimed to investigate the role of H4R on these effector T cells in psoriasis. We enrolled three patients each with active psoriasis, inactive psoriasis, scalp seborrheic dermatitis, and three normal controls, and compared the basal expression of H4R mRNA in their peripheral blood CD4 + T cells. Then, we identified H4R expression in dermal CD4 + T cells. Furthermore, we investigated H4R expression after stimulating separated peripheral blood CD4 + T cells with several inflammatory cytokines. The results showed higher H4R expression in the active psoriasis group compared to the inactive psoriasis group. It was interesting that interleukin (IL)-23, which is a representative cytokine contributing to T h 17 cell differentiation, stimulated H4R expression significantly. After adding a selective H4R antagonist (JNJ-7777120) while the CD4 + T cells were polarized into T h 17 cells, we observed a tendency toward suppressed IL-17 secretion. Histamine stimulation influences the IL-17 pathway in psoriasis via the fourth histamine receptor subtype, H4R, on CD4 + T cells. The immunomodulatory roles of H4R suggest its potency as a new therapeutic target for obstinate psoriasis. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

  16. CB1 receptor antagonism increases hippocampal acetylcholine release: site and mechanism of action.

    Science.gov (United States)

    Degroot, Aldemar; Köfalvi, Attila; Wade, Mark R; Davis, Richard J; Rodrigues, Ricardo J; Rebola, Nelson; Cunha, Rodrigo A; Nomikos, George G

    2006-10-01

    Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB1 receptor (CB1R) antagonism, several in vitro functional studies recently have suggested non-CB1R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB1R antagonists, different methods of in vivo microdialysis, CB1R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB1R antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR-141716A) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB1R antagonists on hippocampal ACh release were completely abolished in CB1R KO mice. CB1R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D1 receptor antagonism counteracted the stimulatory effect of CB1R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB1R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB1 receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB1Rs located on both cholinergic and dopaminergic neuronal projections, and CB1R antagonism increases hippocampal ACh release, probably through both a direct

  17. Impairments of exploration and memory after systemic or prelimbic D1-receptor antagonism in rats

    DEFF Research Database (Denmark)

    Clausen, Bettina; Schachtman, Todd R.; Mark, Louise T.

    2011-01-01

    to examine the effects on memory: cross-maze and object recognition task. Systemic administration reduced spatial exploration in cross-maze as well as in an open field test, and also reduced object exploration. Spatial (hippocampus-dependent) short-term memory was inhibited in the cross-maze and non......-spatial short-term object retention was also impaired. In contrast to these systemic effects, bilateral injections of SCH23390 into the prelimbic cortices altered neither spatial nor object exploration, but did inhibit short-term memory in both cross-maze and object recognition task. Therefore, the inhibiting......D1-receptor antagonism is known to impair rodent memory but also inhibits spontaneous exploration of stimuli to be remembered. Hypo-exploration could contribute to impaired memory by influencing event processing. In order to explore this effect, the D1 receptor antagonist, SCH23390...

  18. Ghrelin receptor antagonism of hyperlocomotion in cocaine-sensitized mice requires βarrestin-2.

    Science.gov (United States)

    Toth, Krisztian; Slosky, Lauren M; Pack, Thomas F; Urs, Nikhil M; Boone, Peter; Mao, Lan; Abraham, Dennis; Caron, Marc G; Barak, Lawrence S

    2018-01-01

    The "brain-gut" peptide ghrelin, which mediates food-seeking behaviors, is recognized as a very strong endogenous modulator of dopamine (DA) signaling. Ghrelin binds the G protein-coupled receptor GHSR1a, and administration of ghrelin increases the rewarding properties of psychostimulants while ghrelin receptor antagonists decrease them. In addition, the GHSR1a signals through βarrestin-2 to regulate actin/stress fiber rearrangement, suggesting βarrestin-2 participation in the regulation of actin-mediated synaptic plasticity for addictive substances like cocaine. The effects of ghrelin receptor ligands on reward strongly suggest that modulation of ghrelin signaling could provide an effective strategy to ameliorate undesirable behaviors arising from addiction. To investigate this possibility, we tested the effects of ghrelin receptor antagonism in a cocaine behavioral sensitization paradigm using DA neuron-specific βarrestin-2 KO mice. Our results show that these mice sensitize to cocaine as well as wild-type littermates. The βarrestin-2 KO mice, however, no longer respond to the locomotor attenuating effects of the GHSR1a antagonist YIL781. The data presented here suggest that the separate stages of addictive behavior differ in their requirements for βarrestin-2 and show that pharmacological inhibition of βarrestin-2 function through GHSR1a antagonism is not equivalent to the loss of βarrestin-2 function achieved by genetic ablation. These data support targeting GHSR1a signaling in addiction therapy but indicate that using signaling biased compounds that modulate βarrestin-2 activity differentially from G protein activity may be required. © 2017 Wiley Periodicals, Inc.

  19. Design of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) Trial.

    Science.gov (United States)

    Rajagopalan, Sanjay; Alaiti, M Amer; Broadwater, Kylene; Goud, Aditya; Gaztanaga, Juan; Connelly, Kim; Fares, Anas; Shirazian, Shayan; Kreatsoulas, Catherine; Farkouh, Michael; Dobre, Mirela; Fink, Jeffrey C; Weir, Matthew R

    2017-09-01

    Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher-risk patients who otherwise may not be candidates for such a therapeutic approach. In this double-blind, randomized, placebo-controlled trial, subjects with T2DM with chronic kidney disease (≥ stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4-week period). The co-primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24-hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA-IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event-based trials. © 2017 Wiley Periodicals, Inc.

  20. ANTAGONISM OF PROGESTERONE RECEPTOR SUPPRESSES CAROTID BODY RESPONSES TO HYPOXIA AND NICOTINE IN RAT PUPS

    Science.gov (United States)

    JOSEPH, V.; NIANE, L. M.; BAIRAM, A.

    2013-01-01

    We tested the hypothesis that antagonism of progesterone receptor (PR) in newborn rats alters carotid body and respiratory responses to hypoxia and nicotinic receptor agonists. Rats were treated with the PR antagonist mifepristone (daily oral gavage 40 μg/g/d) or vehicle between post-natal days 3 and 15. In 11–14-day-old rats, we used in vitro carotid body/carotid sinus nerve preparation and whole body plethysmography to assess the carotid body and ventilatory responses to hypoxia (65 mmHg in vitro, 10% O2 in vivo) and to nicotinic receptor agonists (as an excitatory modulator of carotid body activity—nicotine 100 μM for in vitro studies, and epibatidine 5 μg/kg, i.p., which mainly acts on peripheral nicotinic receptors, for in vivo studies). The carotid body responses to hypoxia and nicotine were drastically reduced by mifepristone. Compared with vehicle, mifepristone-treated rats had a reduced body weight. The ventilatory response to epibatidine was attenuated; however, the hypoxic ventilatory response was similar between vehicle and mifepristone-treated pups. Immunohistochemical staining revealed that mifepristone treatment did not change carotid body morphology. We conclude that PR activity is a critical factor ensuring proper carotid body function in newborn rats. PMID:22326965

  1. Substance P Receptor Antagonism: A Potential Novel Treatment Option for Viral-Myocarditis

    Directory of Open Access Journals (Sweden)

    Prema Robinson

    2015-01-01

    Full Text Available Viral-myocarditis is an important cause of heart failure for which no specific treatment is available. We previously showed the neuropeptide substance P (SP is associated with the pathogenesis of murine myocarditis caused by encephalomyocarditis virus (EMCV. The current studies determined if pharmacological inhibition of SP-signaling via its high affinity receptor, NK1R and downstream G-protein, Ras homolog gene family, member-A (RhoA, will be beneficial in viral-myocarditis. Aprepitant (1.2 mg/kg, a SP-receptor antagonist, or fasudil (10 mg/kg, a RhoA inhibitor, or saline control was administered daily to mice orally for 3 days, prior to, or 5 days following, intraperitoneal infection with and without 50 PFU of EMCV, following which disease assessment studies, including echocardiogram and cardiac Doppler were performed in day 14 after infection. Pretreatment and posttreatment with aprepitant significantly reduced mortality, heart and cardiomyocyte size, and cardiac viral RNA levels (P<0.05 all, ANOVA. Only aprepitant pretreatment improved heart functions; it significantly decreased end systolic diameter, improved fractional shortening, and increased peak aortic flow velocity (P<0.05 all, ANOVA. Pre- or posttreatment with fasudil did not significantly impact disease manifestations. These findings indicate that SP contributes to cardiac-remodeling and dysfunction following ECMV infection via its high affinity receptor, but not through the Rho-A pathway. These studies suggest that SP-receptor antagonism may be a novel therapeutic-option for patients with viral-myocarditis.

  2. Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect: a current preclinical & clinical perspective.

    Science.gov (United States)

    Mahmood, Danish

    2016-10-01

    Histamine H 3 receptors are present as autoreceptors on histaminergic neurons and as heteroreceptors on nonhistaminergic neurones. They control the release and synthesis of histamine and several other key neurotransmitters in the brain. H 3 antagonism may be a novel approach to develop a new class of antipsychotic medications given the gathering evidence reporting therapeutic efficacy in several central nervous system disorders. Several medications such as cariprazine, lurasidone, LY214002, bexarotene, rasagiline, raloxifene, BL-1020 and ITI-070 are being developed to treat the negative symptoms and cognitive impairments of schizophrenia. These medications works through diverse mechanisms which include agonism at metabotropic glutamate receptor (mGluR2/3), partial agonism at dopamine D 2 , D 3 and serotonin 5-HT 1A receptors, antagonism at D 2 , 5-HT 2A, 5-HT 2B and 5-HT 7 receptors, combined dopamine antagonism with GABA agonist activity, inhibition of monoamine oxidase-B, modulation of oestrogen receptor, and activation of nuclear retinoid X receptor. However, still specific safe therapy for psychosis remains at large. Schizophrenia is a severe neuropsychiatric disorder result both from hyper- and hypo-dopaminergic transmission causing positive and negative symptoms, respectively. Pharmacological stimulation of dopamine release in the prefrontal cortex has been a viable approach in treating negative symptoms and cognitive deficits of schizophrenia symptoms that are currently not well treated and continue to represent significant unmet medical challenges. Administration of H 3 antagonists/inverse agonists increase extracellular dopamine concentrations in rat prefrontal cortex, but not in the striatum suggesting that antagonism via H 3 receptor may be a potential target for treating negative symptoms and cognitive deficits associated with schizophrenia. Further, insights are emerging into the potential role of histamine H 3 receptors as a target of antiobesity

  3. Androgen Receptor Antagonism By Divalent Ethisterone Conjugates In Castrate-Resistant Prostate Cancer Cells

    Science.gov (United States)

    Levine, Paul M.; Lee, Eugine; Greenfield, Alex; Bonneau, Richard; Logan, Susan K.; Garabedian, Michael J.; Kirshenbaum, Kent

    2013-01-01

    Sustained treatment of prostate cancer with Androgen Receptor (AR) antagonists can evoke drug resistance, leading to castrate-resistant disease. Elevated activity of the AR is often associated with this highly aggressive disease state. Therefore, new therapeutic regimens that target and modulate AR activity could prove beneficial. We previously introduced a versatile chemical platform to generate competitive and non-competitive multivalent peptoid oligomer conjugates that modulate AR activity. In particular, we identified a linear and a cyclic divalent ethisterone conjugate that exhibit potent anti-proliferative properties in LNCaP-abl cells, a model of castrate-resistant prostate cancer. Here, we characterize the mechanism of action of these compounds utilizing confocal microscopy, time-resolved fluorescence resonance energy transfer, chromatin immunoprecipitation, flow cytometry, and microarray analysis. The linear conjugate competitively blocks AR action by inhibiting DNA binding. In addition, the linear conjugate does not promote AR nuclear localization or co-activator binding. In contrast, the cyclic conjugate promotes AR nuclear localization and induces cell-cycle arrest, despite its inability to compete against endogenous ligand for binding to AR in vitro. Genome-wide expression analysis reveals that gene transcripts are differentially affected by treatment with the linear or cyclic conjugate. Although the divalent ethisterone conjugates share extensive chemical similarities, we illustrate that they can antagonize the AR via distinct mechanisms of action, establishing new therapeutic strategies for potential applications in AR pharmacology. PMID:22871957

  4. 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.

  5. Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex

    Science.gov (United States)

    Toriumi, Kazuya; Mouri, Akihiro; Narusawa, Shiho; Aoyama, Yuki; Ikawa, Natsumi; Lu, Lingling; Nagai, Taku; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

    2012-01-01

    N-methyl--aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression. PMID:22257896

  6. Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells

    International Nuclear Information System (INIS)

    Goto, Aya; Mouri, Akihiro; Nagai, Tomoko; Yoshimi, Akira; Ukigai, Mako; Tsubai, Tomomi; Hida, Hirotake; Ozaki, Norio; Noda, Yukihiro

    2016-01-01

    Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100 μM) and doxorubicin (0.2 µM) decreased the cell survival rate, but olanzapine (1–100 µM) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H 4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H 4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H 4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H 4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation. - Highlights: • HL-60

  7. Differential effects of early-life NMDA receptor antagonism on aspartame-impaired insulin tolerance and behavior.

    Science.gov (United States)

    Collison, Kate S; Inglis, Angela; Shibin, Sherin; Andres, Bernard; Ubungen, Rosario; Thiam, Jennifer; Mata, Princess; Al-Mohanna, Futwan A

    2016-12-01

    We have previously showed that lifetime exposure to aspartame, commencing in utero via the mother's diet, may impair insulin tolerance and cause behavioral deficits in adulthood via mechanisms which are incompletely understood. The role of the CNS in regulating glucose homeostasis has been highlighted by recent delineation of the gut-brain axis, in which N-methyl-d-aspartic acid receptors (NMDARs) are important in maintaining glucose homeostasis, in addition to regulating certain aspects of behavior. Since the gut-brain axis can be modulated by fetal programming, we hypothesized that early-life NMDAR antagonism may affect aspartame-induced glucose deregulation in adulthood, and may alter the aspartame behavioral phenotype. Accordingly, C57Bl/6J mice were chronically exposed to aspartame commencing in utero, in the presence and absence of maternal administration of the competitive NMDAR antagonist CGP 39551, from conception until weaning. Drug/diet interactions in adulthood glucocentric and behavioral parameters were assessed. Aspartame exposure elevated blood glucose and impaired insulin-induced glucose disposal during an insulin tolerance test, which could be normalized by NMDAR antagonism. The same effects were not observed in control diet mice, suggesting an early-life drug/diet interaction. Behavioral analysis of adult offspring indicated that NMDAR antagonism of control diet mice caused hyperlocomotion and impaired spatial navigation. Conversely hypolocomotion, reduced exploratory activity and increased anxiety-related behavior were apparent in aspartame diet mice with early-life NMDAR antagonism. significant drug/diet interactions in glucocentric and behavioral parameters were identified in aspartame-exposed mice with early-life NMDAR antagonism. This suggests a possible involvement of early NMDAR interactions in aspartame-impaired glucose homeostasis and behavioral deficits. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

    Directory of Open Access Journals (Sweden)

    Högberg Thomas

    2007-02-01

    Full Text Available Abstract Background Mast cell-derived prostaglandin D2 (PGD2, may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2, a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology. Methods Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. Results TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia. Conclusion This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban.

  9. The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory & urological disorders

    Directory of Open Access Journals (Sweden)

    Anthony eFord

    2013-12-01

    Full Text Available A sensory role for ATP was proposed long before general acceptance of its extracellular role. ATP activates & sensitizes signal transmission at multiple sites along the sensory axis, across multiple synapses. P2X & P2Y receptors mediate ATP modulation of sensory pathways & participate in dysregulation, where ATP action directly on primary afferent neurons (PANs, linking receptive field to CNS, has received much attention. Many PANs, especially C-fibers, are activated by ATP, via P2X3-containing trimers. P2X3 knock-out mice & knock-down in rats led to reduced nocifensive activity & visceral reflexes, suggesting that antagonism may offer benefit in sensory disorders. Recently, drug-like P2X3 antagonists, active in a many inflammatory & visceral pain models, have emerged. Significantly, these compounds have no overt CNS action & are inactive versus acute nociception. Selectively targeting ATP sensitization of PANs may lead to therapies that block inappropriate chronic signals at their source, decreasing drivers of peripheral & central wind-up, yet leaving defensive nociceptive and brain functions unperturbed. This article reviews this evidence, focusing on how ATP sensitization of PANs in visceral hollow organs primes them to chronic discomfort, irritation & pain (symptoms as well as exacerbated autonomic reflexes (signs, & how the use of isolated organ-nerve preparations has revealed this mechanism. Urinary & airways systems share many features: dependence on continuous afferent traffic to brainstem centers to coordinate efferent autonomic outflow; loss of descending inhibitory influence in functional & sensory disorders; dependence on ATP in mediating sensory responses to diverse mechanical and chemical stimuli; a mechanistically overlapping array of existing medicines for pathological conditions. These similarities may also play out in terms of future treatment of signs & symptoms, in the potential for benefit of P2X3 antagonists.

  10. Selective augmentation of striatal functional connectivity following NMDA receptor antagonism: implications for psychosis.

    Science.gov (United States)

    Dandash, Orwa; Harrison, Ben J; Adapa, Ram; Gaillard, Raphael; Giorlando, Francesco; Wood, Stephen J; Fletcher, Paul C; Fornito, Alex

    2015-02-01

    The psychotomimetic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is thought to arise from a functional modulation of the brain's fronto-striato-thalamic (FST) circuits. Animal models suggest a pronounced effect on ventral 'limbic' FST systems, although recent work in patients with psychosis and high-risk individuals suggests specific alterations of dorsal 'associative' FST circuits. Here, we used functional magnetic resonance imaging to investigate the effects of a subanesthetic dose of ketamine on measures of functional connectivity as indexed by the temporal coherence of spontaneous neural activity in both dorsal and ventral FST circuits, as well as their symptom correlates. We adopted a placebo-controlled, double-blind, randomized, repeated-measures design in which 19 healthy participants received either an intravenous saline infusion or a racemic mixture of ketamine (100 ng/ml) separated by at least 1 week. Compared with placebo, ketamine increased functional connectivity between the dorsal caudate and both the thalamus and midbrain bilaterally. Ketamine additionally increased functional connectivity of the ventral striatum/nucleus accumbens and ventromedial prefrontal cortex. Both connectivity increases significantly correlated with the psychosis-like and dissociative symptoms under ketamine. Importantly, dorsal caudate connectivity with the ventrolateral thalamus and subthalamic nucleus showed inverse correlation with ketamine-induced symptomatology, pointing to a possible resilience role to disturbances in FST circuits. Although consistent with the role of FST in mediating psychosis, these findings contrast with previous research in clinical samples by suggesting that acute NMDAR antagonism may lead to psychosis-like experiences via a mechanism that is distinct from that implicated in frank psychotic illness.

  11. Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.

    Science.gov (United States)

    Ring, Rebecca M; Regan, Ciaran M

    2013-10-01

    The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.

  12. Progesterone receptor activates Msx2 expression by downregulating TNAP/Akp2 and activating the Bmp pathway in EpH4 mouse mammary epithelial cells.

    Directory of Open Access Journals (Sweden)

    Jodie M Fleming

    Full Text Available Previously we demonstrated that EpH4 mouse mammary epithelial cells induced the homeobox transcription factor Msx2 either when transfected with the progesterone receptor (PR or when treated with Bmp2/4. Msx2 upregulation was unaffected by Wnt inhibitors s-FRP or Dkk1, but was inhibited by the Bmp antagonist Noggin. We therefore hypothesized that PR signaling to Msx2 acts through the Bmp receptor pathway. Herein, we confirm that transcripts for Alk2/ActR1A, a non-canonical BmpR Type I, are upregulated in mammary epithelial cells overexpressing PR (EpH4-PR. Increased phosphorylation of Smads 1,5, 8, known substrates for Alk2 and other BmpR Type I proteins, was observed as was their translocation to the nucleus in EpH4-PR cells. Analysis also showed that Tissue Non-Specific Alkaline Phosphatase (TNAP/Akp2 was also found to be downregulated in EpH4-PR cells. When an Akp2 promoter-reporter construct containing a ½PRE site was transfected into EpH4-PR cells, its expression was downregulated. Moreover, siRNA mediated knockdown of Akp2 increased both Alk2 and Msx2 expression. Collectively these data suggest that PR inhibition of Akp2 results in increased Alk2 activity, increased phosphorylation of Smads 1,5,8, and ultimately upregulation of Msx2. These studies imply that re-activation of the Akp2 gene could be helpful in downregulating aberrant Msx2 expression in PR+ breast cancers.

  13. Neuropeptide Y Y5 receptor antagonism causes faster extinction and attenuates reinstatement in cocaine-induced place preference

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Wörtwein, Gitta; Fink-Jensen, Anders

    2013-01-01

    Several studies have suggested a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. Recently, our group showed a role for the NPY Y5 receptor in the modulation of acute reinforcing effects of cocaine using self-administration and hyperlocomotion paradigms. In the pre......Several studies have suggested a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. Recently, our group showed a role for the NPY Y5 receptor in the modulation of acute reinforcing effects of cocaine using self-administration and hyperlocomotion paradigms....... In the present study, we further explored potential anti-addiction-related effects of Y5 antagonism in another murine model of cocaine addiction-related behavior: conditioned place-preference (CPP). Using this model, it was tested whether blockade or deficiency of the NPY Y5 receptor could influence......, and reinstatement of cocaine-induced CPP was absent. The development of CPP for cocaine was similar between Y5-KO and WT mice. Taken together, the present data show that Y5 antagonism attenuates relapse to cocaine addiction-related behavior. Prevention of relapse is considered to be of pivotal importance...

  14. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

    DEFF Research Database (Denmark)

    Uller, Lena; Mathiesen, Jesper Mosolff; Alenmyr, Lisa

    2007-01-01

    BACKGROUND: Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells......, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist...... in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. RESULTS: TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other...

  15. Involvement of Angiopoietin-2 and Tie2 Receptor Phosphorylation in STEC-HUS Mediated by Escherichia coli O104:H4

    Directory of Open Access Journals (Sweden)

    Alexander Lukasz

    2015-01-01

    Full Text Available Escherichia coli O104:H4-associated hemolytic uremic syndrome (HUS is characterized by Shiga toxin-induced vascular damage. As indicated by recent studies, dysregulation of the angiopoietin (Angpt/Tie2 ligand receptor system may be crucial for endothelial dysfunction in HUS. Early Angpt-2 levels quantified in 48 adult HUS patients were predictive for a complicated clinical course, in particular for need of hemodialysis and mechanical ventilation as well as occurrence of seizures. In vitro challenge of human umbilical vein endothelial cells with patients’ sera indicated an injurious mediator role of Angpt-2 opening future perspectives for mitigating endothelial activation in HUS.

  16. Unsurmountable antagonism of brain 5-hydroxytryptamine2 receptors by (+)-lysergic acid diethylamide and bromo-lysergic acid diethylamide.

    Science.gov (United States)

    Burris, K D; Sanders-Bush, E

    1992-11-01

    Lysergic acid diethylamide (LSD) and its structural analogue 2-bromo-lysergic acid diethylamide (BOL) act as unsurmountable antagonists of serotonin-elicited contractions in smooth muscle preparations. Two different models, allosteric and kinetic, have been invoked to explain these findings. The present studies investigate the mechanism of antagonism of brain 5-hydroxytryptamine (5HT)2 receptors, utilizing cells transfected with 5HT2 receptor cDNA cloned from rat brain. A proximal cellular response, phosphoinositide hydrolysis, was examined in order to minimize possible postreceptor effects. Even though LSD behaved as a partial agonist and BOL as a pure antagonist, both drugs blocked the effect of serotonin in an unsurmountable manner, i.e., increasing concentrations of serotonin could not overcome the blocking effect of LSD or BOL. Radioligand binding studies showed that preincubation of membranes with either LSD or BOL reduced the density of [3H]ketanserin binding sites, suggesting that the drugs bind tightly to the 5HT2 receptor and are not displaced during the binding assay. Two additional experiments supported this hypothesis. First, the off-rate of [3H] LSD was slow (20 min), relative to that of [3H]ketanserin (approximately 4 min). Second, when the length of incubation with [3H]ketanserin was increased to 60 min, the LSD-induced decrease in Bmax was essentially eliminated. The possibility that LSD and BOL decrease [3H]ketanserin binding by interacting with an allosteric site was rejected, because neither drug altered the rate of dissociation of [3H]ketanserin. The most parsimonious interpretation of these results is that unsurmountable antagonism reflects prolonged occupancy of the receptor by slowly reversible antagonists.

  17. Antagonism of serotonin receptor 1B decreases viability and promotes apoptosis in the COS canine osteosarcoma cell line.

    Science.gov (United States)

    Viall, A K; Goodall, C P; Stang, B; Marley, K; Chappell, P E; Bracha, S

    2016-06-01

    Serotonin receptor 1B (5HTR1B) traditionally exhibits anti-proliferative activity in osteoblasts. We examined the expression and function of 5HTR1B in the COS canine osteosarcoma cell line and normal canine osteoblasts. Equal levels of 5HTR1B gene and protein expression were found between normal and malignant osteoblasts. Treatment with serotonin enhanced viability of osteosarcoma cells but not normal osteoblasts. Challenge with the 5HTR1B agonist anpirtoline caused no change in cell viability. Rather incubation with the specific receptor antagonist SB224289 caused reduction in osteoblast viability, with this effect more substantial in osteosarcoma cells. Investigation of this inhibitory activity showed 5HTR1B antagonism induces apoptosis in malignant cells. Evaluation of phosphorylated levels of CREB and ERK, transcriptional regulators associated with serotonin receptor signalling in osteoblasts, revealed aberrant 5HTR1B signalling in COS. Our results confirm the presence of 5HTR1B in a canine osteosarcoma cell line and highlight this receptor as a possible novel therapeutic target. © 2014 John Wiley & Sons Ltd.

  18. [6-chloro-3-pyridylmethyl-3H]neonicotinoids as high-affinity radioligands for the nicotinic acetylcholine receptor: preparation using NaB3H4 and LiB3H4

    International Nuclear Information System (INIS)

    Latli, Bachir; Casida, J.E.

    1996-01-01

    NaB 3 H 4 and LiB 3 H 4 at 78% and 97% isotopic enrichments, respectively, were used in the synthesis of 3 H-labeled 1-(6-chloro-3-pyridyl)-methyl-2-nitromethyleneimidazolidine (CH-IMI) and N'-[(6-chloro-3-pyridyl)methyl]-n''-cyano-n'-methylacetamidine (acetamiprid) (two very potent insecticides) and of 1-(6-chloro-3-pyridyl)methyl-2-iminoimidazolidine (desnitro-IMI) (a metabolite of the commercial insecticides imidacloprid). 6-Chloronicotinoyl chloride was treated with either NaB 3 H 4 in methanol or LiB 3 H 4 in tetrahydrofuran and the resulting alcohol transformed to 2-chloro-5-chloromethylpyridine, which was then coupled to N-cyano-N'-methylacetamidine to give [ 3 H] acetamiprid (45 Ci/mmol). 2-Chloro-5-chloro[ 3 H]methylpyridine was also reacted with ethylenediamine and the product was either refluxed in absolute ethanol with 1,1-bis(methylthio)-2-nitro-ethylene to provide [ 3 H]CH-IMI or reacted in toluene with a solution of cyanogen bromide to produce [ 3 H] desnitro-IMI (each 55 Ci/mmol. (author)

  19. Antagonism of Lateral Amygdala Alpha1-Adrenergic Receptors Facilitates Fear Conditioning and Long-Term Potentiation

    Science.gov (United States)

    Lazzaro, Stephanie C.; Hou, Mian; Cunha, Catarina; LeDoux, Joseph E.; Cain, Christopher K.

    2010-01-01

    Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala…

  20. Baseline characteristics in PRIORITY study: Proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in type 2 diabetes

    DEFF Research Database (Denmark)

    Tofte, Nete

    diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria) trial, the aim is to confirm that CKD273 can predict microalbuminuria prospectively, and to test whether mineralocorticoid receptor antagonism (MRA) delays progression to microalbuminuria. Here we report the association between CKD273...... and traditional risk factors for diabetic nephropathy at baseline. Materials and methods PRIORITY is an investigator-initiated, prospective, randomized, double blind, placebo-controlled multicentre clinical trial and observational study in normoalbuminuric type 2 diabetic patients. Patients are stratified...... is development of microalbuminuria. Results In total 2277 type 2 diabetic patients have been screened over a time period of 2.5 years and 1811 are included from 15 sites. Table 1 shows the baseline characteristics. 224 (12.4%) have the high-risk CKD273 pattern. The high- and low-risk populations differ...

  1. Analogues of neuroactive polyamine wasp toxins that lack inner basic sites exhibit enhanced antagonism toward a muscle-type mammalian nicotinic acetylcholine receptor

    DEFF Research Database (Denmark)

    Stromgaard, K; Brierley, M J; Andersen, K

    1999-01-01

    noncompetitively antagonized the nicotinic acetylcholine receptor (nAChR) in a concentration-, time-, and voltage-dependent manner. The amplitudes of acetylcholine-induced currents were compared at their peaks and at the end of a 1 s application in the presence or absence of the analogues. Most of the analogues...

  2. Facilitation of Contextual Fear Extinction by Orexin-1 Receptor Antagonism Is Associated with the Activation of Specific Amygdala Cell Subpopulations.

    Science.gov (United States)

    Flores, África; Herry, Cyril; Maldonado, Rafael; Berrendero, Fernando

    2017-08-01

    Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated. We used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation. Treatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala. These data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867. © The Author 2017. Published by Oxford University Press on behalf of CINP.

  3. Kappa opioid receptor antagonism and chronic antidepressant treatment have beneficial activities on social interactions and grooming deficits during heroin abstinence.

    Science.gov (United States)

    Lalanne, L; Ayranci, G; Filliol, D; Gavériaux-Ruff, C; Befort, K; Kieffer, B L; Lutz, P-E

    2017-07-01

    Addiction is a chronic brain disorder that progressively invades all aspects of personal life. Accordingly, addiction to opiates severely impairs interpersonal relationships, and the resulting social isolation strongly contributes to the severity and chronicity of the disease. Uncovering new therapeutic strategies that address this aspect of addiction is therefore of great clinical relevance. We recently established a mouse model of heroin addiction in which, following chronic heroin exposure, 'abstinent' mice progressively develop a strong and long-lasting social avoidance phenotype. Here, we explored and compared the efficacy of two pharmacological interventions in this mouse model. Because clinical studies indicate some efficacy of antidepressants on emotional dysfunction associated with addiction, we first used a chronic 4-week treatment with the serotonergic antidepressant fluoxetine, as a reference. In addition, considering prodepressant effects recently associated with kappa opioid receptor signaling, we also investigated the kappa opioid receptor antagonist norbinaltorphimine (norBNI). Finally, we assessed whether fluoxetine and norBNI could reverse abstinence-induced social avoidance after it has established. Altogether, our results show that two interspaced norBNI administrations are sufficient both to prevent and to reverse social impairment in heroin abstinent animals. Therefore, kappa opioid receptor antagonism may represent a useful approach to alleviate social dysfunction in addicted individuals. © 2016 Society for the Study of Addiction.

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

    OpenAIRE

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

    1986-01-01

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

  5. Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription

    Science.gov (United States)

    Vidal, Marcos; Ramana, Chilakamarti V.; Dusso, Adriana S.

    2002-01-01

    The cytokine gamma interferon (IFN-γ) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-γ induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-γ-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of Stat1 and vitamin D receptor (VDR) by IFN-γ and 1,25D promotes protein-protein interactions between Stat1 and the DNA binding domain of the VDR. This prevents VDR-retinoid X receptor (RXR) binding to the vitamin D-responsive element, thus diverting the VDR from its normal genomic target on the 24-hydroxylase promoter and antagonizing 1,25D-VDR transactivation of this gene. In contrast, 1,25D enhances IFN-γ action. Stat1-VDR interactions, by preventing Stat1 deactivation by tyrosine dephosphorylation, cooperate with IFN-γ/Stat1-induced transcription. This novel 1,25D-IFN-γ cross talk explains the pathogenesis of abnormal 1,25D homeostasis in granulomatous processes and provides new insights into 1,25D immunomodulatory properties. PMID:11909970

  6. Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer

    OpenAIRE

    Singhal, Hari; Greene, Marianne E.; Tarulli, Gerard; Zarnke, Allison L.; Bourgo, Ryan J.; Laine, Muriel; Chang, Ya-Fang; Ma, Shihong; Dembo, Anna G.; Raj, Ganesh V.; Hickey, Theresa E.; Tilley, Wayne D.; Greene, Geoffrey L.

    2016-01-01

    The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor?positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak ...

  7. Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory.

    Science.gov (United States)

    Naef, M; Müller, U; Linssen, A; Clark, L; Robbins, T W; Eisenegger, C

    2017-04-25

    Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We believe we report for the first time, the effects of a higher (800 mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo-controlled design. We measure outcomes in the difficult versions of the Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better SWM capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.

  8. Activation of histamine H4 receptor inhibits TNFα/IMD-0354-induced apoptosis in human salivary NS-SV-AC cells.

    Science.gov (United States)

    Stegajev, Vasili; Kouri, Vesa-Petteri; Salem, Abdelhakim; Rozov, Stanislav; Stark, Holger; Nordström, Dan C E; Konttinen, Yrjö T

    2014-12-01

    Apoptosis is involved in the pathogenesis of Sjögren's syndrome (SS), an autoimmune disease affecting exocrine glands. Our recent studies revealed diminished histamine H4 receptor (H₄R) expression and impaired histamine transport in the salivary gland epithelial cells in SS. The aim was now to test if nanomolar histamine and high-affinity H₄R signaling affect apoptosis of human salivary gland epithelial cell. Simian virus 40-immortalized acinar NS-SV-AC cells were cultured in serum-free keratinocyte medium ± histamine H₄R agonist HST-10. Expression and internalization of H₄R were studied by immunofluorescence staining ± clathrin inhibitor methyl-β-cyclodextrin (MβCD). Apoptosis induced using tumor necrosis factor-α with nuclear factor-κB inhibitor IMD-0354 was studied using phase contrast microscopy, Western blot, flow cytometry and polymerase chain reaction (qRT-PCR). HST-10-stimulated H₄R internalization was inhibited by MβCD. Western blotting revealed diminished phosphorylated c-Jun N-terminal kinase JNK, but unchanged levels of phosphorylated extracellular signal regulated kinase pERK1/2 in H₄R-stimulated samples compared to controls. qRT-PCR showed up-regulated expression of anti-apoptotic B cell lymphoma-extra large/Bcl-xL mRNAs and proteins, whereas pro-apoptotic Bcl-2-associated X protein/BAX remained unchanged in H4R-stimulated samples. H₄R stimulation diminished cleavage of PARP and flow cytometry showed significant dose-dependent inhibitory effect of H₄R stimulation on apoptosis. As far as we know this is the first study showing inhibitory effect of H₄R activation on apoptosis of human salivary gland cells. Diminished H₄R-mediated activation may contribute to loss of immune tolerance in autoimmune diseases and in SS in particular.

  9. 5-HT(1A) receptor antagonism reverses and prevents fluoxetine-induced sexual dysfunction in rats.

    Science.gov (United States)

    Sukoff Rizzo, Stacey J; Pulicicchio, Claudine; Malberg, Jessica E; Andree, Terrance H; Stack, Gary P; Hughes, Zoë A; Schechter, Lee E; Rosenzweig-Lipson, Sharon

    2009-09-01

    Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.

  10. Neurokinin-1 receptor antagonism in a rat model of subarachnoid hemorrhage

    DEFF Research Database (Denmark)

    Ansar, Saema; Svendgaard, Niels-Aage; Edvinsson, Lars

    2007-01-01

    OBJECT: Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced cerebral blood flow (CBF) and to cerebral ischemia, in some cases even producing infarction and long-term disability. The goal of the present study was to investigate the hypothesis that inhibition of neurokinin-1...... receptors (NK1Rs) by administration of L-822429 blunts the decrease in CBF as well as cerebrovascular receptor upregulation in an animal model of SAH. METHODS: Subarachnoid hemorrhage was induced in rats by injection of 250 microl of blood into the prechiasmatic cistern. The NK1R inhibitor L-822429...

  11. A2A Receptor Antagonism and Dyskinesia in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Micaela Morelli

    2012-01-01

    Full Text Available Dyskinesia, a major complication of treatment of Parkinson’s disease (PD, involves two phases: induction, which is responsible for dyskinesia onset, and expression, which underlies its clinical manifestation. The unique cellular and regional distribution of adenosine A2A receptors in basal ganglia areas that are richly innervated by dopamine, and their antagonistic role towards dopamine receptor stimulation, have positioned A2A receptor antagonists as an attractive nondopaminergic target to improve the motor deficits that characterize PD. In this paper, we describe the biochemical characteristics of A2A receptors and the effects of adenosine A2A antagonists in rodent and primate models of PD on L-DOPA-induced dyskinesia, together with relevant biomarker studies. We also review clinical trials of A2A antagonists as adjuncts to L-DOPA in PD patients with motor fluctuations. These studies have generally demonstrated that the addition of an A2A antagonist to a stable L-DOPA regimen reduces OFF time and mildly increases dyskinesia. However, limited clinical data suggest that the addition of an A2A antagonist along with a reduction of L-DOPA might maintain anti-Parkinsonian benefit and reduce dyskinesia. Whether A2A antagonists might reduce the development of dyskinesia has not yet been tested clinically.

  12. Delta receptor antagonism, ethanol taste reactivity, and ethanol consumption in outbred male rats.

    Science.gov (United States)

    Higley, Amanda E; Kiefer, Stephen W

    2006-11-01

    Naltrexone, a nonspecific opioid antagonist, produces significant changes in ethanol responsivity in rats by rendering the taste of ethanol aversive as well as producing a decrease in voluntary ethanol consumption. The present study investigated the effect of naltrindole, a specific antagonist of delta opioid receptors, on ethanol taste reactivity and ethanol consumption in outbred rats. In the first experiment, rats received acute treatment of naltrexone, naltrindole, or saline followed by the measurement of ethanol consumption in a short-term access period. The second experiment involved the same treatments and investigated ethanol palatability (using the taste-reactivity test) as well as ethanol consumption. Results indicated that treatment with 3 mg/kg naltrexone significantly affected palatability (rendered ethanol more aversive, Experiment 2) and decreased voluntary ethanol consumption (Experiments 1 and 2). The effects of naltrindole were inconsistent. In Experiment 1, 8 mg/kg naltrindole significantly decreased voluntary ethanol consumption but this was not replicated in Experiment 2. The 8 mg/kg dose produced a significant increase in aversive responding (Experiment 2) but did not affect ingestive responding. Lower doses of naltrindole (2 and 4 mg/kg) were ineffective in altering rats' taste-reactivity response to and consumption of ethanol. While these data suggest that delta receptors are involved in rats' taste-reactivity response to ethanol and rats' ethanol consumption, it is likely that multiple opioid receptors mediate both behavioral responses.

  13. Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.

    Science.gov (United States)

    Levy, Bruce D; Lukacs, Nicholas W; Berlin, Aaron A; Schmidt, Birgitta; Guilford, William J; Serhan, Charles N; Parkinson, John F

    2007-12-01

    Cellular recruitment during inflammatory/immune responses is tightly regulated. The ability to dampen inflammation is imperative for prevention of chronic immune responses, as in asthma. Here we investigated the ability of lipoxin A4 (LXA4) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA4 analog (ATLa) and a 3-oxa-15-epi-LXA4 analog (ZK-994) prevented excessive eosinophil and T lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged with ovalbumin. At 50% and to a greater extent than equivalent doses of the CysLT1 receptor antagonist montelukast. Distinct from montelukast, ATLa treatment led to marked reductions in cysteinyl leukotrienes, interleukin-4 (IL-4), and IL-10, and both ATLa and ZK-994 inhibited levels of IL-13. In cockroach allergen-induced airway responses, both intraperitoneal and oral administration of ZK-994 significantly reduced parameters of airway inflammation and hyper-responsiveness in a dose-dependent manner. ZK-994 also significantly changed the balance of Th1/Th2-specific cytokine levels. Thus, the ATLa/LXA4 analog actions are distinct from CysLT1 antagonism and potently block both allergic airway inflammation and hyper-reactivity. Moreover, these results demonstrate these analogs' therapeutic potential as new agonists for the resolution of inflammation.

  14. Neurokinin B receptor antagonism decreases luteinising hormone pulse frequency and amplitude and delays puberty onset in the female rat.

    Science.gov (United States)

    Li, S Y; Li, X F; Hu, M H; Shao, B; Poston, L; Lightman, S L; O'Byrne, K T

    2014-08-01

    The neural mechanisms controlling puberty onset remain enigmatic. Humans with loss of function mutations in TAC3 or TACR3, the genes encoding neurokinin B (NKB) or its receptor, neurokinin-3 receptor (NK3R), respectively, present with severe congenital gonadotrophin deficiency and pubertal failure. Animal studies have shown ambiguous actions of NKB-NK3R signalling with respect to controlling puberty onset. The present study aimed to determine the role of endogenous NKB-NK3R signalling in the control of pulsatile luteinising hormone (LH) secretion and the timing of puberty onset, and also whether precocious pubertal onset as a result of an obesogenic diet is similarly regulated by this neuropeptide system. Prepubertal female rats, chronically implanted with i.c.v. cannulae, were administered SB222200, a NK3R antagonist, or artificial cerebrospinal fluid via an osmotic mini-pump for 14 days. SB222200 significantly delayed the onset of vaginal opening and first oestrus (as markers of puberty) compared to controls in both normal and high-fat diet fed animals. Additionally, serial blood sampling, via chronic indwelling cardiac catheters, revealed that the increase in LH pulse frequency was delayed and that the LH pulse amplitude was reduced in response to NK3R antagonism, regardless of dietary status. These data suggest that endogenous NKB-NK3R signalling plays a role in controlling the timing of puberty and the associated acceleration of gonadotrophin-releasing hormone pulse generator frequency in the female rat. © 2014 British Society for Neuroendocrinology.

  15. Orexin Receptor Antagonism Improves Sleep and Reduces Seizures in Kcna1-null Mice.

    Science.gov (United States)

    Roundtree, Harrison M; Simeone, Timothy A; Johnson, Chaz; Matthews, Stephanie A; Samson, Kaeli K; Simeone, Kristina A

    2016-02-01

    Comorbid sleep disorders occur in approximately one-third of people with epilepsy. Seizures and sleep disorders have an interdependent relationship where the occurrence of one can exacerbate the other. Orexin, a wake-promoting neuropeptide, is associated with sleep disorder symptoms. Here, we tested the hypothesis that orexin dysregulation plays a role in the comorbid sleep disorder symptoms in the Kcna1-null mouse model of temporal lobe epilepsy. Rest-activity was assessed using infrared beam actigraphy. Sleep architecture and seizures were assessed using continuous video-electroencephalography-electromyography recordings in Kcna1-null mice treated with vehicle or the dual orexin receptor antagonist, almorexant (100 mg/kg, intraperitoneally). Orexin levels in the lateral hypothalamus/perifornical region (LH/P) and hypothalamic pathology were assessed with immunohistochemistry and oxygen polarography. Kcna1-null mice have increased latency to rapid eye movement (REM) sleep onset, sleep fragmentation, and number of wake epochs. The numbers of REM and non-REM (NREM) sleep epochs are significantly reduced in Kcna1-null mice. Severe seizures propagate to the wake-promoting LH/P where injury is apparent (indicated by astrogliosis, blood-brain barrier permeability, and impaired mitochondrial function). The number of orexin-positive neurons is increased in the LH/P compared to wild-type LH/P. Treatment with a dual orexin receptor antagonist significantly increases the number and duration of NREM sleep epochs and reduces the latency to REM sleep onset. Further, almorexant treatment reduces the incidence of severe seizures and overall seizure burden. Interestingly, we report a significant positive correlation between latency to REM onset and seizure burden in Kcna1-null mice. Dual orexin receptor antagonists may be an effective sleeping aid in epilepsy, and warrants further study on their somnogenic and ant-seizure effects in other epilepsy models. © 2016 Associated

  16. The Tetherin Antagonism of the Ebola Virus Glycoprotein Requires an Intact Receptor-Binding Domain and Can Be Blocked by GP1-Specific Antibodies.

    Science.gov (United States)

    Brinkmann, Constantin; Nehlmeier, Inga; Walendy-Gnirß, Kerstin; Nehls, Julia; González Hernández, Mariana; Hoffmann, Markus; Qiu, Xiangguo; Takada, Ayato; Schindler, Michael; Pöhlmann, Stefan

    2016-12-15

    The glycoprotein of Ebola virus (EBOV GP), a member of the family Filoviridae, facilitates viral entry into target cells. In addition, EBOV GP antagonizes the antiviral activity of the host cell protein tetherin, which may otherwise restrict EBOV release from infected cells. However, it is unclear how EBOV GP antagonizes tetherin, and it is unknown whether the GP of Lloviu virus (LLOV), a filovirus found in dead bats in Northern Spain, also counteracts tetherin. Here, we show that LLOV GP antagonizes tetherin, indicating that tetherin may not impede LLOV spread in human cells. Moreover, we demonstrate that appropriate processing of N-glycans in tetherin/GP-coexpressing cells is required for tetherin counteraction by EBOV GP. Furthermore, we show that an intact receptor-binding domain (RBD) in the GP1 subunit of EBOV GP is a prerequisite for tetherin counteraction. In contrast, blockade of Niemann-Pick disease type C1 (NPC1), a cellular binding partner of the RBD, did not interfere with tetherin antagonism. Finally, we provide evidence that an antibody directed against GP1, which protects mice from a lethal EBOV challenge, may block GP-dependent tetherin antagonism. Our data, in conjunction with previous reports, indicate that tetherin antagonism is conserved among the GPs of all known filoviruses and demonstrate that the GP1 subunit of EBOV GP plays a central role in tetherin antagonism. Filoviruses are reemerging pathogens that constitute a public health threat. Understanding how Ebola virus (EBOV), a highly pathogenic filovirus responsible for the 2013-2016 Ebola virus disease epidemic in western Africa, counteracts antiviral effectors of the innate immune system might help to define novel targets for antiviral intervention. Similarly, determining whether Lloviu virus (LLOV), a filovirus detected in bats in northern Spain, is inhibited by innate antiviral effectors in human cells might help to determine whether the virus constitutes a threat to humans. The

  17. Effector stage CC chemokine receptor-1 selective antagonism reduces multiple sclerosis-like rat disease.

    Science.gov (United States)

    Eltayeb, Sana; Sunnemark, Dan; Berg, Anna-Lena; Nordvall, Gunnar; Malmberg, Asa; Lassmann, Hans; Wallström, Erik; Olsson, Tomas; Ericsson-Dahlstrand, Anders

    2003-09-01

    We have studied the role of the chemokine receptor CCR1 during the effector stage of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in DA rats. In situ hybridization histochemistry revealed local production of the CCR1 ligands CCL3 (MIP-1 alpha) and CCL5 (RANTES), as well as large numbers of CCR1 and CCR5 expressing cells within inflammatory brain lesions. A low-molecular weight CCR1 selective antagonist potently abrogated both clinical and histopathological disease signs during a 5-day treatment period, without signs of peripheral immune compromise. Thus, we demonstrate therapeutic targeting of CCR1-dependent leukocyte recruitment to the central nervous system in a multiple sclerosis (MS)-like rat model.

  18. Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABAA receptors

    International Nuclear Information System (INIS)

    Shakarjian, Michael P.; Velíšková, Jana; Stanton, Patric K.; Velíšek, Libor

    2012-01-01

    Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic–clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic–clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic–clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABA A receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists is more likely to be effective in treating TMDT poisoning. -- Highlights: ► TMDT produces convulsions and lethality at low doses in mice. ► Diazepam pre- or post-treatments inhibit TMDT-induced convulsions and death.

  19. Effect of the adenosine A2A receptor antagonist MSX-3 on motivational disruptions of maternal behavior induced by dopamine antagonism in the early postpartum rat.

    Science.gov (United States)

    Pereira, Mariana; Farrar, Andrew M; Hockemeyer, Jörg; Müller, Christa E; Salamone, John D; Morrell, Joan I

    2011-01-01

    Mesolimbic dopamine (DA), particularly in the nucleus accumbens, importantly regulates activational aspects of maternal responsiveness. DA antagonism and accumbens DA depletions interfere with early postpartum maternal motivation by selectively affecting most forms of active maternal behaviors, while leaving nursing behavior relatively intact. Considerable evidence indicates that there is a functional interaction between DA D2 and adenosine A(2A) receptors in striatal areas, including the nucleus accumbens. This study was conducted to determine if adenosine A(2A) receptor antagonism could reverse the effects of DA receptor antagonism on early postpartum maternal behavior. The adenosine A(2A) receptor antagonist MSX-3 (0.25-2.0 mg/kg, IP) was investigated for its ability to reverse the effects of the DA D2 receptor antagonist haloperidol (0.1 mg/kg, IP) on the maternal behavior of early postpartum female rats. Haloperidol severely impaired the expression of active maternal components, including retrieval and grouping the pups at the nest site, pup licking, and nest building. Co-administration of MSX-3 (0.25-2.0 mg/kg, IP) with haloperidol produced a dose-related attenuation of the haloperidol-induced behavioral deficits in early postpartum females. Doses of MSX-3 that effectively reversed the effects of haloperidol (0.5, 1.0 mg/kg), when administered in the absence of haloperidol, did not affect maternal responding or locomotor activity. Adenosine and DA systems interact to regulate early postpartum maternal responsiveness. This research may potentially contribute to the development of strategies for treatments of psychiatric disorders during the postpartum period, with particular emphasis in maintaining or restoring the mother-infant relationship.

  20. Pharmacologic antagonism of dopamine receptor D3 attenuates neurodegeneration and motor impairment in a mouse model of Parkinson's disease.

    Science.gov (United States)

    Elgueta, Daniela; Aymerich, María S; Contreras, Francisco; Montoya, Andro; Celorrio, Marta; Rojo-Bustamante, Estefanía; Riquelme, Eduardo; González, Hugo; Vásquez, Mónica; Franco, Rafael; Pacheco, Rodrigo

    2017-02-01

    Neuroinflammation involves the activation of glial cells, which is associated to the progression of neurodegeneration in Parkinson's disease. Recently, we and other researchers demonstrated that dopamine receptor D3 (D3R)-deficient mice are completely refractory to neuroinflammation and consequent neurodegeneration associated to the acute intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study we examined the therapeutic potential and underlying mechanism of a D3R-selective antagonist, PG01037, in mice intoxicated with a chronic regime of administration of MPTP and probenecid (MPTPp). Biodistribution analysis indicated that intraperitoneally administered PG01037 crosses the blood-brain barrier and reaches the highest concentration in the brain 40 min after the injection. Furthermore, the drug was preferentially distributed to the brain in comparison to the plasma. Treatment of MPTPp-intoxicated mice with PG01037 (30 mg/kg, administrated twice a week for five weeks) attenuated the loss of dopaminergic neurons in the substantia nigra pars compacta, as evaluated by stereological analysis, and the loss of striatal dopaminergic terminals, as determined by densitometric analyses of tyrosine hydroxylase and dopamine transporter immunoreactivities. Accordingly, the treatment resulted in significant improvement of motor performance of injured animals. Interestingly, the therapeutic dose of PG01037 exacerbated astrogliosis and resulted in increased ramification density of microglial cells in the striatum of MPTPp-intoxicated mice. Further analyses suggested that D3R expressed in astrocytes favours a beneficial astrogliosis with anti-inflammatory consequences on microglia. Our findings indicate that D3R-antagonism exerts a therapeutic effect in parkinsonian animals by reducing the loss of dopaminergic neurons in the nigrostriatal pathway, alleviating motor impairments and modifying the pro-inflammatory phenotype of glial cells. Copyright

  1. Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Gerlach, Lars-Ole; Jakobsen, Janus S

    2004-01-01

    , respectively. Metal ion binding in the cyclam rings of AMD3100 increased its dependence on Asp(262) and provided a tighter molecular map of the binding site, where borderline mutational hits became clear hits for the Zn(II)-loaded analog. The proposed binding site for AMD3100 was confirmed by a gradual build......-up in the rather distinct CXCR3 receptor, for which the compound normally had no effect. Introduction of only a Glu at position VII:06 and the removal of a neutralizing Lys residue at position VII:02 resulted in a 1000-fold increase in affinity of AMD3100 to within 10-fold of its affinity in CXCR4. We conclude...

  2. Pharmacological Characterization of 5-Substituted 1-[(2,3-dihydro-1-benzofuran-2-ylmethyl]piperazines: Novel Antagonists for the Histamine H3 and H4 Receptors with Anti-inflammatory Potential

    Directory of Open Access Journals (Sweden)

    Michelle F. Corrêa

    2017-11-01

    Full Text Available The histamine receptors (HRs are traditional G protein-coupled receptors of extensive therapeutic interest. Recently, H3R and H4R subtypes have been targeted in drug discovery projects for inflammation, asthma, pain, cancer, Parkinson’s, and Alzheimer’s diseases, which includes searches for dual acting H3R/H4R ligands. In the present work, nine 1-[(2,3-dihydro-1-benzofuran-2-ylmethyl]piperazine (LINS01 series molecules were synthesized and evaluated as H3R and H4R ligands. Our data show that the N-allyl-substituted compound LINS01004 bears the highest affinity for H3R (pKi 6.40, while the chlorinated compound LINS01007 has moderate affinity for H4R (pKi 6.06. In addition, BRET assays to assess the functional activity of Gi1 coupling indicate that all compounds have no intrinsic activity and act as antagonists of these receptors. Drug-likeness assessment indicated these molecules are promising leads for further improvements. In vivo evaluation of compounds LINS01005 and LINS01007 in a mouse model of asthma showed a better anti-inflammatory activity of LINS01007 (3 g/kg than the previously tested compound LINS01005. This is the first report with functional data of these compounds in HRs, and our results also show the potential of their applications as anti-inflammatory.

  3. A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism

    Science.gov (United States)

    Hasbi, Ahmed; Perreault, Melissa L.; Shen, Maurice Y. F.; Zhang, Lucia; To, Ryan; Fan, Theresa; Nguyen, Tuan; Ji, Xiaodong; O'Dowd, Brian F.; George, Susan R.

    2014-01-01

    Although the dopamine D1-D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1-D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1-D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues 404Glu and 405Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1-D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmunoprecipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G-protein affinities and loss of calcium signaling, resulting in the inhibition of D1-D2 heteromer function. The use of the D1-D2 heteromer-disrupting peptide in vivo revealed a pathophysiological role for the D1-D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment.—Hasbi, A., Perreault, M. L., Shen, M. Y. F., Zhang, L., To, R., Fan, T., Nguyen, T., Ji, X., O'Dowd, B. F., George, S. R. A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism. PMID:25063849

  4. Metabotropic Glutamate Receptor I (mGluR1) Antagonism Impairs Cocaine-Induced Conditioned Place Preference via Inhibition of Protein Synthesis

    OpenAIRE

    Yu, Fei; Zhong, Peng; Liu, Xiaojie; Sun, Dalong; Gao, Hai-qing; Liu, Qing-song

    2013-01-01

    Antagonism of group I metabotropic glutamate receptors (mGluR1 and mGluR5) reduces behavioral effects of drugs of abuse, including cocaine. However, the underlying mechanisms remain poorly understood. Activation of mGluR5 increases protein synthesis at synapses. Although mGluR5-induced excessive protein synthesis has been implicated in the pathology of fragile X syndrome, it remains unknown whether group I mGluR-mediated protein synthesis is involved in any behavioral effects of drugs of abus...

  5. Inhibition of Dengue Virus Replication by a Class of Small-Molecule Compounds That Antagonize Dopamine Receptor D4 and Downstream Mitogen-Activated Protein Kinase Signaling

    Science.gov (United States)

    Smith, Jessica L.; Stein, David A.; Shum, David; Fischer, Matthew A.; Radu, Constantin; Bhinder, Bhavneet; Djaballah, Hakim; Nelson, Jay A.; Früh, Klaus

    2014-01-01

    ABSTRACT Dengue viruses (DENV) are endemic pathogens of tropical and subtropical regions that cause significant morbidity and mortality worldwide. To date, no vaccines or antiviral therapeutics have been approved for combating DENV-associated disease. In this paper, we describe a class of tricyclic small-molecule compounds—dihydrodibenzothiepines (DHBTs), identified through high-throughput screening—with potent inhibitory activity against DENV serotype 2. SKI-417616, a highly active representative of this class, displayed activity against all four serotypes of DENV, as well as against a related flavivirus, West Nile virus (WNV), and an alphavirus, Sindbis virus (SINV). This compound was characterized to determine its mechanism of antiviral activity. Investigation of the stage of the viral life cycle affected revealed that an early event in the life cycle is inhibited. Due to the structural similarity of the DHBTs to known antagonists of the dopamine and serotonin receptors, we explored the roles of two of these receptors, serotonin receptor 2A (5HTR2A) and the D4 dopamine receptor (DRD4), in DENV infection. Antagonism of DRD4 and subsequent downstream phosphorylation of epidermal growth factor receptor (EGFR)-related kinase (ERK) were found to impact DENV infection negatively, and blockade of signaling through this network was confirmed as the mechanism of anti-DENV activity for this class of compounds. IMPORTANCE The dengue viruses are mosquito-borne, reemerging human pathogens that are the etiological agents of a spectrum of febrile diseases. Currently, there are no approved therapeutic treatments for dengue-associated disease, nor is there a vaccine. This study identifies a small molecule, SKI-417616, with potent anti-dengue virus activity. Further analysis revealed that SKI-417616 acts through antagonism of the host cell dopamine D4 receptor and subsequent repression of the ERK phosphorylation pathway. These results suggest that SKI-417616, or other

  6. Behavioral effects of gamma-hydroxybutyrate, its precursor gamma-butyrolactone, and GABA(B) receptor agonists: time course and differential antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348).

    Science.gov (United States)

    Koek, Wouter; Mercer, Susan L; Coop, Andrew; France, Charles P

    2009-09-01

    Gamma-hydroxybutyrate (GHB) is used therapeutically and recreationally. The mechanism by which GHB produces its therapeutic and recreational effects is not entirely clear, although GABA(B) receptors seem to play an important role. This role could be complex, because there are indications that different GABA(B) receptor mechanisms mediate the effects of GHB and the prototypical GABA(B) receptor agonist baclofen. To further explore possible differences in underlying GABA(B) receptor mechanisms, the present study examined the effects of GHB and baclofen on operant responding and their antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348). Pigeons were trained to peck a key for access to food during response periods that started at different times after the beginning of the session. In these pigeons, GHB, its precursor gamma-butyrolactone (GBL), and the GABA(B) receptor agonists baclofen and 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF97541) decreased the rate of responding in a dose- and time-dependent manner. CGP35348 shifted the dose-response curve of each agonist to the right, but the magnitude of the shift differed among the agonists. Schild analysis yielded a pA(2) value of CGP35348 to antagonize GHB and GBL [i.e., 3.9 (3.7-4.2)] that was different (P = 0.0011) from the pA(2) value to antagonize baclofen and SKF97541 [i.e., 4.5 (4.4-4.7)]. This finding is further evidence that the GABA(B) receptor mechanisms mediating the effects of GHB and prototypical GABA(B) receptor agonists are not identical. A better understanding of the similarities and differences between these mechanisms, and their involvement in the therapeutic effects of GHB and baclofen, could lead to more effective medications with fewer adverse effects.

  7. From medicinal plant extracts to defined chemical compounds targeting the histamine H4 receptor: Curcuma longa in the treatment of inflammation.

    Science.gov (United States)

    Frank, Annika; Abu-Lafi, Saleh; Adawi, Azmi; Schwed, Johannes S; Stark, Holger; Rayan, Anwar

    2017-10-01

    The aim was to evaluate the activity of seven medicinal, anti-inflammatory plants at the hH 4 R with focus on defined chemical compounds from Curcuma longa. Activities were analyzed with membrane preparations from Sf9 cells, transiently expressing the hH 4 R, G αi2 and G β1γ2 subunits. From the methanolic extract of C. longa curcumin (1), demethoxycurcumin (2) and bis(4-hydroxy-cinnamoyl)methane (3) were isolated, purified with HPLC (elution-time 10.20, 9.66, 9.20 min, respectively) and together with six additional extracts, were characterized via radioligand binding studies at the hH 4 R. Compounds from C. longa were the most potent ligands at the hH 4 R. They exhibited estimated K i values of 4.26-6.26 µM (1.57-2.31 µg/mL) (1); 6.66--8.97 µM (2.26-3.04 µg/mL) (2) and 10.24-14.57 µM (3.16-4.49 µg/mL) (3) (95% CI). The estimated K i value of the crude extract of curcuma was 0.50-0.81 µg/mL. Fractionated curcumin and the crude extract surpassed the effect of pure curcumin with a K i value of 5.54 µM or 2.04 µg/mL [95% CI (4.47-6.86 µM), (1.65-2.53 µg/mL)]. Within this study, defined compounds of C. longa were recognized as potential ligands and reasonable lead structures at the hH 4 R. The mode of anti-inflammatory action of curcumin was further elucidated and the role of extracts in traditional phytomedicine was strengthened.

  8. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet

    DEFF Research Database (Denmark)

    McClean, Paula L; Irwin, Nigel; Cassidy, Roslyn S

    2007-01-01

    The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, (Pro(3))GIP, in mice previously fed a high-fat diet for 160 days to induce...... obesity and related diabetes. Daily intraperitoneal injection of (Pro(3))GIP over 50 days significantly decreased body weight compared with saline-treated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic......))GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro(3))GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet....

  9. Metabotropic glutamate receptor I (mGluR1) antagonism impairs cocaine-induced conditioned place preference via inhibition of protein synthesis.

    Science.gov (United States)

    Yu, Fei; Zhong, Peng; Liu, Xiaojie; Sun, Dalong; Gao, Hai-Qing; Liu, Qing-Song

    2013-06-01

    Antagonism of group I metabotropic glutamate receptors (mGluR1 and mGluR5) reduces behavioral effects of drugs of abuse, including cocaine. However, the underlying mechanisms remain poorly understood. Activation of mGluR5 increases protein synthesis at synapses. Although mGluR5-induced excessive protein synthesis has been implicated in the pathology of fragile X syndrome, it remains unknown whether group I mGluR-mediated protein synthesis is involved in any behavioral effects of drugs of abuse. We report that group I mGluR agonist DHPG induced more pronounced initial depression of inhibitory postsynaptic currents (IPSCs) followed by modest long-term depression (I-LTD) in dopamine neurons of rat ventral tegmental area (VTA) through the activation of mGluR1. The early component of DHPG-induced depression of IPSCs was mediated by the cannabinoid CB1 receptors, while DHPG-induced I-LTD was dependent on protein synthesis. Western blotting analysis indicates that mGluR1 was coupled to extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) signaling pathways to increase translation. We also show that cocaine conditioning activated translation machinery in the VTA via an mGluR1-dependent mechanism. Furthermore, intra-VTA microinjections of mGluR1 antagonist JNJ16259685 and protein synthesis inhibitor cycloheximide significantly attenuated or blocked the acquisition of cocaine-induced conditioned place preference (CPP) and activation of translation elongation factors. Taken together, these results suggest that mGluR1 antagonism inhibits de novo protein synthesis; this effect may block the formation of cocaine-cue associations and thus provide a mechanism for the reduction in CPP to cocaine.

  10. Lack of association between dopaminergic antagonism and negative symptoms in schizophrenia: a positron emission tomography dopamine D2/3 receptor occupancy study

    Science.gov (United States)

    Fervaha, Gagan; Caravaggio, Fernando; Mamo, David C.; Mulsant, Benoit H.; Pollock, Bruce G.; Nakajima, Shinichiro; Gerretsen, Philip; Rajji, Tarek K.; Mar, Wanna; Iwata, Yusuke; Plitman, Eric; Chung, Jun Ku; Remington, Gary; Graff-Guerrero, Ariel

    2016-01-01

    Rationale Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial. Objective The objective of this study was to examine the relationship between antipsychotic-related dopamine D2/3 receptor occupancy and negative symptoms in patients with schizophrenia. Methods Forty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [11C]-raclopride PET scans were performed before and after participants underwent gradual dose reduction of their antipsychotic medication by up to 40% from the baseline dose. Results No significant relationship was found between antipsychotic-related dopamine D2/3 receptor occupancy and negative symptom severity at baseline or follow-up. Similar null findings were found for subdomains of negative symptoms (amotivation and diminished expression). Occupancy was significantly lower following dose reduction; however, negative symptom severity did not change significantly, though a trend toward reduction was noted. Examination of change scores between these two variables revealed no systematic relationship. Conclusions Our cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioural effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined. PMID:27557949

  11. Rainbow trout estrogen receptor (ER) competitive bindng and vitellogenin induction agonism/antagonism data for 94 chemicals

    Data.gov (United States)

    U.S. Environmental Protection Agency — This dataset is from screening 94 diverse chemicals for estrogen receptor (ER) activation in a competitive rainbow trout ER binding assay and a trout liver slice...

  12. The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription.

    Directory of Open Access Journals (Sweden)

    Baca Chan

    2017-05-01

    Full Text Available The type I interferon (IFN response is imperative for the establishment of the early antiviral immune response. Here we report the identification of the first type I IFN antagonist encoded by murine cytomegalovirus (MCMV that shuts down signaling following pattern recognition receptor (PRR sensing. Screening of an MCMV open reading frame (ORF library identified M35 as a novel and strong negative modulator of IFNβ promoter induction following activation of both RNA and DNA cytoplasmic PRR. Additionally, M35 inhibits the proinflammatory cytokine response downstream of Toll-like receptors (TLR. Using a series of luciferase-based reporters with specific transcription factor binding sites, we determined that M35 targets NF-κB-, but not IRF-mediated, transcription. Expression of M35 upon retroviral transduction of immortalized bone marrow-derived macrophages (iBMDM led to reduced IFNβ transcription and secretion upon activation of stimulator of IFN genes (STING-dependent signaling. On the other hand, M35 does not antagonize interferon-stimulated gene (ISG 56 promoter induction or ISG transcription upon exogenous stimulation of the type I IFN receptor (IFNAR. M35 is present in the viral particle and, upon MCMV infection of fibroblasts, is immediately shuttled to the nucleus where it exerts its immunomodulatory effects. Deletion of M35 from the MCMV genome and hence from the viral particle resulted in elevated type I IFN transcription and secretion in vitro and in vivo. In the absence of M35, lower viral titers are observed during acute infection of the host, and productive infection in the salivary glands was not detected. In conclusion, the M35 protein is released by MCMV immediately upon infection in order to deftly inhibit the antiviral type I IFN response by targeting NF-κB-mediated transcription. The identification of this novel viral protein reinforces the importance of timely countermeasures in the complex relationship between virus and host.

  13. Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior.

    Science.gov (United States)

    Gass, Natalia; Becker, Robert; Sack, Markus; Schwarz, Adam J; Reinwald, Jonathan; Cosa-Linan, Alejandro; Zheng, Lei; von Hohenberg, Christian Clemm; Inta, Dragos; Meyer-Lindenberg, Andreas; Weber-Fahr, Wolfgang; Gass, Peter; Sartorius, Alexander

    2018-04-01

    Evidence indicates that ketamine's rapid antidepressant efficacy likely results from its antagonism of NR2B-subunit-containing NMDA receptors (NMDAR). Since ketamine equally blocks NR2A- and NR2B-containing NMDAR, and has affinity to other receptors, NR2B-selective drugs might have improved therapeutic efficiency and side effect profile. We aimed to compare the effects of (S)-ketamine and two different types of NR2B-selective antagonists on functional brain networks in rats, in order to find common circuits, where their effects intersect, and that might explain their antidepressant action. The experimental design comprised four parallel groups of rats (N = 37), each receiving (S)-Ketamine, CP-101,606, Ro 25-6981 or saline. After compound injection, we acquired resting-state functional magnetic resonance imaging time series. We used graph theoretical approach to calculate brain network properties. Ketamine and CP-101,606 diminished the global clustering coefficient and small-worldness index. At the nodal level, all compounds induced increased connectivity of the regions mediating reward and cognitive aspects of emotional processing, such as ventromedial prefrontal cortex, septal nuclei, and nucleus accumbens. The dorsal hippocampus and regions involved in sensory processing and aversion, such as superior and inferior colliculi, exhibited an opposite effect. The effects common to ketamine and NR2B-selective compounds were localized to the same brain regions as those reported in depression, but in the opposite direction. The upregulation of the reward circuitry might partially underlie the antidepressant and anti-anhedonic effects of the antagonists and could potentially serve as a translational imaging phenotype for testing putative antidepressants, especially those targeting the NR2B receptor subtype.

  14. Metabolite Profiling and a Transcriptional Activation Assay Provide Direct Evidence of Androgen Receptor Antagonism by Bisphenol A in Fish.

    Science.gov (United States)

    Widespread environmental contamination by bisphenol A (BPA) has created the need to fully define its potential toxic mechanisms of action (MOA) to properly assess human health and ecological risks from exposure. Although long recognized as an estrogen receptor (ER) agonist, some ...

  15. Endothelin receptor antagonism in single ventricle physiology with fontan palliation: A systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Gwendolyn Derk

    2015-04-01

    Conclusions: Bosentan was found to be a safe and well tolerated endothelin receptor antagonist in Fontan patients over 3–6 months of therapy. Bosentan use was associated with improved functional capacity. Future studies with larger sample size and longer duration are warranted to examine the long-term safety and efficacy of endothelin blockade in Fontan physiology.

  16. Polyuria due to vasopressin V2 receptor antagonism is not associated with increased ureter diameter in ADPKD patients

    NARCIS (Netherlands)

    Casteleijn, Niek F.; Messchendorp, A. Lianne; Bae, Kyong T.; Higashihara, Eiji; Kappert, Peter; Torres, Vicente; Meijer, Esther; Leliveld, Anna M.

    Tolvaptan, a vasopressin V2 receptor antagonist, has been shown to reduce the rates of growth in total kidney volume (TKV) and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. Prolonged polyuria can result in ureter dilatation with consequently renal

  17. Noncompetitive antagonism and inverse agonism as mechanism of action of nonpeptidergic antagonists at primate and rodent CXCR3 chemokine receptors

    NARCIS (Netherlands)

    Verzijl, D.; Storelli, S.; Scholten, D.J.; Bosch, L.; Reinhart, T.A.; Streblow, D.N.; Tensen, C.P.; Fitzsimons, C.P.; Zaman, G.J.; Pease, J.E.; de Esch, I.J.P.; Smit, M.J.; Leurs, R.

    2008-01-01

    The chemokine receptor CXCR3 is involved in various inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, and allograft rejection in transplantation patients. The CXCR3 ligands CXCL9, CXCL10, and CXCL11 are expressed at sites of inflammation, and they attract

  18. Age-dependent effects on social interaction of NMDA GluN2A receptor subtype-selective antagonism.

    Science.gov (United States)

    Green, Torrian L; Burket, Jessica A; Deutsch, Stephen I

    2016-07-01

    NMDA receptor-mediated neurotransmission is implicated in the regulation of normal sociability in mice. The heterotetrameric NMDA receptor is composed of two obligatory GluN1 and either two "modulatory" GluN2A or GluN2B receptor subunits. GluN2A and GluN2B-containing receptors differ in terms of their developmental expression, distribution between synaptic and extrasynaptic locations, and channel kinetic properties, among other differences. Because age-dependent differences in disruptive effects of GluN2A and GluN2B subtype-selective antagonists on sociability and locomotor activity have been reported in rats, the current investigation explored age-dependent effects of PEAQX, a GluN2A subtype-selective antagonist, on sociability, stereotypic behaviors emerging during social interaction, and spatial working memory in 4- and 8-week old male Swiss Webster mice. The data implicate an age-dependent contribution of GluN2A-containing NMDA receptors to the regulation of normal social interaction in mice. Specifically, at a dose of PEAQX devoid of any effect on locomotor activity and mouse rotarod performance, the social interaction of 8-week old mice was disrupted without any effect on the social salience of a stimulus mouse. Moreover, PEAQX attenuated stereotypic behavior emerging during social interaction in 4- and 8-week old mice. However, PEAQX had no effect on spontaneous alternations, a measure of spatial working memory, suggesting that neural circuits mediating sociability and spatial working memory may be discrete and dissociable from each other. Also, the data suggest that the regulation of stereotypic behaviors and sociability may occur independently of each other. Because expression of GluN2A-containing NMDA receptors occurs at a later developmental stage, they may be more involved in mediating the pathogenesis of ASDs in patients with histories of "regression" after a period of normal development than GluN2B receptors. Copyright © 2016 Elsevier Inc. All rights

  19. β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat.

    Science.gov (United States)

    Wohleb, Eric S; Hanke, Mark L; Corona, Angela W; Powell, Nicole D; Stiner, La'Tonia M; Bailey, Michael T; Nelson, Randy J; Godbout, Jonathan P; Sheridan, John F

    2011-04-27

    Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression. Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner. Repeated social defeat also significantly increased the number of CD11b(+)/CD45(high)/Ly6C(high) macrophages that trafficked to the brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes [glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)]. The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist. Microglia isolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharide compared with microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1-deficient mice, but did not promote anxiety-like behavior or microglia activation in the absence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergic and IL-1 receptors.

  20. Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo.

    Science.gov (United States)

    Traboulsi, Wael; Sergent, Frédéric; Boufettal, Houssine; Brouillet, Sophie; Slim, Rima; Hoffmann, Pascale; Benlahfid, Mohammed; Zhou, Qun Y; Balboni, Gianfranco; Onnis, Valentina; Bolze, Pierre A; Salomon, Aude; Sauthier, Philippe; Mallet, François; Aboussaouira, Touria; Feige, Jean J; Benharouga, Mohamed; Alfaidy, Nadia

    2017-11-15

    Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland-derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy. Experimental Design: Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control ( n = 20) and in distinctive CHM ( n = 38) and CC ( n = 9) cohorts, (ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice. Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions. Conclusions: Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130-40. ©2017 AACR . ©2017 American Association for Cancer Research.

  1. GABA(A) receptor antagonism in the ventrocaudal periaqueductal gray increases anxiety in the anxiety-resistant postpartum rat.

    Science.gov (United States)

    Miller, Stephanie M; Piasecki, Christopher C; Peabody, Mitchell F; Lonstein, Joseph S

    2010-06-01

    Postpartum mammals show suppressed anxiety, which is necessary for their ability to appropriately care for offspring. It is parsimonious to suggest that the neurobiological basis of this reduced anxiety is similar to that of non-parturient animals, involving GABA(A) receptor activity in sites including the midbrain periaqueductal gray (PAG). In Experiment 1, postpartum and diestrous virgin female rats received an intraperitoneal injection of the GABA(A) receptor antagonist (+)-bicuculline (0, 2 and 4 mg/kg) and anxiety-related behavior was assessed with an elevated plus maze. The 4 mg/kg dose of (+)-bicuculline significantly increased anxiety-related behavior, particularly in the postpartum females. Experiment 2 revealed that bicuculline's action was within the central nervous system, because anxiety in neither dams nor virgins was significantly affected by intraperitoneal injection of bicuculline methiodide (0, 2 and 6 mg/kg), which does not readily cross the blood-brain-barrier. In Experiment 3, bicuculline methiodide (2.5 ng/side) was directly infused into the ventrocaudal PAG (cPAGv) and significantly increased dams' anxiety compared to saline-infused controls. These studies expand our knowledge of how GABA(A) receptor modulators affect anxiety behaviors in postpartum rats to the widely-used elevated plus maze, and indicate that the postpartum suppression of anxiety is in part a consequence of elevated GABAergic neurotransmission in the cPAGv. Copyright 2010 Elsevier Inc. All rights reserved.

  2. Antagonism of ionotropic glutamate receptors attenuates chemical ischemia-induced injury in rat primary cultured myenteric ganglia.

    Directory of Open Access Journals (Sweden)

    Elisa Carpanese

    Full Text Available Alterations of the enteric glutamatergic transmission may underlay changes in the function of myenteric neurons following intestinal ischemia and reperfusion (I/R contributing to impairment of gastrointestinal motility occurring in these pathological conditions. The aim of the present study was to evaluate whether glutamate receptors of the NMDA and AMPA/kainate type are involved in myenteric neuron cell damage induced by I/R. Primary cultured rat myenteric ganglia were exposed to sodium azide and glucose deprivation (in vitro chemical ischemia. After 6 days of culture, immunoreactivity for NMDA, AMPA and kainate receptors subunits, GluN(1 and GluA(1-3, GluK(1-3 respectively, was found in myenteric neurons. In myenteric cultured ganglia, in normal metabolic conditions, -AP5, an NMDA antagonist, decreased myenteric neuron number and viability, determined by calcein AM/ethidium homodimer-1 assay, and increased reactive oxygen species (ROS levels, measured with hydroxyphenyl fluorescein. CNQX, an AMPA/kainate antagonist exerted an opposite action on the same parameters. The total number and viability of myenteric neurons significantly decreased after I/R. In these conditions, the number of neurons staining for GluN1 and GluA(1-3 subunits remained unchanged, while, the number of GluK(1-3-immunopositive neurons increased. After I/R, -AP5 and CNQX, concentration-dependently increased myenteric neuron number and significantly increased the number of living neurons. Both -AP5 and CNQX (100-500 µM decreased I/R-induced increase of ROS levels in myenteric ganglia. On the whole, the present data provide evidence that, under normal metabolic conditions, the enteric glutamatergic system exerts a dualistic effect on cultured myenteric ganglia, either by improving or reducing neuron survival via NMDA or AMPA/kainate receptor activation, respectively. However, blockade of both receptor pathways may exert a protective role on myenteric neurons following and I

  3. The peptidomimetic Lau-(Lys-βNSpe)6-NH2 antagonizes formyl peptide receptor 2 expressed in mouse neutrophils

    DEFF Research Database (Denmark)

    Skovbakke, Sarah Line; Winther, Malene; Gabl, Michael

    2016-01-01

    /differences between the human and murine FPR family members is required. Compared to FPR1 and FPR2 expressed by human neutrophils, very little is known about agonist/antagonist recognition patterns for their murine orthologues, but now we have identified two potent and selective formylated peptide agonists (f...... to be devoid of effect on their murine orthologues as determined by their inability to inhibit superoxide release from murine neutrophils upon stimulation with receptor-specific agonists. The Boc-FLFLF peptide was found to be a selective antagonist for Fpr1, whereas the lipidated peptidomimetic Lau...

  4. Disruptions in effort-based decision-making and consummatory behavior following antagonism of the dopamine D2 receptor.

    Science.gov (United States)

    Robles, Cindee F; Johnson, Alexander W

    2017-03-01

    Dopamine is known to influence motivational processes, however the precise role of this neurotransmitter remains a contentious issue. In the current study we sought to further characterize dopamine signaling in reward-based decision-making and consummatory behavior in mice, via lateral ventricle infusion of the dopamine D2 receptor antagonist eticlopride. In Experiment 1, we examined effort-based decision-making, in which mice had a choice between one lever, where a single response led to the delivery of a low value reward (2% sucrose); and a second lever, which led to a higher value reward (20% sucrose) that gradually required more effort to obtain. As the response schedule for the high value reward became more strict, low dose (4μg in 0.5μl) central infusions of eticlopride biased preference away from the high value reward, and toward the lever that led to the low value reward. Similarly, a higher dose of eticlopride (8μg in 0.5μl) also disrupted choice responding for the high value reward, however it did so by increasing omissions. In Experiment 2, we assessed the effects of eticlopride on consumption of 20% sucrose. The antagonist led to a dose-dependent reduction in intake, and through an analysis of licking microstructure, it was revealed that this in part reflected a reduction in the motivation to engage in consummatory behavior, rather than alterations in the evaluation of the reward. These results suggest that disruptions in D2 receptor signaling reduce the willingness to engage in effortful operant responding and consumption of a desirable outcome. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Effects of Chronic Social Defeat Stress on Sleep and Circadian Rhythms Are Mitigated by Kappa-Opioid Receptor Antagonism.

    Science.gov (United States)

    Wells, Audrey M; Ridener, Elysia; Bourbonais, Clinton A; Kim, Woori; Pantazopoulos, Harry; Carroll, F Ivy; Kim, Kwang-Soo; Cohen, Bruce M; Carlezon, William A

    2017-08-09

    Stress plays a critical role in the neurobiology of mood and anxiety disorders. Sleep and circadian rhythms are affected in many of these conditions. Here we examined the effects of chronic social defeat stress (CSDS), an ethological form of stress, on sleep and circadian rhythms. We exposed male mice implanted with wireless telemetry transmitters to a 10 day CSDS regimen known to produce anhedonia (a depressive-like effect) and social avoidance (an anxiety-like effect). EEG, EMG, body temperature, and locomotor activity data were collected continuously during the CSDS regimen and a 5 day recovery period. CSDS affected numerous endpoints, including paradoxical sleep (PS) and slow-wave sleep (SWS), as well as the circadian rhythmicity of body temperature and locomotor activity. The magnitude of the effects increased with repeated stress, and some changes (PS bouts, SWS time, body temperature, locomotor activity) persisted after the CSDS regimen had ended. CSDS also altered mRNA levels of the circadian rhythm-related gene mPer2 within brain areas that regulate motivation and emotion. Administration of the κ-opioid receptor (KOR) antagonist JDTic (30 mg/kg, i.p.) before CSDS reduced stress effects on both sleep and circadian rhythms, or hastened their recovery, and attenuated changes in mPer2 Our findings show that CSDS produces persistent disruptions in sleep and circadian rhythmicity, mimicking attributes of stress-related conditions as they appear in humans. The ability of KOR antagonists to mitigate these disruptions is consistent with previously reported antistress effects. Studying homologous endpoints across species may facilitate the development of improved treatments for psychiatric illness. SIGNIFICANCE STATEMENT Stress plays a critical role in the neurobiology of mood and anxiety disorders. We show that chronic social defeat stress in mice produces progressive alterations in sleep and circadian rhythms that resemble features of depression as it appears in

  6. Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABA{sub A} receptors

    Energy Technology Data Exchange (ETDEWEB)

    Shakarjian, Michael P., E-mail: michael_shakarjian@nymc.edu [Department of Environmental Health Science, School of Health Sciences and Practice, Institute of Public Health, New York Medical College, Valhalla, NY, 10595 (United States); Department of Medicine, Division of Pulmonary and Critical Care Medicine, UMDNJ–Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Velíšková, Jana [Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595 (United States); Department of Obstetrics and Gynecology, New York Medical College, Valhalla, NY 10595 (United States); Department of Neurology, New York Medical College, Valhalla, NY 10595 (United States); Stanton, Patric K., E-mail: patric_stanton@nymc.edu [Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595 (United States); Department of Neurology, New York Medical College, Valhalla, NY 10595 (United States); Velíšek, Libor [Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595 (United States); Department of Neurology, New York Medical College, Valhalla, NY 10595 (United States); Department of Pediatrics, New York Medical College, Valhalla, NY 10595 (United States)

    2012-11-15

    Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic–clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic–clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic–clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABA{sub A} receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists is more likely to be effective in treating TMDT poisoning. -- Highlights: ► TMDT produces convulsions and lethality at low doses in mice. ► Diazepam pre- or post-treatments inhibit TMDT-induced convulsions and death

  7. Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference.

    Science.gov (United States)

    Jerlhag, Elisabet; Egecioglu, Emil; Dickson, Suzanne L; Engel, Jörgen A

    2010-09-01

    Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine. We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist. Thus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

  8. Anti-analgesic effect of the mu/delta opioid receptor heteromer revealed by ligand-biased antagonism.

    Directory of Open Access Journals (Sweden)

    Laura Milan-Lobo

    Full Text Available Delta (DOR and mu opioid receptors (MOR can complex as heteromers, conferring functional properties in agonist binding, signaling and trafficking that can differ markedly from their homomeric counterparts. Because of these differences, DOR/MOR heteromers may be a novel therapeutic target in the treatment of pain. However, there are currently no ligands selective for DOR/MOR heteromers, and, consequently, their role in nociception remains unknown. In this study, we used a pharmacological opioid cocktail that selectively activates and stabilizes the DOR/MOR heteromer at the cell surface by blocking its endocytosis to assess its role in antinociception. We found that mice treated chronically with this drug cocktail showed a significant right shift in the ED50 for opioid-mediated analgesia, while mice treated with a drug that promotes degradation of the heteromer did not. Furthermore, promoting degradation of the DOR/MOR heteromer after the right shift in the ED50 had occurred, or blocking signal transduction from the stabilized DOR/MOR heteromer, shifted the ED50 for analgesia back to the left. Taken together, these data suggest an anti-analgesic role for the DOR/MOR heteromer in pain. In conclusion, antagonists selective for DOR/MOR heteromer could provide an avenue for alleviating reduced analgesic response during chronic pain treatment.

  9. Antagonism of Secreted PCSK9 Increases Low Density Lipoprotein Receptor Expression in HepG2 Cells

    Energy Technology Data Exchange (ETDEWEB)

    McNutt, Markey C.; Kwon, Hyock Joo; Chen, Chiyuan; Chen, Justin R.; Horton, Jay D.; Lagace, Thomas A.; (USMC); (UTSMC)

    2009-07-10

    PCSK9 is a secreted protein that degrades low density lipoprotein receptors (LDLRs) in liver by binding to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. It is not known whether PCSK9 causes degradation of LDLRs within the secretory pathway or following secretion and reuptake via endocytosis. Here we show that a mutation in the LDLR EGF-A domain associated with familial hypercholesterolemia, H306Y, results in increased sensitivity to exogenous PCSK9-mediated cellular degradation because of enhanced PCSK9 binding affinity. The crystal structure of the PCSK9-EGF-A(H306Y) complex shows that Tyr-306 forms a hydrogen bond with Asp-374 in PCSK9 at neutral pH, which strengthens the interaction with PCSK9. To block secreted PCSK9 activity, LDLR (H306Y) subfragments were added to the medium of HepG2 cells stably overexpressing wild-type PCSK9 or gain-of-function PCSK9 mutants associated with hypercholesterolemia (D374Y or S127R). These subfragments blocked secreted PCSK9 binding to cell surface LDLRs and resulted in the recovery of LDLR levels to those of control cells. We conclude that PCSK9 acts primarily as a secreted factor to cause LDLR degradation. These studies support the concept that pharmacological inhibition of the PCSK9-LDLR interaction extracellularly will increase hepatic LDLR expression and lower plasma low density lipoprotein levels.

  10. Management of idiopathic recurrent pericarditis in adults and in children: a role for IL-1 receptor antagonism.

    Science.gov (United States)

    Brucato, Antonio; Emmi, Giacomo; Cantarini, Luca; Di Lenarda, Andrea; Gattorno, Marco; Lopalco, Giuseppe; Marcolongo, Renzo; Imazio, Massimo; Martini, Alberto; Prisco, Domenico

    2018-06-01

    Recurrent pericarditis is one of the most frequent pericardial diseases, affecting up to 30% of the patients who have experienced acute pericarditis. While the diagnosis of acute pericarditis is sometime straight forward, its etiology and therapeutic management are still a challenge for physicians. In developed countries, the idiopathic form is the most frequent, and the search for an infectious etiology is almost invariably negative. Nevertheless, since standard treatment with nonsteroidal anti-inflammatory drugs and colchicine is not always able to neutralize pericardial inflammation in recurrent pericarditis, anakinra, an IL-1 receptor antagonist, has been proposed as a possible therapeutic alternative for refractory forms. IL-1 is a cytokine that exerts a pivotal role in innate immunity and in the pathogenesis of some autoimmune diseases, such as rheumatoid arthritis, and in autoinflammatory disorders, as familial Mediterranean fever and cryopyrin-associated periodic syndromes. The successful management of patients with acute idiopathic recurrent pericarditis (IRP) needs a teamwork approach, where cardiologists, rheumatologists, clinical immunologists and internists are involved. In this review, we will discuss the clinical and therapeutical challenges of IRP both in adults and children from a clinical practice standpoint. We will also briefly illustrate the main pathogenic mechanisms of IRP to provide internists and cardiologists with the rationale for approaching the use of anakinra in selected clinical cases.

  11. P2X7 Receptor Antagonism Attenuates the Intermittent Hypoxia-induced Spatial Deficits in a Murine Model of Sleep Apnea Via Inhibiting Neuroinflammation and Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Yan Deng

    2015-01-01

    Conclusions: The P2X7R antagonism attenuates the CIH-induced neuroinflammation, oxidative stress, and spatial deficits, demonstrating that the P2X7R is an important therapeutic target in the cognition deficits accompanied OSAS.

  12. Ghrelin receptor antagonism of morphine-induced conditioned place preference and behavioral and accumbens dopaminergic sensitization in rats.

    Science.gov (United States)

    Jerabek, Pavel; Havlickova, Tereza; Puskina, Nina; Charalambous, Chrysostomos; Lapka, Marek; Kacer, Petr; Sustkova-Fiserova, Magdalena

    2017-11-01

    An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine and nicotine abuse. However, the role of ghrelin in opioid effects has rarely been examined. Recently we substantiated in rats that ghrelin growth hormone secretagogue receptors (GHS-R1A) appear to be involved in acute opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit morphine-induced biased conditioned place preference and challenge-morphine-induced accumbens dopaminergic sensitization and behavioral sensitization in adult male rats. In the place preference model, the rats were conditioned for 8 days with morphine (10 mg/kg s.c.). On the experimental day, JMV2959 (3 and 6 mg/kg i.p.) or saline were administered before testing. We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens in rats following challenge-morphine dose (5 mg/kg s.c.) with or without JMV2959 (3 and 6 mg/kg i.p.) pretreatment, administered on the 12th day of spontaneous abstinence from morphine repeated treatment (5 days, 10-40 mg/kg). Induced behavioral changes were simultaneously monitored. Pretreatment with JMV2959 significantly and dose dependently reduced the morphine-induced conditioned place preference and significantly and dose dependently reduced the challenge-morphine-induced dopaminergic sensitization and affected concentration of by-products associated with dopamine metabolism in the nucleus accumbens. JMV2959 pretreatment also significantly reduced challenge-morphine-induced behavioral sensitization. Our present data suggest that GHS-R1A antagonists deserve to be further investigated as a novel treatment strategy for opioid addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Brain catalase activity inhibition as well as opioid receptor antagonism increases ethanol-induced HPA axis activation.

    Science.gov (United States)

    Pastor, Raúl; Sanchis-Segura, Carles; Aragon, Carlos M G

    2004-12-01

    Growing evidence indicates that brain catalase activity is involved in the psychopharmacological actions of ethanol. Recent data suggest that participation of this enzymatic system in some ethanol effects could be mediated by the endogenous opioid system. The present study assessed whether brain catalase has a role in ethanol-induced activation of the HPA axis, a neuroendocrine system modulated by the endogenous opioid neurotransmission. Swiss male mice received an intraperitoneal injection of the catalase inhibitor 3-amino-1,2,4-triazole (AT; 0-1 g/kg), and 0 to 20 hr after this administration, animals received an ethanol (0-4 g/kg; intraperitoneally) challenge. Thirty, 60, or 120 min after ethanol administration, plasma corticosterone levels were determined immunoenzymatically. In addition, we tested the effects of 45 mg/kg of cyanamide (another catalase inhibitor) and 0 to 2 mg/kg of naltrexone (nonselective opioid receptor antagonist) on ethanol-induced enhancement in plasma corticosterone values. The present study revealed that AT boosts ethanol-induced increase in plasma corticosterone levels in a dose- and time-dependent manner. However, it did not affect corticosterone values when measured after administration of saline, cocaine (4 mg/kg, intraperitoneally), or morphine (30 mg/kg, intraperitoneally). The catalase inhibitor cyanamide (45 mg/kg, intraperitoneally) also increased ethanol-related plasma corticosterone levels. These effects of AT and cyanamide on ethanol-induced corticosterone values were observed under treatment conditions that decreased significantly brain catalase activity. Indeed, a significant correlation between effects of catalase manipulations on both variables was found. Finally, we found that the administration of naltrexone enhanced the levels of plasma corticosterone after the administration of saline or ethanol. This study shows that the inhibition of brain catalase increases ethanol-induced plasma corticosterone levels. Results are

  14. Polyuria due to vasopressin V2 receptor antagonism is not associated with increased ureter diameter in ADPKD patients.

    Science.gov (United States)

    Casteleijn, Niek F; Messchendorp, A Lianne; Bae, Kyong T; Higashihara, Eiji; Kappert, Peter; Torres, Vicente; Meijer, Esther; Leliveld, Anna M

    2017-06-01

    Tolvaptan, a vasopressin V2 receptor antagonist, has been shown to reduce the rates of growth in total kidney volume (TKV) and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. Prolonged polyuria can result in ureter dilatation with consequently renal function loss. Therefore, we aimed to investigate the effect of tolvaptan-induced polyuria on ureter diameter in ADPKD patients. 70 ADPKD patients were included (51 were randomized to tolvaptan and 19 to placebo). At baseline and after 3 years of treatment renal function was measured (mGFR) and MRI was performed to measure TKV and ureter diameter at the levels of renal pelvis and fifth lumbar vertebral body (L5). In these patients [65.7 % male, age 41 ± 9 years, mGFR 74 ± 27 mL/min/1.73 m 2 and TKV 1.92 (1.27-2.67) L], no differences were found between tolvaptan and placebo-treated patients in 24-h urine volume at baseline (2.5 vs. 2.5 L, p = 0.8), nor in ureter diameter at renal pelvis and L5 (4.0 vs. 4.2 mm, p = 0.4 and 3.0 vs. 3.1 mm, p = 0.3). After 3 years of treatment 24-h urine volume was higher in tolvaptan-treated patients when compared to placebo (4.7 vs. 2.3 L, p polyuria did not lead to an increase in ureter diameter, suggesting that tolvaptan is a safe therapy from a urological point of view.

  15. Long-term antagonism of κ opioid receptors prevents escalation of and increased motivation for heroin intake.

    Science.gov (United States)

    Schlosburg, Joel E; Whitfield, Timothy W; Park, Paula E; Crawford, Elena F; George, Olivier; Vendruscolo, Leandro F; Koob, George F

    2013-12-04

    The abuse of opioid drugs, both illicit and prescription, is a persistent problem in the United States, accounting for >1.2 million users who require treatment each year. Current treatments rely on suppressing immediate withdrawal symptoms and replacing illicit drug use with long-acting opiate drugs. However, the mechanisms that lead to preventing opiate dependence are still poorly understood. We hypothesized that κ opioid receptor (KOR) activation during chronic opioid intake contributes to negative affective states associated with withdrawal and the motivation to take increasing amounts of heroin. Using a 12 h long-access model of heroin self-administration, rats showed escalation of heroin intake over several weeks. This was prevented by a single high dose (30 mg/kg) of the long-acting KOR antagonist norbinaltorphimine (nor-BNI), paralleled by reduced motivation to respond for heroin on a progressive-ratio schedule of reinforcement, a measure of compulsive-like responding. Systemic nor-BNI also significantly decreased heroin withdrawal-associated anxiety-like behavior. Immunohistochemical analysis showed prodynorphin content increased in the nucleus accumbens core in all heroin-exposed rats, but selectively increased in the nucleus accumbens shell in long-access rats. Local infusion of nor-BNI (4 μg/side) into accumbens core altered the initial intake of heroin but not the rate of escalation, while local injection into accumbens shell selectively suppressed increases in heroin intake over time without altering initial intake. These data suggest that dynorphin activity in the nucleus accumbens mediates the increasing motivation for heroin taking and compulsive-like responding for heroin, suggesting that KOR antagonists may be promising targets for the treatment of opioid addiction.

  16. Orexin 1 and orexin 2 receptor antagonism in the basolateral amygdala modulate long-term potentiation of the population spike in the perforant path-dentate gyrus-evoked field potential in rats.

    Science.gov (United States)

    Ardeshiri, Motahareh Rouhi; Hosseinmardi, Narges; Akbari, Esmaeil

    2018-03-01

    Involvement of amygdalo-hippocampal substructures in patients with narcolepsy due to deficiencies in the orexinergic system, and the presence of hippocampus-dependent memory impairments in this disorder, have led us to investigate the effects of orexin 1 and 2 receptor antagonism in the basolateral amygdala (BLA) on long-term potentiation (LTP) of dentate gyrus (DG) granular cells. We used a 200-Hz high-frequency stimulation protocol in anesthetized rats. We studied the long-term synaptic plasticity of perforant path-dentate gyrus granule cells following the inactivation of orexin receptors before and after tetanic stimulation. LTP of the DG population spike was attenuated in the presence of orexin 1 and 2 receptor antagonism (treatment with SB-334867-A and TCS-OX2-29, respectively) in the BLA when compared to that observed following treatment with dimethyl sulfoxide (DMSO). However, the population excitatory post-synaptic potentials were not affected. Moreover, when orexin 1 and 2 receptors in the BLA were blocked after LTP induction, there were no differences between the DMSO and treatment groups. Our findings suggest that the orexinergic system of the BLA plays a modulatory role in the regulation of hippocampal plasticity in rats. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. The retinoid X receptor response element in the human aldehyde dehydrogenase 2 promoter is antagonized by the chicken ovalbumin upstream promoter family of orphan receptors

    NARCIS (Netherlands)

    Pinaire, J; Hasanadka, R; Fang, M; Chou, WY; Stewart, MJ; Kruijer, W; Crabb, D

    2000-01-01

    Two tandem sites in the aldehyde dehydrogenase 2 promoter (designated FP330-5' and FP330-3') that bind members of the nuclear receptor superfamily mere recently identified. Antibodies against apolipoprotein regulatory protein (ARP-1) altered DNA-protein interactions in electrophoretic mobility shift

  18. Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task.

    Directory of Open Access Journals (Sweden)

    Simon R O Nilsson

    Full Text Available Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS-, in a T- or Y-maze configuration. This was followed by three conditions; (1 Full reversal, where contingencies reversed; (2 Perseverance, where the previous CS+ became CS- and the previous CS- was replaced by a novel CS+; (3 Learned non-reward, where the previous CS- became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss

  19. P2X7 Receptor Antagonism Attenuates the Intermittent Hypoxia-induced Spatial Deficits in a Murine Model of Sleep Apnea Via Inhibiting Neuroinflammation and Oxidative Stress.

    Science.gov (United States)

    Deng, Yan; Guo, Xue-Ling; Yuan, Xiao; Shang, Jin; Zhu, Die; Liu, Hui-Guo

    2015-08-20

    The mechanism of the neural injury caused by chronic intermittent hypoxia (CIH) that characterizes obstructive sleep apnea syndrome (OSAS) is not clearly known. The purpose of this study was to investigate whether P2X7 receptor (P2X7R) is responsible for the CIH-induced neural injury and the possible pathway it involves. Eight-week-old male C57BL/6 mice were used. For each exposure time point, eight mice divided in room air (RA) and IH group were assigned to the study of P2X7R expression. Whereas in the 21 days-Brilliant Blue G (BBG, a selective P2X7R antagonist) study, 48 mice were randomly divided into CIH group, BBG-treated CIH group, RA group and BBG-treated RA group. The hippocampus P2X7R expression was determined by Western blotting and real-time polymerase chain reaction (PCR). The spatial learning was analyzed by Morris water maze. The nuclear factor kappa B (NFκB) and NADPH oxidase 2 (NOX2) expressions were analyzed by Western blotting. The expressions of tumor necrosis factor α, interleukin 1β (IL-β), IL-18, and IL-6 were measured by real-time PCR. The malondialdehyde and superoxide dismutase levels were detected by colorimetric method. Cell damage was evaluated by Hematoxylin and Eosin staining and Terminal Transferase dUTP Nick-end Labeling method. The P2X7R mRNA was elevated and sustained after 3-day IH exposure and the P2X7R protein was elevated and sustained after 7-day IH exposure. In the BBG study, the CIH mice showed severer neuronal cell damage and poorer performance in the behavior test. The increased NFκB and NOX2 expressions along with the inflammation injury and oxidative stress were also observed in the CIH group. BBG alleviated CIH-induced neural injury and consequent functional deficits. The P2X7R antagonism attenuates the CIH-induced neuroinflammation, oxidative stress, and spatial deficits, demonstrating that the P2X7R is an important therapeutic target in the cognition deficits accompanied OSAS.

  20. Extract of Kuding tea prevents high-fat diet-induced metabolic disorders in C57BL/6 mice via liver X receptor (LXR β antagonism.

    Directory of Open Access Journals (Sweden)

    Shengjie Fan

    Full Text Available To investigate the effects of ilex kudingcha C. J. Tseng (kuding tea, a traditional beverage in China, on the metabolic disorders in C57BL/6 mice induced by high-fat diets.For the preventive experiment, the female C57BL/6 mice were fed with a standard diet (Chow, high-fat diet (HF, and high-fat diet mixed with 0.05% ethanol extract of kuding tea (EK for 5 weeks. For the therapeutic experiment, the C57BL/6 mice were fed high-fat diet for 3 months, and then mice were split and EK was given with oral gavages for 2 weeks at 50 mg/day/kg. Body weight and daily food intake amounts were measured. At the end of treatment, the adipocyte images were assayed with a scanning electron microscope, and the fasting blood glucose, glucose tolerance test, serum lipid profile and lipids in the livers were analyzed. A reporter gene assay system was used to test the whether EK could act on nuclear receptor transcription factors, and the gene expression analysis was performed with a quantitative PCR assay.In the preventive treatment, EK blocked the body weight gain, reduced the size of the adipocytes, lowered serum triglyceride, cholesterol, LDL-cholesterol, fasting blood glucose levels and glucose tolerance in high-fat diet-fed C57BL/6 mice. In the therapeutic treatment, EK reduced the size of the white adipocytes, serum TG and fasting blood glucose levels in obese mice. With the reporter assay, EK inhibited LXRβ transactivity and mRNA expression of LXRβ target genes.We observed that EK has both preventive and therapeutic roles in metabolic disorders in mice induced with high-fat diets. The effects appear to be mediated through the antagonism of LXRβ transactivity. Our data indicate that kuding tea is a useful dietary therapy and a potential source for the development of novel anti-obesity and lipid lowering drugs.

  1. Differential down-regulation of aquaporin-2 in rat kidney zones by peripheral nociceptin/orphanin FQ receptor agonism and vasopressin type-2 receptor antagonism

    DEFF Research Database (Denmark)

    Hadrup, Niels; Petersen, Jørgen S; Windfeld, Søren

    2007-01-01

    ) of the vasopressin type-2 receptor antagonist 5-dimethylamine-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzapine (OPC31260) (32 nmol/kg/min). ZP120 decreased the aquaporin-2 protein level in the rat cortex/outer stripe of outer medulla and decreased apical plasma membrane localization of aquaporin-2......We previously showed that aquaresis induced by the peripherally acting nociceptin/orphanin FQ receptor agonist ZP120 is associated with a decreased protein level of aquaporin-2 (AQP2) in whole-kidney homogenates. We now examined the effects of Ac-RYYRWKKKKKKK-NH(2) (ZP120) (1 nmol/kg/min i.v. for 4...... h) on renal regional expression (cortex/outer stripe of outer medulla, inner stripe of outer medulla, and inner medulla) and subcellular localization of aquaporin-2. Responses to ZP120 were compared to the effects of an equi-aquaretic dose ( approximately 40% inhibition of distal water reabsorption...

  2. Genetic characterization of avian influenza subtype H4N6 and H4N9 from live bird market, Thailand

    Directory of Open Access Journals (Sweden)

    Kitikoon Pravina

    2011-03-01

    Full Text Available Abstract A one year active surveillance program for influenza A viruses among avian species in a live-bird market (LBM in Bangkok, Thailand was conducted in 2009. Out of 970 samples collected, influenza A virus subtypes H4N6 (n = 2 and H4N9 (n = 1 were isolated from healthy Muscovy ducks. All three viruses were characterized by whole genome sequencing with subsequent phylogenetic analysis and genetic comparison. Phylogenetic analysis of all eight viral genes showed that the viruses clustered in the Eurasian lineage of influenza A viruses. Genetic analysis showed that H4N6 and H4N9 viruses display low pathogenic avian influenza characteristics. The HA cleavage site and receptor binding sites were conserved and resembled to LPAI viruses. This study is the first to report isolation of H4N6 and H4N9 viruses from birds in LBM in Thailand and shows the genetic diversity of the viruses circulating in the LBM. In addition, co-infection of H4N6 and H4N9 in the same Muscovy duck was observed.

  3. Histone H4 Lysine 20 methylation

    DEFF Research Database (Denmark)

    Jørgensen, Stine; Schotta, Gunnar; Sørensen, Claus Storgaard

    2013-01-01

    of histones have emerged as key regulators of genomic integrity. Intense research during the past few years has revealed histone H4 lysine 20 methylation (H4K20me) as critically important for the biological processes that ensure genome integrity, such as DNA damage repair, DNA replication and chromatin...... compaction. The distinct H4K20 methylation states are mediated by SET8/PR-Set7 that catalyses monomethylation of H4K20, whereas SUV4-20H1 and SUV4-20H2 enzymes mediate further H4K20 methylation to H4K20me2 and H4K20me3. Disruption of these H4K20-specific histone methyltransferases leads to genomic...

  4. NMDA receptor antagonism by repetitive MK801 administration induces schizophrenia-like structural changes in the rat brain as revealed by voxel-based morphometry and diffusion tensor imaging.

    Science.gov (United States)

    Wu, H; Wang, X; Gao, Y; Lin, F; Song, T; Zou, Y; Xu, L; Lei, H

    2016-05-13

    Animal models of N-methyl-d-aspartate receptor (NMDAR) antagonism have been widely used for schizophrenia research. Less is known whether these models are associated with macroscopic brain structural changes that resemble those in clinical schizophrenia. Magnetic resonance imaging (MRI) was used to measure brain structural changes in rats subjected to repeated administration of MK801 in a regimen (daily dose of 0.2mg/kg for 14 consecutive days) known to be able to induce schizophrenia-like cognitive impairments. Voxel-based morphometry (VBM) revealed significant gray matter (GM) atrophy in the hippocampus, ventral striatum (vStr) and cortex. Diffusion tensor imaging (DTI) demonstrated microstructural impairments in the corpus callosum (cc). Histopathological results corroborated the MRI findings. Treatment-induced behavioral abnormalities were not measured such that correlation between the brain structural changes observed and schizophrenia-like behaviors could not be established. Chronic MK801 administration induces MRI-observable brain structural changes that are comparable to those observed in schizophrenia patients, supporting the notion that NMDAR hypofunction contributes to the pathology of schizophrenia. Imaging-derived brain structural changes in animal models of NMDAR antagonism may be useful measurements for studying the effects of treatments and interventions targeting schizophrenia. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Nogo-receptor 1 antagonization in combination with neurotrophin-4/5 is not superior to single factor treatment in promoting survival and morphological complexity of cultured dopaminergic neurons.

    Science.gov (United States)

    Seiler, Stefanie; Di Santo, Stefano; Sahli, Sebastian; Andereggen, Lukas; Widmer, Hans Rudolf

    2017-08-01

    Cell transplantation using ventral mesencephalic tissue is an experimental approach to treat Parkinson's disease. This approach is limited by poor survival of the transplants and the high number of dopaminergic neurons needed for grafting. Increasing the yield of dopaminergic neurons in donor tissue is of great importance. We have previously shown that antagonization of the Nogo-receptor 1 by NEP1-40 promoted survival of cultured dopaminergic neurons and exposure to neurotrophin-4/5 increased dopaminergic cell densities in organotypic midbrain cultures. We investigated whether a combination of both treatments offers a novel tool to further improve dopaminergic neuron survival. Rat embryonic ventral mesencephalic neurons grown as organotypic free-floating roller tube or primary dissociated cultures were exposed to neurotrophin-4/5 and NEP1-40. The combined and single factor treatment resulted in significantly higher numbers of tyrosine hydroxylase positive neurons compared to controls. Significantly stronger tyrosine hydroxylase signal intensity was detected by Western blotting in the combination-treated cultures compared to controls but not compared to single factor treatments. Neurotrophin-4/5 and the combined treatment showed significantly higher signals for the neuronal marker microtubule-associated protein 2 in Western blots compared to control while no effects were observed for the astroglial marker glial fibrillary acidic protein between groups, suggesting that neurotrophin-4/5 targets mainly neuronal cells. Finally, NEP1-40 and the combined treatment significantly augmented tyrosine hydroxylase positive neurite length. Summarizing, our findings substantiate that antagonization of the Nogo-receptor 1 promotes dopaminergic neurons but does not further increase the yield of dopaminergic neurons and their morphological complexity when combined with neurotrophin-4/5 hinting to the idea that these treatments might exert their effects by activating common

  6. 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.

  7. Electronic structure of homoleptic transition metal hydrides: TiH4, VH4, CrH4, MnH4, FeH4, CoH4, and NiH4

    International Nuclear Information System (INIS)

    Hood, D.M.; Pitzer, R.M.; Schaefer III, H.F.

    1979-01-01

    Ab initio molecular electronic structure theory has been applied to the family of transition metal tetrahydrides TiH 4 through NiH 4 . For the TiH 4 molecule a wide range of contracted Gaussian basis sets has been tested at the self-consistent-field (SCF) level of theory. The largest basis, labeled M(14s 11p 6d/10s 8p 3d), H(5s 1p/3s 1p), was used for all members of the series and should yield wave functions approaching true Hartree-Fock quality. Predicted SCF dissociation energies (relative to M+4H) and M--H bond distances are TiH 4 132 kcal, 1.70 A; VH 4 86 kcal, 1.64 A; CrH 4 65 kcal, 1.59 A; MnH 4 -- 36 kcal, 1.58 A; FeH 4 0 kcal, 1.58 A; CoH 4 27 kcal, 1.61 A; and NiH 4 18 kcal, 1.75 A. It should be noted immediately that each of these SCF dissociation energies will be increased by electron correlation effects by perhaps as much as 90 kcal. For all of these molecules except TiH 4 excited states have also been studied. One of the most interesting trends seen for these excited states is the shortening of the M--H bond as electrons are transferred from the antibonding 4t 2 orbital to the nonbonding 1e orbitals

  8. Dynamic changes in the expression of DEP-1 and other PDGF receptor-antagonizing PTPs during onset and termination of neointima formation.

    Science.gov (United States)

    Kappert, Kai; Paulsson, Janna; Sparwel, Jan; Leppänen, Olli; Hellberg, Carina; Ostman, Arne; Micke, Patrick

    2007-02-01

    Growth factor-dependent tissue remodeling, such as restenosis, is believed to be predominantly regulated by changes in expression of receptor-tyrosine-kinases (RTKs) and their ligands. As endogenous antagonists of RTKs, protein-tyrosine-phosphatases (PTPs) are additional candidate regulators of these processes. Using laser-capture-microdissection and quantitative RT-polymerase chain reaction (qRT-PCR), we investigated the layer-specific expression of the four platelet-derived growth factor (PDGF) isoforms, the PDGF-alpha and beta receptors, and five PTPs implied in control of PDGF-receptor signaling 8 and 14 days after balloon injury of the rat carotid. Results were correlated with analyses of PDGF-beta receptor phosphorylation and vascular smooth muscle cell (VSMC) proliferation in vivo. The expression levels of all components, as well as receptor activation and VSMC proliferation, showed specific changes, which varied between media and neointima. Interestingly, PTP expression--particularly, DEP-1 levels--appeared to be the dominating factor determining receptor-phosphorylation and VSMC proliferation. In support of these findings, cultured DEP-1(-/-) cells displayed increased PDGF-dependent cell signaling. Hyperactivation of PDGF-induced signaling was also observed after siRNA-down-regulation of DEP-1 in VSMCs. The results indicate a previously unrecognized role of PDGF-receptor-targeting PTPs in controlling neointima formation. In more general terms, the observations indicate transcriptional regulation of PTPs as an important mechanism for controlling onset and termination of RTK-dependent tissue remodeling.

  9. Antagonism of bradykinin B2 receptor prevents inflammatory responses in human endothelial cells by quenching the NF-kB pathway activation.

    Directory of Open Access Journals (Sweden)

    Erika Terzuoli

    Full Text Available Bradykinin (BK induces angiogenesis by promoting vessel permeability, growth and remodeling. This study aimed to demonstrate that the B2R antagonist, fasitibant, inhibits the BK pro-angiogenic effects.We assesed the ability of fasibitant to antagonize the BK stimulation of cultured human cells (HUVEC and circulating pro-angiogenic cells (PACs, in producing cell permeability (paracellular flux, migration and pseocapillary formation. The latter parameter was studied in vitro (matrigel assay and in vivo in mice (matrigel plug and in rat model of experimental osteoarthritis (OA. We also evaluated NF-κB activation in cultured cells by measuring its nuclear translocation and its downstream effectors such as the proangiogenic ciclooxygenase-2 (COX-2, prostaglandin E-2 and vascular endothelial growth factor (VEGF.HUVEC, exposed to BK (1-10 µM, showed increased permeability, disassembly of adherens and tight-junction, increased cell migration, and pseudocapillaries formation. We observed a significant increase of vessel density in the matrigel assay in mice and in rats OA model. Importantly, B2R stimulation elicited, both in HUVEC and PACs, NF-κB activation, leading to COX-2 overexpression, enhanced prostaglandin E-2 production. and VEGF output. The BK/NF-κB axis, and the ensuing amplification of inflammatory/angiogenic responses were fully prevented by fasitibant as well as by IKK VII, an NF-κB. Inhibitor.This work illustrates the role of the endothelium in the inflammation provoked by the BK/NF-κB axis. It also demonstates that B2R blockade by the antaogonist fasibitant, abolishes both the initial stimulus and its amplification, strongly attenuating the propagation of inflammation.

  10. Endothelin-A-receptor antagonism with atrasentan exhibits limited activity on the KU-19-19 bladder cancer cell line in a mouse model.

    Science.gov (United States)

    Herrmann, Edwin; Tiemann, Arne; Eltze, Elke; Bolenz, Christian; Bremer, Christoph; Persigehl, Thorsten; Hertle, Lothar; Wülfing, Christian

    2009-10-01

    The endothelin axis consists of endothelin-1 (ET-1) and its two receptors, ET(A)- and ET(B)-receptor (ET(A)-R and ET(B)-R). In several tumor entities, the ET(A)-R plays a significant role as a drug target. In our study, we investigated whether inhibition of ET(A)-R with atrasentan leads to an antitumor effect in urinary bladder carcinoma as well. Twenty nude mice with thymic aplasia were subcutaneously administered 2 x 10(6) KU-19-19 bladder cancer cells in the right flank. Starting on the 22nd day after the injection, ten animals were treated with atrasentan (2.5 mg/kg BW intraperitoneally), and another ten animals were treated with placebo. During treatment, absolute tumor growth and relative growth rate over time were determined. After the end of treatment, the mitosis and necrosis rates, microvessel density, and receptor density in the tumor tissue were analyzed by immunohistochemistry. In addition, the expression intensities of ET-1, ET(A)-R, and ET(B)-R were evaluated semiquantitatively and compared between the groups. No significant differences between the active-treatment and placebo groups were detected, either with respect to absolute tumor growth (P = 0.333) or mitosis rate (P = 0.217). In the analysis of the necrosis rate and receptor density for ET(A)-R, a trend toward higher values in the active-treatment group (mean necrosis rate = 63.67%, receptor density: 1.417) than in the placebo group (mean necrosis rate = 46.25%, receptor density: 1.270) was found; however, neither difference was statistically significant (P = 0.08 and 0.219, respectively). ET(A)-R blockade with atrasentan in a bladder cancer xenograft model shows no significant antitumor effect.

  11. The CytR repressor antagonizes cyclic AMP-cyclic AMP receptor protein activation of the deoCp2 promoter of Escherichia coli K-12

    DEFF Research Database (Denmark)

    Søgaard-Andersen, L; Martinussen, J; Møllegaard, N E

    1990-01-01

    We have investigated the regulation of the Escherichia coli deoCp2 promoter by the CytR repressor and the cyclic AMP (cAMP) receptor protein (CRP) complexed to cAMP. Promoter regions controlled by these two proteins characteristically contain tandem cAMP-CRP binding sites. Here we show that (i) Cyt...

  12. Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease

    NARCIS (Netherlands)

    Wiesmann, M.; Roelofs, M.; Lugt, R. Van Der; Heerschap, A.; Kiliaan, A.J.; Claassen, J.A.H.R.

    2017-01-01

    Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced

  13. Antagonism of lateral saphenous vein serotonin receptors from steers grazing endophyte-free, wild-type, or novel endophyte-infected tall fescue

    Science.gov (United States)

    Pharmacologic profiling of 5-hydroxytryptamine (5HT) receptors of bovine lateral saphenous vein has shown that cattle grazing endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have altered responses to ergovaline (ERV), 5HT, 5HT2A and 5HT7 agonists. To determine if 5HT...

  14. Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity.

    Science.gov (United States)

    Isherwood, Sarah N; Robbins, Trevor W; Nicholson, Janet R; Dalley, Jeffrey W; Pekcec, Anton

    2017-09-01

    Metabotropic glutamate receptor 4 (mGluR4) and dopamine D 2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D 2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D 2 receptor antagonist eticlopride, on two distinct forms of impulsivity. Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. These findings demonstrate that mGluR4s, in conjunction with D 2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. B7-H4 as a Target for Breast Cancer Immunotherapy

    Science.gov (United States)

    2013-06-01

    papain proteinase K pronase trypsin B7-H4R B """""" B7-H4R-APC CD25-FITC...Figure 5. B7-H4 receptor is protease resistant. Karpas 299 cells were treated with 0.3 mg/mL papain , 0.025 mg/mL proteinase K, 0.15 mg/mL pronase

  16. Enhanced motivation for food reward induced by stress and attenuation by corticotrophin-releasing factor receptor antagonism in rats: implications for overeating and obesity.

    Science.gov (United States)

    Liu, Xiu

    2015-06-01

    Overeating beyond individuals' homeostatic needs critically contributes to obesity. The neurobehavioral mechanisms underlying the motivation to consume excessive foods with high calories are not fully understood. The present study examined whether a pharmacological stressor, yohimbine, enhances the motivation to procure food reward with an emphasis on comparisons between standard lab chow and high-fat foods. The effects of corticotropin-releasing factor (CRF) receptor blockade by a CRF1-selective antagonist NBI on the stress-enhanced motivation for food reward were also assessed. Male Sprague-Dawley rats with chow available ad libitum in their home cages were trained to press a lever under a progressive ratio schedule for deliveries of either standard or high-fat food pellets. For testing yohimbine stress effects, rats received an intraperitoneal administration of yohimbine 10 min before start of the test sessions. For testing effects of CRF1 receptor blockade on stress responses, NBI was administered 20 min prior to yohimbine challenge. The rats emitted higher levels of lever responses to procure the high-fat food pellets compared with their counterparts on standard food pellets. Yohimbine challenge facilitated lever responses for the reward in all of the rats, whereas the effect was more robust in the rats on high-fat food pellets compared with their counterparts on standard food pellets. An inhibitory effect of pretreatment with NBI was observed on the enhancing effect of yohimbine challenge but not on the responses under baseline condition without yohimbine administration. Stress challenge significantly enhanced the motivation of satiated rats to procure extra food reward, especially the high-fat food pellets. Activation of CRF1 receptors is required for the stress-enhanced motivation for food reward. These results may have implications for our better understanding of the biobehavioral mechanisms of overeating and obesity.

  17. Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome

    DEFF Research Database (Denmark)

    Didriksen, Michael; Fejgin, Kim; Nilsson, Simon R O

    2016-01-01

    BACKGROUND: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neurodevelopmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. METHODS: We present a new mouse model (Df...... displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice...

  18. Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome

    DEFF Research Database (Denmark)

    Didriksen, Michael; Fejgin, Kim; Nilsson, Simon R O

    2017-01-01

    Background: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neurodevelopmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. Methods: We present a new mouse model (Df...... displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice...

  19. Effects of cannabinoid CB(1) receptor agonism and antagonism on SKF81297-induced dyskinesia and haloperidol-induced dystonia in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Madsen, Morten V; Peacock, Linda P; Werge, Thomas

    2011-01-01

    81297 (SKF) and acute dystonia induced by the dopamine D(2) receptor antagonist haloperidol in Cebus apella monkeys. The monkeys were sensitised to EPS by prior exposure to D(2) receptor antagonists. SKF (0.3 mg/kg) was administered alone and in combination with the CB(1) agonist CP55,940 (0.......0025-0.01 mg/kg) or the CB(1) antagonist SR141716A (0.25-0.75 mg/kg). Haloperidol (individual doses at 0.01-0.02 mg/kg) was administered alone and in combination with CP55,940 (0.005 or 0.01 mg/kg) or SR141716A (0.5 or 0.75 mg/kg). Subsequently, the monkeys were videotaped, and the recordings were rated...... for oral dyskinesia or dystonia. SKF-induced oral dyskinesia was dose-dependently reduced by CP55,940, with no effect of SR141716A. Haloperidol-induced dystonia was not affected by either CP55,940 or SR141716A....

  20. The effect of caffeine to increase reaction time in the rat during a test of attention is mediated through antagonism of adenosine A2A receptors.

    Science.gov (United States)

    Higgins, Guy A; Grzelak, Michael E; Pond, Annamarie J; Cohen-Williams, Mary E; Hodgson, Robert A; Varty, Geoffrey B

    2007-12-11

    Caffeine produces effects on cognitive function particularly relating to aspects of attention such as reaction time. Considering the plasma exposure levels following regular caffeine intake, and the affinity of caffeine for known protein targets, these effects are likely mediated by either the adenosine A(1) or A(2A) receptor. In the present studies, two rat strains [Long-Evans (LE) and CD] were trained to asymptote performance in a test of selective attention, the 5-choice serial reaction time task (5-CSRTT). Next, the effects of caffeine were compared to the selective A(2A) antagonists, SCH 412348 and KW-6002 (Istradefylline), and the A(1) antagonist, DPCPX. Further studies compared the psychostimulant effects of each drug. Finally, we tested the A(2A) agonist, CGS-21680, on 5-CSRTT performance and given the antipsychotic potential of this drug class, studied the interaction between CGS-21680 and amphetamine in this task. Caffeine (3-10mg/kg IP) increased reaction time in both LE and CD rats, with no effect on accuracy, an effect replicated by SCH 412348 (0.1-1mg/kg PO) and KW-6002 (1-3mg/kg PO), but not DPCPX (3-30 mg/kg PO). At least with SCH 412348, these effects were at doses that were not overtly psychostimulant. In contrast, CGS-21680 (0.03-0. 3mg/kg IP) slowed reaction speed and increased omissions. Interestingly, at a comparatively low dose of 0.03 mg/kg, CGS-21680 attenuated the increased premature responding produced by amphetamine (1mg/kg IP). The present results suggest that the attention-enhancing effects of caffeine are mediated through A(2A) receptor blockade, and selective A(2A) receptor antagonists may have potential as therapies for attention-related disorders. Furthermore, the improvement in response control in amphetamine-treated rats following CGS-21680 pretreatment supports the view that A(2A) agonists have potential as novel antipsychotics.

  1. Certain and progressive methylation of histone H4 at lysine 20 during the cell cycle.

    Science.gov (United States)

    Pesavento, James J; Yang, Hongbo; Kelleher, Neil L; Mizzen, Craig A

    2008-01-01

    Methylation of histone H4 at lysine 20 (K20) has been implicated in transcriptional activation, gene silencing, heterochromatin formation, mitosis, and DNA repair. However, little is known about how this modification is regulated or how it contributes to these diverse processes. Metabolic labeling and top-down mass spectrometry reveal that newly synthesized H4 is progressively methylated at K20 during the G(2), M, and G(1) phases of the cell cycle in a process that is largely inescapable and irreversible. Approximately 98% of new H4 becomes dimethylated within two to three cell cycles, and K20 methylation turnover in vivo is undetectable. New H4 is methylated regardless of prior acetylation, and acetylation occurs predominantly on K20-dimethylated H4, refuting the hypothesis that K20 methylation antagonizes H4 acetylation and represses transcription epigenetically. Despite suggestions that it is required for normal mitosis and cell cycle progression, K20 methylation proceeds normally during colchicine treatment. Moreover, delays in PR-Set7 synthesis and K20 methylation which accompany altered cell cycle progression during sodium butyrate treatment appear to be secondary to histone hyperacetylation or other effects of butyrate since depletion of PR-Set7 did not affect cell cycle progression. Together, our data provide an unbiased perspective of the regulation and function of K20 methylation.

  2. Antagonism of brain insulin-like growth factor-1 receptors blocks estradiol effects on memory and levels of hippocampal synaptic proteins in ovariectomized rats

    Science.gov (United States)

    Nelson, Britta S.; Springer, Rachel C.; Daniel, Jill M.

    2013-01-01

    Rationale Treatment with estradiol, the primary estrogen produced by the ovaries, enhances hippocampus-dependent spatial memory and increases levels of hippocampal synaptic proteins in ovariectomized rats. Increasing evidence indicates that the ability of estradiol to impact the brain and behavior is dependent upon its interaction with insulin-like growth factor-1 (IGF-1). Objectives The goal of the current experiment was to test the hypothesis that the ability of estradiol to impact hippocampus-dependent memory and levels of hippocampal synaptic proteins is dependent on its interaction with IGF-1. Methods Adult rats were ovariectomized and implanted with estradiol or control capsules and trained on a radial-maze spatial memory task. After training, rats were implanted with intracerebroventricular cannulae attached to osmotic minipumps (flow rate 0.15 μl/hr). Half of each hormone treatment group received continuous delivery of JB1 (300 μg/ml), an IGF-1 receptor antagonist, and half received delivery of aCSF vehicle. Rats were tested on trials in the radial-arm maze during which delays were imposed between the 4th and 5th arm choices. Hippocampal levels of synaptic proteins were measured by western blotting. Results Estradiol treatment resulted in significantly enhanced memory. JB1 blocked that enhancement. Estradiol treatment resulted in significantly increased hippocampal levels of postsynaptic density protein 95 (PSD-95), spinophilin, and synaptophysin. JB1 blocked the estradiol-induced increase of PSD-95 and spinophilin and attenuated the increase of synaptophysin. Conclusions Results support a role for IGF-1 receptor activity in estradiol-induced enhancement of spatial memory that may be dependent on changes in synapse structure in the hippocampus brought upon by estradiol/IGF-1 interactions. PMID:24146138

  3. Systemic modulation of serotonergic synapses via reuptake blockade or 5HT1A receptor antagonism does not alter perithreshold taste sensitivity in rats.

    Science.gov (United States)

    Mathes, Clare M; Spector, Alan C

    2014-09-01

    Systemic blockade of serotonin (5HT) reuptake with paroxetine has been shown to increase sensitivity to sucrose and quinine in humans. Here, using a 2-response operant taste detection task, we measured the effect of paroxetine and the 5HT1A receptor antagonist WAY100635 on the ability of rats to discriminate sucrose, NaCl, and citric acid from water. After establishing individual psychometric functions, 5 concentrations of each taste stimulus were chosen to represent the dynamic portion of the concentration-response curve, and the performance of the rats to these stimuli was assessed after vehicle, paroxetine (7mg/kg intraperitoneally), and WAY100635 (0.3mg/kg subcutaneously; 1mg/kg intravenously) administration. Although, at times, overall performance across concentrations dropped, at most, 5% from vehicle to drug conditions, no differences relative to vehicle were seen on the parameters of the psychometric function (asymptote, slope, or EC50) after drug administration. In contrast to findings in humans, our results suggest that modulation of 5HT activity has little impact on sucrose detectability at perithreshold concentrations in rats, at least at the doses used in this task. In the rat model, the purported paracrine/neurocrine action of serotonin in the taste bud may work in a manner that does not impact overt taste detection behavior. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Quantification of the uncertainties in extrapolating from in vitro androgen receptor (AR) antagonism to key events in in vivo screening assays and adverse reproductive outcomes in F1 male rats

    Science.gov (United States)

    There are multiple molecular initiating events (MIEs) that can disrupt male sexual differentiation including AR antagonism and inhibition of synthesis, and metabolism of fetal testosterone. Disruption of this event by pesticides like vinclozolin that act as AR antagonists and ph...

  5. Adenosine A1 Receptor Antagonism Abolished the Anti-seizure Effects of Exogenous Ketone Supplementation in Wistar Albino Glaxo Rijswijk Rats

    Directory of Open Access Journals (Sweden)

    Zsolt Kovács

    2017-07-01

    Full Text Available The state of therapeutic ketosis can be achieved by using the ketogenic diet (KD or exogenous ketone supplementation. It was suggested previously that the adenosinergic system may be involved in the mediating effect of KD on suppressing seizure activity in different types of epilepsies, likely by means of adenosine A1 receptors (A1Rs. Thus, we tested in the present study whether exogenous ketone supplements (ketone ester: KE, 2.5 g/kg/day; ketone salt/KS + medium chain triglyceride/MCT: KSMCT, 2.5 g/kg/day applied sub-chronically (for 7 days by intragastric gavage can modulate absence epileptic activity in genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij rats. The number of spike-wave discharges (SWDs significantly and similarly decreased after both KE and KSMCT treatment between 3rd and 7th days of gavage. Moreover, blood beta-hydroxybutyrate (βHB levels were significantly increased alike after KE and KSMCT gavage, compared to control levels. The SWD number and βHB levels returned to the baseline levels on the first day without ketone supplementation. To determine whether A1Rs can modify ketone supplement-evoked changes in absence epileptic activity, we applied a non-pro-epileptic dose of a specific A1R antagonist DPCPX (1,3-dipropyl-8-cyclopentylxanthine (intraperitoneal/i.p. 0.2 mg/kg in combination with KSMCT (2.5 g/kg/day, gavage. As expected, DPCPX abolished the KSMCT-evoked decrease in SWD number. Thus, we concluded that application of exogenous ketone supplements may decrease absence epileptic activity in WAG/Rij rats. Moreover, our results suggest that among others the adenosinergic system, likely via A1Rs, may modulate the exogenous ketone supplements-evoked anti-seizure effects.

  6. Bacterial Associations: Antagonism to Symbiosis

    Digital Repository Service at National Institute of Oceanography (India)

    Nair, S.

    mutualism through commensalisms and competition, to antagonism, determined ultimately by balancing the cost of the association against the benefits received (Pianka, 1994). A continuum can be envisioned that spans a dynamic bridge from antagonism... when two organisms form a relationship, which provides an advantage for both the partners at least temporarily. In commensalisms only one partner derives benefit and the other does not. Symbiosis The word, ?symbiosis? is derived from the Greek word...

  7. Analysis of thyroid hormone receptor βA mRNA expression in Xenopus laevis tadpoles as a means to detect agonism and antagonism of thyroid hormone action

    International Nuclear Information System (INIS)

    Opitz, Robert; Lutz, Ilka; Nguyen, Ngoc-Ha; Scanlan, Thomas S.; Kloas, Werner

    2006-01-01

    Amphibian metamorphosis represents a unique biological model to study thyroid hormone (TH) action in vivo. In this study, we examined the utility of thyroid hormone receptors α (TRα) and βA (TRβA) mRNA expression patterns in Xenopus laevis tadpoles as molecular markers indicating modulation of TH action. During spontaneous metamorphosis, only moderate changes were evident for TRα gene expression whereas a marked up-regulation of TRβA mRNA occurred in hind limbs (prometamorphosis), head (late prometamorphosis), and tail tissue (metamorphic climax). Treatment of premetamorphic tadpoles with 1 nM 3,5,3'-triiodothyronine (T3) caused a rapid induction of TRβA mRNA in head and tail tissue within 6 to 12 h which was maintained for at least 72 h after initiation of T3 treatment. Developmental stage had a strong influence on the responsiveness of tadpole tissues to induce TRβA mRNA during 24 h treatment with thyroxine (0, 1, 5, 10 nM T4) or T3 (0, 1, 5, 10 nM). Premetamorphic tadpoles were highly sensitive in their response to T4 and T3 treatments, whereas sensitivity to TH was decreased in early prometamorphic tadpoles and strongly diminished in late prometamorphic tadpoles. To examine the utility of TRβA gene expression analysis for detection of agonistic and antagonistic effects on T3 action, mRNA expression was assessed in premetamorphic tadpoles after 48 h of treatment with the synthetic agonist GC-1 (0, 10, 50, 250 nM), the synthetic antagonist NH-3 (0, 40, 200, 1000 nM), and binary combinations of NH-3 (0, 40, 200, 1000 nM) and T3 (1 nM). All tested concentrations of GC-1 as well as the highest concentration of NH-3 caused an up-regulation of TRβA expression. Co-treatment with NH-3 and T3 revealed strong antagonistic effects by NH-3 on T3-induced TRβA mRNA up-regulation. Results of this study suggest that TRβA mRNA expression analysis could serve as a sensitive molecular testing approach to study effects of environmental compounds on the thyroid system in

  8. CGRP-receptor antagonism in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, Lars; Petersen, Kenneth Ahrend

    2007-01-01

    Primary headaches are among the most prevalent neurological disorders, afflicting up to 16% of the adult population. Associated pain originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. In primary headaches, there is a clear association...... between the headache and the release of calcitonin gene-related peptide (CGRP) but not with other neuronal messengers. The specific purpose of this review is to describe CGRP in the human cranial circulation and to elucidate a possible role for a specific antagonist in the treatment of primary headaches...... nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small molecule CGRP antagonists, which would predictably have less cardiovascular side effects as compared to the triptans. The initial pharmacological profile of such a group of compounds has...

  9. Memantine, a Low-Affinity NMDA Receptor Antagonist, Protects against Methylmercury-Induced Cytotoxicity of Rat Primary Cultured Cortical Neurons, Involvement of Ca2+ Dyshomeostasis Antagonism, and Indirect Antioxidation Effects.

    Science.gov (United States)

    Liu, Wei; Xu, Zhaofa; Yang, Tianyao; Xu, Bin; Deng, Yu; Feng, Shu

    2017-09-01

    Methylmercury (MeHg) is an extremely dangerous environmental pollutant that induces severe toxic effects in the central nervous system. Neuronal damage plays critical roles mediating MeHg-induced loss of brain function and neurotoxicity. The molecular mechanisms of MeHg neurotoxicity are incompletely understood. The objective of the study is to explore mechanisms that contribute to MeHg-induced neurocyte injuries focusing on neuronal Ca 2+ dyshomeostasis and alteration of N-methyl-D-aspartate receptors (NMDARs) expression, as well as oxidative stress in primary cultured cortical neurons. In addition, the neuroprotective effects of memantine against MeHg cytotoxicity were also investigated. The cortical neurons were exposed to 0, 0.01, 0.1, 1, or 2 μM methylmercury chloride (MeHgCl) for 0.5-12 h, or pre-treated with 2.5, 5, 10, or 20 μM memantine for 0.5-6 h, respectively; cell viability and LDH release were then quantified. For further experiments, 2.5, 5, and 10 μM of memantine pre-treatment for 3 h followed by 1 μM MeHgCl for 6 h were performed for evaluation of neuronal injuries, specifically addressing apoptosis; intracellular free Ca 2+ concentrations; ATPase activities; calpain activities; expressions of NMDAR subunits (NR1, NR2A, NR2B); NPSH levels; and ROS formation. Exposure of MeHgCl resulted in toxicity of cortical neurons, which were shown as a loss of cell viability, high levels of LDH release, morphological changes, and cell apoptosis. Moreover, intracellular Ca 2+ dyshomeostasis, ATPase activities inhibition, calpain activities, and NMDARs expression alteration were observed with 1 μM MeHgCl administration. Last but not least, NPSH depletion and reactive oxygen species (ROS) overproduction showed an obvious oxidative stress in neurons. However, memantine pre-treatment dose-dependently antagonized MeHg-induced neuronal toxic effects, apoptosis, Ca 2+ dyshomeostasis, NMDARs expression alteration, and oxidative stress. In conclusion, the

  10. B7-H4 Treatment of T Cells Inhibits ERK, JNK, p38, and AKT Activation.

    Directory of Open Access Journals (Sweden)

    Xiaojie Wang

    Full Text Available B7-H4 is a newly identified B7 homolog that plays an important role in maintaining T-cell homeostasis by inhibiting T-cell proliferation and lymphokine-secretion. In this study, we investigated the signal transduction pathways inhibited by B7-H4 engagement in mouse T cells. We found that treatment of CD3(+ T cells with a B7-H4.Ig fusion protein inhibits anti-CD3 elicited T-cell receptor (TCR/CD28 signaling events, including phosphorylation of the MAP kinases, ERK, p38, and JNK. B7-H4.Ig treatment also inhibited the phosphorylation of AKT kinase and impaired its kinase activity as assessed by the phosphorylation of its endogenous substrate GSK-3. Expression of IL-2 is also reduced by B7-H4. In contrast, the phosphorylation state of the TCR proximal tyrosine kinases ZAP70 and lymphocyte-specific protein tyrosine kinase (LCK are not affected by B7-H4 ligation. These results indicate that B7-H4 inhibits T-cell proliferation and IL-2 production through interfering with activation of ERK, JNK, and AKT, but not of ZAP70 or LCK.

  11. Annealing study of the electron-irradiation-induced defects H4 and E11 in InP: Defect transformation (H4-E11)→H4'

    International Nuclear Information System (INIS)

    Bretagnon, T.; Bastide, G.; Rouzeyre, M.

    1990-01-01

    Capacitance spectroscopy has been used to study the two dominant deep levels, H 4 and E 11 , produced in InP by low-energy electron irradiation. The annealing rates of H 4 and E 11 in the p-type material are found to be identical, as is also the dependence on free-carrier recombination and on the chemical nature of the acceptor (Cd or Zn). Recombination-enhanced annealing converts these traps to a hole trap H 4 ' , which is not detectable by conventional deep-level transient spectroscopy. Its emission and capture properties are measured and analyzed. The similarity of the creation and annealing behavior of H 4 and E 11 shows that they share a common point defect. Our results lead to the tentative identification of the defect as a phosphorous vacancy-acceptor complex and we show how this may anneal to the H 4 ' center

  12. Probes for narcotic receptor mediated phenomena 22. Pt.1: Synthesis and characterization of optically pure [{sup 3}H](+)-4-[({alpha}R)-{alpha}-((2S,5R)-4-propyl-2,5-dimethyl-1-pi perazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide, [{sup 3}H]SNC 121, a novel high affinity and selective ligand for delta opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Calderon, S.N.; Bertha, C.M.; Rice, K.C. [National Inst. of Diabetes and Digestive and Kidney Diseases, Medicinal Chemistry Lab., Bethesda, MD (United States); Gutkind, J.S. [National Inst. of Dental Research, Bethesda, MD (United States); Heng Xu; Partilla, J.S.; Rothman, R.B. [National Inst. on Drug Abuse, Clinical Psychopharmacology Section, Baltimore, MD (United States)

    1996-09-01

    The synthesis of unlabelled and labelled SNC 121, a selective nonpeptide ligand for the delta opioid receptor is reported. [{sup 3}H]SNC 121 of specific activity of 26.8 Ci/mmol, was synthesized by catalytic tritiation of the optically pure precursor SNC 80. (author).

  13. Probes for narcotic receptor mediated phenomena 22. Pt.1: Synthesis and characterization of optically pure [3H](+)-4-[(αR)-α-((2S,5R)-4-propyl-2,5-dimethyl-1-pi perazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide, [3H]SNC 121, a novel high affinity and selective ligand for delta opioid receptors

    International Nuclear Information System (INIS)

    Calderon, S.N.; Bertha, C.M.; Rice, K.C.; Gutkind, J.S.; Heng Xu; Partilla, J.S.; Rothman, R.B.

    1996-01-01

    The synthesis of unlabelled and labelled SNC 121, a selective nonpeptide ligand for the delta opioid receptor is reported. [ 3 H]SNC 121 of specific activity of 26.8 Ci/mmol, was synthesized by catalytic tritiation of the optically pure precursor SNC 80. (author)

  14. Design and Rationale for the Endothelin-1 Receptor Antagonism in the Prevention of Microvascular Injury in Patients with non-ST Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention (ENDORA-PCI) Trial.

    Science.gov (United States)

    Liou, Kevin; Jepson, Nigel; Buckley, Nicolas; Chen, Vivien; Thomas, Shane; Russell, Elizabeth Anne; Ooi, Sze-Yuan

    2016-04-01

    Peri-procedural myocardial infarction (PMI) occurs in a small but significant portion of patients undergoing percutaneous intervention (PCI). The underlying mechanisms are complex and may include neurohormonal activation and release of vasoactive substances resulting in disruption of the coronary microcirculation. Endothelin in particular has been found in abundance in atherosclerotic plaques and in systemic circulation following PCI, and may be a potential culprit for PMI through its action on microvascular vasoconstriction, and platelet and neutrophil activation. In this study we aim to characterize the behavior of the coronary microcirculation during a PCI with the index of microvascular resistance (IMR) and the effect of peri-procedural endothelin antagonism. The ENDORA-PCI trial is a randomized, double-blind, placebo-controlled, single-center clinical trial designed to evaluate the efficacy of endothelin antagonism in attenuating the peri-procedural rise in IMR as a surrogate marker for PMI. The patients of interest are those with non-ST elevation acute coronary syndrome (NSTEACS) undergoing PCI, and we aim to recruit 52 patients overall to give the study a power of 80 % at an α level of 5 %. Patients will be randomized in a 1:1 fashion to either Ambrisentan, an endothelin antagonist, or placebo, prior to their PCI. IMR will be measured before and after PCI. The primary endpoint is the difference in peri-procedural changes in patients' IMR between the two groups. The ENDORA-PCI study will investigate whether endothelin antagonism with Ambrisentan attenuates the peri-procedural rise in IMR in patients with NSTEACS undergoing PCI, and thus potentially the risk of PMI.

  15. 42 CFR 52h.4 - Composition of peer review groups.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Composition of peer review groups. 52h.4 Section... PEER REVIEW OF RESEARCH GRANT APPLICATIONS AND RESEARCH AND DEVELOPMENT CONTRACT PROJECTS § 52h.4 Composition of peer review groups. (a) To the extent applicable, the selection and appointment of members of...

  16. Interferon Induction by RNA Viruses and Antagonism by Viral Pathogens

    Directory of Open Access Journals (Sweden)

    Yuchen Nan

    2014-12-01

    Full Text Available Interferons are a group of small proteins that play key roles in host antiviral innate immunity. Their induction mainly relies on host pattern recognition receptors (PRR. Host PRR for RNA viruses include Toll-like receptors (TLR and retinoic acid-inducible gene I (RIG-I like receptors (RLR. Activation of both TLR and RLR pathways can eventually lead to the secretion of type I IFNs, which can modulate both innate and adaptive immune responses against viral pathogens. Because of the important roles of interferons, viruses have evolved multiple strategies to evade host TLR and RLR mediated signaling. This review focuses on the mechanisms of interferon induction and antagonism of the antiviral strategy by RNA viruses.

  17. Compression of glycolide-h4 to 6GPa

    DEFF Research Database (Denmark)

    Hutchison, Ian B.; Bull, Craig L.; Marshall, William G.

    2017-01-01

    This study details the structural characterization of glycolide-h4 as a function of pressure to 6GPa using neutron powder diffraction on the PEARL instrument at ISIS Neutron and Muon source. Glycolide-h4, rather than its deuterated isotopologue, was used in this study due to the difficulty...... of deuteration. The low background afforded by zirconia-toughened alumina anvils nevertheless enabled the collection of data suitable for structural analysis to be obtained to a pressure of 5GPa. Glycolide-h4 undergoes a reconstructive phase transition at 0.15GPa to a previously identified form (II), which...

  18. Valence bond model potential energy surface for H4

    International Nuclear Information System (INIS)

    Silver, D.M.; Brown, N.J.

    1980-01-01

    Potential energy surfaces for the H 4 system are derived using the valence bond procedure. An ab initio evaluation of the valence bond energy expression is described and some of its numerical properties are given. Next, four semiempirical evaluations of the valence bond energy are defined and parametrized to yield reasonable agreement with various ab initio calculations of H 4 energies. Characteristics of these four H 4 surfaces are described by means of tabulated energy minima and equipotential contour maps for selected geometrical arrangements of the four nuclei

  19. Comparison of effects of angiotensin-converting enzyme inhibition with those of angiotensin II receptor antagonism on functional and metabolic recovery in postischemic working rat heart as studied by [31P] nuclear magnetic resonance.

    Science.gov (United States)

    Werrmann, J G; Cohen, S M

    1994-10-01

    To assess the role of angiotensin II (AII) in development of myocardial injury during ischemia and reperfusion, the effects of short-term treatment with the angiotensin-converting enzyme (ACE) inhibitor lisinopril were compared with the effects of short-term treatment with L-158,338, an AII antagonist, in isolated working rat heart. Myocardial function was assessed and correlated with simultaneous measurement of high-energy phosphate metabolism and intracellular pH by [31P] nuclear magnetic resonance (NMR) before, during, and after global ischemia. Hearts from rats treated with 1 mg/kg lisinopril in vivo recovered substantially more function than those of controls (p effect on functional recovery. A dose-dependent increase in functional recovery was observed in rat heart treated with 0.3, 1, or 3 mg/kg L-158,338 in vivo (p energy phosphate metabolism was essentially unchanged by any treatment regimen. AII antagonism alone resulted in a degree of improvement in functional recovery comparable to that observed with oral ACE inhibitor treatment.

  20. Antagonism of acetylcholine by adrenaline antagonists

    Science.gov (United States)

    Benfey, B. G.; Grillo, S. A.

    1963-01-01

    Phenoxybenzamine antagonized the inhibitory action of acetylcholine on the guinea-pig isolated atrium. The antagonism was slow in onset, very slowly reversible, and could be overcome by increased concentrations of acetylcholine. In contrast, atropine inhibited the action of acetylcholine quickly, and the effect disappeared soon after withdrawal. The pA10 of phenoxybenzamine (2 hr of contact) was 6.8, and that of atropine (30 min of contact) was 8.4. In the presence of atropine phenoxybenzamine did not exert a slowly reversible antagonism, and the dose-ratio of acetylcholine returned to normal soon after withdrawal of both drugs. Phenoxybenzamine also antagonized acetylcholine in the guinea-pig isolated ileum, but with higher concentrations acetylcholine did not overcome the antagonism. The pA10 (60 min of contact) was 6.6. The pA10 of chlorpromazine in the atrium (2 hr of contact) and ileum (60 min of contact) was 5.9. Phentolamine, 2-diethylaminomethylbenzo-1,4-dioxan hydrochloride (883 F), and yohimbine antagonized acetylcholine in the atrium and ileum but required higher concentrations than chlorpromazine. PMID:13967429

  1. High pressure oxidation of C2H4/NO mixtures

    DEFF Research Database (Denmark)

    Giménez-López, J.; Alzueta, M.U.; Rasmussen, C.T.

    2011-01-01

    An experimental and kinetic modeling study of the interaction between C2H4 and NO has been performed under flow reactor conditions in the intermediate temperature range (600–900K), high pressure (60bar), and for stoichiometries ranging from reducing to oxidizing conditions. The main reaction...... pathways of the C2H4/O2/NOx conversion, the capacity of C2H4 to remove NO, and the influence of the presence of NOx on the C2H4 oxidation are analyzed. Compared to the C2H4/O2 system, the presence of NOx shifts the onset of reaction 75–150K to lower temperatures. The mechanism of sensitization involves...... the reaction HOCH2CH2OO+NO→CH2OH+CH2O+NO2, which pushes a complex system of partial equilibria towards products. This is a confirmation of the findings of Doughty et al. [3] for a similar system at atmospheric pressure. Under reducing conditions and temperatures above 700K, a significant fraction of the NOx...

  2. Synthesis and in vivo evaluation of a novel 5-HT{sub 1A} receptor agonist radioligand [O-methyl-{sup 11}C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Dileep Kumar, J.S.; Parsey, Ramin V. [Columbia University College of Physicians and Surgeons, Department of Psychiatry, New York (United States); New York State Psychiatric Institute, Division of Brain Imaging, Department of Neuroscience, New York (United States); Prabhakaran, Jaya; Majo, Vattoly J.; Milak, Matthew S.; Hsiung, Shu-Chi; Tamir, Hadassah [Columbia University College of Physicians and Surgeons, Department of Psychiatry, New York (United States); Simpson, Norman R. [Columbia University College of Physicians and Surgeons, Department of Radiology, New York (United States); Heertum, Ronald L. Van [New York State Psychiatric Institute, Division of Brain Imaging, Department of Neuroscience, New York (United States); Columbia University College of Physicians and Surgeons, Department of Radiology, New York (United States); Mann, J. John [Columbia University College of Physicians and Surgeons, Department of Psychiatry, New York (United States); New York State Psychiatric Institute, Division of Brain Imaging, Department of Neuroscience, New York (United States); Columbia University College of Physicians and Surgeons, Department of Radiology, New York (United States)

    2007-07-15

    Serotonin{sub 1A} (5-HT{sub 1A}) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT{sub 1A} receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT{sub 1A} receptor agonist radiotracer in living brain has not been reported. [{sup 11}C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT{sub 1A} receptor binding. We now report the synthesis and evaluation of [{sup 11}C]MMP as an agonist PET tracer for 5-HT{sub 1A} receptors in baboons. In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT{sub 1A} receptors. [{sup 11}C] labeling of MMP was performed by reacting desmethyl-MMP with [{sup 11}C]CH{sub 3}OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT{sub 1A} receptor ligands WAY-100635 and ({+-})-8-OH-DPAT. MMP is a selective 5-HT{sub 1A} receptor agonist (K{sub i} 0.15 nM). Radiosynthesis of [{sup 11}C]MMP was achieved in 30 {+-} 5% (n = 15) yield at EOS with a specific activity of 2,600 {+-} 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [{sup 11}C]MMP to 5-HT{sub 1A} receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and ({+-})-8-OH-DPAT. We identified [{sup 11}C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT{sub 1A} receptors in baboons. (orig.)

  3. Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost–variable-payoff fixed-ratio cocaine self-administration in rats

    OpenAIRE

    Xi, Zheng-Xiong; Gilbert, Jeremy G.; Pak, Arlene C.; Ashby, Charles R.; Heidbreder, Christian A.; Gardner, Eliot L.

    2005-01-01

    In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D3 receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost–variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3–24 mg/...

  4. Interleukin-1 Antagonism Decreases Cortisol Levels in Obese Individuals.

    Science.gov (United States)

    Urwyler, Sandrine Andrea; Schuetz, Philipp; Ebrahimi, Fahim; Donath, Marc Y; Christ-Crain, Mirjam

    2017-05-01

    Increased cortisol levels in obesity may contribute to the associated metabolic syndrome. In obesity, the activated innate immune system leads to increased interleukin (IL)-1β, which is known to stimulate the release of adrenocorticotropin hormone (ACTH). We hypothesized that in obesity IL-1 antagonism would result in downregulation of the hypothalamo-pituitary-adrenal axis, leading to decreased cortisol levels. In this prospective intervention study, we included 73 patients with obesity (body mass index [BMI] ≥30 kg/m2) and at least one additional feature of the metabolic syndrome. The primary end point was change in morning cortisol from baseline to after the administration of the IL-1 receptor antagonist (anakinra/Kineret®, total dose 3 × 100 mg). Secondary end points were effects on salivary cortisol and ACTH. Median age was 56 years, 50.7% of patients were female, and median BMI was 36.3 kg/m2. Median morning serum cortisol levels (nmol/L) decreased significantly after IL-1 antagonism [from baseline, 452 to 423; absolute difference, -38.7; 95% confidence interval (CI), -64 to -13.4; P = 0.0019]. Similar effects were found for salivary cortisol levels (-2.8; 95% CI, -4.4 to -1.3; P = 0.0007), ACTH levels (-2.2; 95% CI; -4.2 to -0.1; P = 0.038), systolic blood pressure (-5.2, 95% CI, -8.5 to -1.8; P = 0.0006), and heart rate (-2.9; 95% CI, -4.7 to -1.0; P = 0.0029). IL-1 antagonism in obese individuals with features of the metabolic syndrome leads to a decrease in serum cortisol, salivary cortisol, and ACTH levels along with a reduction in systolic blood pressure and heart rate. Copyright © 2017 Endocrine Society

  5. B7-H4-Ig treatment of normal mice changes lymphocyte homeostasis and increases the potential of regulatory T cells

    DEFF Research Database (Denmark)

    Kristensen, Nanna N; Schmidt, Esben G W; Rasmussen, Susanne

    2013-01-01

    Enteroantigens (eAgs) drive tolerogenic and inflammatory immune responses in the gut and are of importance for sustained immune homeostasis in colonic mucosa. Decline of regulatory activity in the gut mucosa might result in chronic colitis. B7-H4 is a co-inhibitory receptor expressed by professio......Enteroantigens (eAgs) drive tolerogenic and inflammatory immune responses in the gut and are of importance for sustained immune homeostasis in colonic mucosa. Decline of regulatory activity in the gut mucosa might result in chronic colitis. B7-H4 is a co-inhibitory receptor expressed...... of severe combined immune-deficient (SCID) mice undergoing T cell transfer colitis did not influence the course of disease probably reflecting the lack of Tregs in this model of chronic colitis. In conclusion, we show that treatment with B7-H4-Ig in vivo changes lymphocyte homeostasis and increases...

  6. H4: A challenging system for natural orbital functional approximations

    International Nuclear Information System (INIS)

    Ramos-Cordoba, Eloy; Lopez, Xabier; Piris, Mario; Matito, Eduard

    2015-01-01

    The correct description of nondynamic correlation by electronic structure methods not belonging to the multireference family is a challenging issue. The transition of D 2h to D 4h symmetry in H 4 molecule is among the most simple archetypal examples to illustrate the consequences of missing nondynamic correlation effects. The resurgence of interest in density matrix functional methods has brought several new methods including the family of Piris Natural Orbital Functionals (PNOF). In this work, we compare PNOF5 and PNOF6, which include nondynamic electron correlation effects to some extent, with other standard ab initio methods in the H 4 D 4h /D 2h potential energy surface (PES). Thus far, the wrongful behavior of single-reference methods at the D 2h –D 4h transition of H 4 has been attributed to wrong account of nondynamic correlation effects, whereas in geminal-based approaches, it has been assigned to a wrong coupling of spins and the localized nature of the orbitals. We will show that actually interpair nondynamic correlation is the key to a cusp-free qualitatively correct description of H 4 PES. By introducing interpair nondynamic correlation, PNOF6 is shown to avoid cusps and provide the correct smooth PES features at distances close to the equilibrium, total and local spin properties along with the correct electron delocalization, as reflected by natural orbitals and multicenter delocalization indices

  7. H4: A challenging system for natural orbital functional approximations

    Science.gov (United States)

    Ramos-Cordoba, Eloy; Lopez, Xabier; Piris, Mario; Matito, Eduard

    2015-10-01

    The correct description of nondynamic correlation by electronic structure methods not belonging to the multireference family is a challenging issue. The transition of D2h to D4h symmetry in H4 molecule is among the most simple archetypal examples to illustrate the consequences of missing nondynamic correlation effects. The resurgence of interest in density matrix functional methods has brought several new methods including the family of Piris Natural Orbital Functionals (PNOF). In this work, we compare PNOF5 and PNOF6, which include nondynamic electron correlation effects to some extent, with other standard ab initio methods in the H4 D4h/D2h potential energy surface (PES). Thus far, the wrongful behavior of single-reference methods at the D2h-D4h transition of H4 has been attributed to wrong account of nondynamic correlation effects, whereas in geminal-based approaches, it has been assigned to a wrong coupling of spins and the localized nature of the orbitals. We will show that actually interpair nondynamic correlation is the key to a cusp-free qualitatively correct description of H4 PES. By introducing interpair nondynamic correlation, PNOF6 is shown to avoid cusps and provide the correct smooth PES features at distances close to the equilibrium, total and local spin properties along with the correct electron delocalization, as reflected by natural orbitals and multicenter delocalization indices.

  8. Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats.

    Science.gov (United States)

    Blacktop, Jordan M; Vranjkovic, Oliver; Mayer, Matthieu; Van Hoof, Matthew; Baker, David A; Mantsch, John R

    2016-03-01

    Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 h/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5" duration, average every 40 s; range 10-70 s) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced cocaine seeking at either dose tested. By contrast, 2-hydroxysaclofen (0.2 or 2 μg/side) prevented reinstatement by both footshock and intra-VTA CRF at a concentration that failed to attenuate food-reinforced lever pressing (45 mg sucrose-sweetened pellets; FR4 schedule) in a separate group of rats. These data suggest that GABA-B receptor-dependent CRF actions in the VTA mediate stress-induced cocaine seeking and that GABA-B receptor antagonists may have utility for the management of stress-induced relapse in cocaine addicts. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic.

    Science.gov (United States)

    Patat, A; Naef, M M; van Gessel, E; Forster, A; Dubruc, C; Rosenzweig, P

    1994-10-01

    Zolpidem is a new imidazopyridine-hypnotic that selectively binds to the central omega 1-receptor subtype. A double-blind, randomized, three-way, crossover placebo-controlled study was carried out in nine healthy male volunteers to assess the possible antagonism of central nervous system--depressant effects of zolpidem by flumazenil. Subjects received zolpidem (0.21 mg/kg) or placebo, intravenously, followed 17 minutes later by flumazenil (0.04 mg/kg) or placebo. Vigilance and performance were assessed by a trained anesthetist with use of ciliary reflex, response to a verbal instruction, subjective sedation, a tracking task, and a free recall task. Zolpidem produced a clinically relevant hypnotic effect in five subjects and significantly impaired performance in all nine subjects up to 90 minutes after dosing. Flumazenil rapidly antagonized clinical sedation in the five subjects who were asleep and significantly reversed the performance decrement within 3 minutes, without any escape phenomenon. Flumazenil did not change zolpidem plasma concentrations, confirming the pharmacodynamic nature of the interaction. Flumazenil may thus be a safe and effective antidote in patients with zolpidem overdosage.

  10. Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost–variable-payoff fixed-ratio cocaine self-administration in rats

    Science.gov (United States)

    Xi, Zheng-Xiong; Gilbert, Jeremy G.; Pak, Arlene C.; Ashby, Charles R.; Heidbreder, Christian A.; Gardner, Eliot L.

    2013-01-01

    In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D3 receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost–variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3–24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self-administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB-277011A (24 mg/kg, i.p.) progressively attenuated cocaine self-administration when: (a) the unit dose of self-administered cocaine was lowered from 0.75 to 0.125–0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB-277011A (6–24 mg/kg i.p.) lowered the PR break point for cocaine self-administration in a dose-dependent manner. The reduction in the cocaine (0.25–1.0 mg/kg) dose–response break-point curve produced by 24 mg/kg SB-277011A is consistent with a reduction in cocaine’s reinforcing efficacy. When substituted for cocaine, SB-277011A alone did not sustain self-administration behaviour. In contrast with the mixed DA D2/D3 receptor antagonist haloperidol (1 mg/kg), SB-277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB-277011A significantly inhibits acute cocaine-induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB-277011A or similar selective DA D3 receptor antagonists may be

  11. Event display of a H -> 4mu candidate event

    CERN Multimedia

    ATLAS, Collaboration

    2012-01-01

    Event display of a H -> 4mu candidate event with m(4l) = 124.1 (125.1) GeV without (with) Z mass constraint. The masses of the lepton pairs are 86.3 GeV and 31.6 GeV. The event was recorded by ATLAS on 10-Jun-2012, 13:24:31 CEST in run number 204769 as event number 71902630. Muon tracks are colored red.

  12. Event display of a H -> 4mu candidate event

    CERN Multimedia

    ATLAS, Collaboration

    2012-01-01

    Event display of a H -> 4mu candidate event with m(4l) = 124.1 (125.1) GeV without (with) Z mass constraint. The masses of the lepton pairs are 86.3 GeV and 31.6 GeV. The event was recorded by ATLAS on 10-Jun-2012, 13:24:31 CEST in run number 204769 as event number 71902630. Zoom into the tracking detector. Muon tracks are colored red.

  13. The Antagonism Mechanism Of Trichoderma spp. Towards Fusarium solani Mold

    OpenAIRE

    Utami Sri Hastuti; Indriana Rahmawati

    2016-01-01

    The antagonism ability of seven Trichoderma isolates towards F.solani have been observed and tested by dual culture technique. The antagonism mechanism observed by microscopic observation with light microscope and Scanning Electron Microscopy (SEM). The research result showed seven species of Trichoderma molds have different antagonism ability towards F.solani each other. The antagonism mechanism observed by light microscope and Scanning Electron Microscopy were mycoparasitism, antibiosis, an...

  14. The Antagonism Mechanism Of Trichoderma spp. Towards Fusarium solani Mold

    Directory of Open Access Journals (Sweden)

    Utami Sri Hastuti

    2016-09-01

    Full Text Available The antagonism ability of seven Trichoderma isolates towards F.solani have been observed and tested by dual culture technique. The antagonism mechanism observed by microscopic observation with light microscope and Scanning Electron Microscopy (SEM. The research result showed seven species of Trichoderma molds have different antagonism ability towards F.solani each other. The antagonism mechanism observed by light microscope and Scanning Electron Microscopy were mycoparasitism, antibiosis, and competition.

  15. Benzodiazepine antagonism by harmane and other beta-carbolines in vitro and in vivo.

    Science.gov (United States)

    Rommelspacher, H; Nanz, C; Borbe, H O; Fehske, K J; Müller, W E; Wollert, U

    1981-03-26

    Harmane and other related beta-carbolines are putative endogenous ligands of the benzodiazepine receptor. Since the compounds are potent convulsants they may have agonist activities at the benzodiazepine receptor while the benzodiazepines may be antagonists. This hypothesis was proved by comparing the in vivo and in vitro antagonism of benzodiazepines by harmane and other beta-carbolines. Harmane is clearly a competitive inhibitor of benzodiazepine receptor binding in vitro. Moreover, harmane-induced convulsions can be inhibited reversibly by diazepam in a manner which is consistent with the assumption of competitive antagonism in vivo. For some beta-carboline derivatives a correlation was found between the affinity for the benzodiazepine receptor in vitro and the convulsive potency in vivo. Thus, the data reported suggest that harmane or other related beta-carbolines are putative endogenous agonists of the benzodiazepine receptor. This suggestion is further supported by the observation that diazepam is equally potent in inhibiting harmane- or picrotoxin-induced convulsions, indicating a convulsive mechanism within the GABA receptor-benzodiazepine receptor system.

  16. Event display of a H -> 4mu candidate event

    CERN Multimedia

    ATLAS, Collaboration

    2012-01-01

    Event display of a H -> 4mu candidate event with m(4l) = 124.1 (125.1) GeV without (with) Z mass constraint. The masses of the lepton pairs are 86.3 GeV and 31.6 GeV. The event was recorded by ATLAS on 10-Jun-2012, 13:24:31 CEST in run number 204769 as event number 71902630. Muon tracks are colored red. The inset on the right-hand side shows a zoom into the tracking detector. The inset on top shows a zoom into the vertex region, indicating that the 4 muons originate from the same primary vertex.

  17. Event display of a H -> 4e candidate event

    CERN Multimedia

    ATLAS, Collaboration

    2012-01-01

    Event display of a H -> 4e candidate event with m(4l) = 124.5 (124.6) GeV without (with) Z mass constraint. The masses of the lepton pairs are 70.6 GeV and 44.7 GeV. The event was recorded by ATLAS on 18-May-2012, 20:28:11 CEST in run number 203602 as event number 82614360. The tracks of the two electron pairs are colored red, the clusters in the LAr calorimeter are colored darkgreen.

  18. Event display of a H -> 4e candidate event

    CERN Multimedia

    ATLAS, Collaboration

    2012-01-01

    Event display of a H -> 4e candidate event with m(4l) = 124.5 (124.6) GeV without (with) Z mass constraint. The masses of the lepton pairs are 70.6 GeV and 44.7 GeV. The event was recorded by ATLAS on 18-May-2012, 20:28:11 CEST in run number 203602 as event number 82614360. Zoom into the tracking detector and the LAr calorimeter where its detailed structure is highlighted. The tracks and clusters of the two electron pairs are colored red and blue, respectively.

  19. Event display of a H -> 4e candidate event

    CERN Multimedia

    ATLAS, Collaboration

    2012-01-01

    Event display of a H -> 4e candidate event with m(4l) = 124.5 (124.6) GeV without (with) Z mass constraint. The masses of the lepton pairs are 70.6 GeV and 44.7 GeV. The event was recorded by ATLAS on 18-May-2012, 20:28:11 CEST in run number 203602 as event number 82614360. The tracks and clusters of the two electron pairs are colored red and blue, respectively.

  20. Event display of a H -> 4e candidate event

    CERN Multimedia

    ATLAS, Collaboration

    2012-01-01

    Event display of a H -> 4e candidate event with m(4l) = 124.5 (124.6) GeV without (with) Z mass constraint. The masses of the lepton pairs are 70.6 GeV and 44.7 GeV. The event was recorded by ATLAS on 18-May-2012, 20:28:11 CEST in run number 203602 as event number 82614360. Zoom into the tracking detector. The tracks and clusters of the two electron pairs are colored red and blue, respectively.

  1. Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset

    DEFF Research Database (Denmark)

    Cabrera, Susanne M; Wang, Xujing; Chen, Yi-Guang

    2016-01-01

    It was hypothesized that IL-1 antagonism would preserve β-cell function in new onset Type 1 diabetes (T1D). However, the Anti-Interleukin-1 in Diabetes Action (AIDA) and TrialNet Canakinumab (TN-14) trials failed to show efficacy of IL-1 receptor antagonist (IL-1Ra) or canakinumab, as measured...

  2. Small molecule antagonism of oxysterol-induced Epstein-Barr virus induced gene 2 (EBI2) activation

    DEFF Research Database (Denmark)

    Benned-Jensen, Tau; Madsen, Christian M; Arfelt, Kristine N

    2013-01-01

    The Epstein-Barr virus induced gene 2 (EBI2) was recently identified as the first oxysterol-activated 7TM receptor. EBI2 is essential for B cell trafficking within lymphoid tissues and thus the humoral immune response in general. Here we characterize the antagonism of the non-peptide molecule GSK...

  3. Reconceptualizing synergism and antagonism among multiple stressors

    OpenAIRE

    Piggott, Jeremy J; Townsend, Colin R; Matthaei, Christoph D

    2015-01-01

    The potential for complex synergistic or antagonistic interactions between multiple stressors presents one of the largest uncertainties when predicting ecological change but, despite common use of the terms in the scientific literature, a consensus on their operational definition is still lacking. The identification of synergism or antagonism is generally straightforward when stressors operate in the same direction, but if individual stressor effects oppose each other, the definition of syner...

  4. Triclosan antagonizes fluconazole activity against Candida albicans.

    LENUS (Irish Health Repository)

    Higgins, J

    2012-01-01

    Triclosan is a broad-spectrum antimicrobial compound commonly used in oral hygiene products. Investigation of its activity against Candida albicans showed that triclosan was fungicidal at concentrations of 16 mg\\/L. However, at subinhibitory concentrations (0.5-2 mg\\/L), triclosan antagonized the activity of fluconazole. Although triclosan induced CDR1 expression in C. albicans, antagonism was still observed in cdr1Δ and cdr2Δ strains. Triclosan did not affect fluconazole uptake or alter total membrane sterol content, but did induce the expression of FAS1 and FAS2, indicating that its mode of action may involve inhibition of fatty acid synthesis, as it does in prokaryotes. However, FAS2 mutants did not exhibit increased susceptibility to triclosan, and overexpression of both FAS1 and FAS2 alleles did not alter triclosan susceptibility. Unexpectedly, the antagonistic effect was specific for C. albicans under hypha-inducing conditions and was absent in the non-filamentous efg1Δ strain. This antagonism may be due to the membranotropic activity of triclosan and the unique composition of hyphal membranes.

  5. Memantine Can Reduce Ethanol-Induced Caspase-3 Activity and Apoptosis in H4 Cells by Decreasing Intracellular Calcium.

    Science.gov (United States)

    Wang, Xiaolong; Chen, Jiajun; Wang, Hongbo; Yu, Hao; Wang, Changliang; You, Jiabin; Wang, Pengfei; Feng, Chunmei; Xu, Guohui; Wu, Xu; Zhao, Rui; Zhang, Guohua

    2017-08-01

    Caspase-3 activation and apoptosis are associated with various neurodegenerative disorders. Calcium activation is an important factor in promoting apoptosis. We, therefore, assessed the role of intracellular calcium in ethanol-induced activation of caspase-3 in H4 human neuroglioma cells and the protective effect of the NMDA receptor antagonist, memantine, on ethanol-induced apoptosis in H4 cells. H4 cells were treated with 100 mM EtOH (in culture medium) for 2 days. For interaction studies, cells were treated with memantine (4 μM), EDTA (1 mM), or BAPTA-AM (10 μM) before treatment with EtOH. Knockdown of the gene encoding the NR1 subunit of the NMDA receptor was performed using RNAi. Apoptosis was detected by Annexin V-FITC/PI staining and flow cytometry. Cell viability was detected using an MTS cell proliferation kit. Fluorescence dual wavelength spectrophotometry was used to determine the intracellular calcium concentration. The levels of NR1, caspase-3, IP3R1, and SERCA1 proteins were detected by western blotting. NR1, IP3R1, and SERCA1 mRNA levels were detected by qPCR. We observed increased expression of NR1, IP3R1, SERCA1, and increased intracellular levels of calcium ions in H4 cells exposed to ethanol. In addition, the calcium chelators, EDTA and BAPTA, and RNAi disruption of the NMDA receptor reduced ethanol-induced caspase-3 activation in H4 cells. Memantine treatment reduced the ethanol-induced increase of intracellular calcium, caspase-3 activation, apoptosis, and the ethanol-induced decrease in cell viability. Our results indicate that ethanol-induced caspase-3 activation and apoptosis are likely to be dependent on cytosolic calcium levels and that they can be reduced by memantine treatment.

  6. Event display of a H -> 4e candidate event

    CERN Multimedia

    ATLAS, Collaboration

    2012-01-01

    Event display of a H -> 4e candidate event with m(4l) = 124.5 (124.6) GeV without (with) Z mass constraint. The masses of the lepton pairs are 70.6 GeV and 44.7 GeV. The event was recorded by ATLAS on 18-May-2012, 20:28:11 CEST in run number 203602 as event number 82614360. The tracks and clusters of the two electron pairs are colored red and blue, respectively. The three displays on the right-hand side show the r-phi view of the event (top), a zoom into the vertex region, indicating that the 4 electrons originate from the same primary vertex (middle), and a Lego plot indicating the amount of transverse energy Et measured in the calorimeters (bottom).

  7. Event display of a H -> 4e candidate event

    CERN Multimedia

    ATLAS, Collaboration

    2012-01-01

    Event display (side view) of a H -> 4e candidate event with m(4l) = 124.5 (124.6) GeV without (with) Z mass constraint. The masses of the lepton pairs are 70.6 GeV and 44.7 GeV. The event was recorded by ATLAS on 18-May-2012, 20:28:11 CEST in run number 203602 as event number 82614360. The tracks of the two electron pairs are colored red and blue, respectively. Electron clusters in the LAr calorimeter are colored darkgreen. The three displays on the right-hand side show the r-phi view of the event (top), a zoom into the vertex region, indicating that the 4 electrons originate from the same primary vertex (middle), and a Lego plot indicating the amount of transverse energy Et measured in the calorimeters (bottom).

  8. Antagonism of a (+)N-allylnormetazocine stimulus by (-)PPAP and several structurally related analogs.

    Science.gov (United States)

    Glennon, R A; Young, R; Herndon, J L

    1993-08-01

    Employing rats trained to discriminate 5 mg/kg of the benzomorphan opioid (+)N-allylnormetazocine [(+)NANM] from vehicle, tests of stimulus generalization and antagonism were conducted to determine the influence of several potential sigma-receptor ligands. It has been previously suggested that the (+)NANM stimulus may involve concurrent action at sigma- and phencyclidine (PCP) receptors. Although the low-affinity sigma-antagonist rimcazole was without stimulus-attenuating effect, three novel sigma-ligands--(-)PPAP, CNS 3018, and CNS 3093 (ID50 doses = 3.2, 6.7, and 4.5 mg/kg, respectively)--antagonized the (+)NANM stimulus in a dose-related fashion. The nonselective serotonergic agent 1-(3-trifluoromethyl)phenylpiperazine (TFMPP) produced partial generalization in (+)NANM-trained animals whereas buspirone, a 5-hydroxytryptamine1A (5-HT1A) agonist, attenuated (to 27% drug-appropriate responding) the (+)NANM stimulus. Because the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) failed to attenuate the (+)NANM stimulus at pharmacologically relevant doses, it seems unlikely that the (+)NANM stimulus involves a 5-HT1A mechanism. TFMPP and buspirone display modest affinity for sigma-receptors and this may account for the present findings with these agents. The present results neither establish a role for sigma involvement in the stimulus properties of (+)NANM nor eliminate a role for PCP receptors. They do, however, demonstrate that sigma-ligands with little to no affinity for PCP receptors are capable of antagonizing the (+)NANM stimulus.

  9. Progranulin shows cytoprotective effects on trophoblast cells in vitro but does not antagonize TNF-α-induced apoptosis.

    Science.gov (United States)

    Stubert, Johannes; Waldmann, Kathrin; Dieterich, Max; Richter, Dagmar-Ulrike; Briese, Volker

    2014-11-01

    The glycoprotein progranulin directly binds to TNF-receptors and thereby can antagonize the inflammatory effects of TNF-α. Here we analyzed the impact of both cytokines on cytotoxicity and viability of trophoblast cells. Isolated villous first trimester human trophoblast cells and the human choriocarcinoma cell line BeWo were treated with recombinant human progranulin and TNF-α. Analyses were performed by LDH- and MTT-assay and measurement of caspase-8-activity. Progranulin treatment showed some cytoprotective effects on isolated trophoblast cells. However, TNF-α-induced apoptosis was not antagonized by addition of progranulin. Effects were similar, but more pronounced in BeWo cells. The cytoprotective activity of progranulin on trophoblast cells in vitro was only weak and of doubtful biologic relevance. It was not able to antagonize TNF-α. Future studies should focus on possible paracrine activities of progranulin.

  10. Silica-induced initiation of circular ZC3H4 RNA/ZC3H4 pathway promotes the pulmonary macrophage activation.

    Science.gov (United States)

    Yang, Xiyue; Wang, Jing; Zhou, Zewei; Jiang, Rong; Huang, Jie; Chen, Lulu; Cao, Zhouli; Chu, Han; Han, Bing; Cheng, Yusi; Chao, Jie

    2018-01-22

    Phagocytosis of silicon dioxide (SiO 2 ) into lung cells causes an inflammatory cascade that results in fibroblast proliferation and migration, followed by fibrosis. Circular RNAs (circRNAs) are a subclass of noncoding RNAs that are present within mammalian cells; however, researchers have not determined whether circRNAs are involved in the pathophysiologic process of silicosis. To elucidate the role of these RNAs in SiO 2 -induced inflammation in pulmonary macrophages, we investigated the upstream molecular mechanisms and functional effects of circRNAs on cell apoptosis, proliferation, and migration. Primary cultures of alveolar macrophages from healthy donors and from patients and the RAW264.7 macrophage cell line were used to explore the functions of circZC3H4 RNA in macrophage activation. The experimental results indicated the following: 1) SiO 2 concomitantly increased circZC3H4 RNA expression and increased ZC3H4 protein levels; 2) circular ZC3H4 (circZC3H4) RNA and ZC3H4 protein participated in SiO 2 -induced macrophage activation; and 3) SiO 2 -activated macrophages promoted fibroblast proliferation and migration via the circZC3H4 RNA/ZC3H4 pathway. The up-regulation of the ZC3H4 protein was confirmed in tissue samples from patients with silicosis. Our study elucidates a link between SiO 2 -induced macrophage activation and the circZC3H4 RNA/ZC3H4 pathway, thereby providing novel insight into the potential use of ZC3H4 to develop novel therapeutic strategies for silicosis.-Yang, X., Wang, J., Zhou, Z., Jiang, R., Huang, J., Chen, L., Cao, Z., Chu, H., Han, B., Cheng, Y., Chao, J. Silica-induced initiation of circular ZC3H4 RNA/ZC3H4 pathway promotes the pulmonary macrophage activation.

  11. Natural Protection of Wood with Antagonism Fungi

    Directory of Open Access Journals (Sweden)

    Alba ZAREMSKI

    2011-03-01

    Full Text Available Biological environments contain a certain number of microbial populations which, within a givenecological niche, display various relations ranging from symbiosis to parasitism. Researchers have beeninterested in these types of relations for around fifty years, especially in one very particular type ofrelationship: the antagonism exerted between individuals of the same microbial population.Today, the role played by biological agents, bringing into play inhibitive or destructive antibioticsubstances, reveals a certain potential for their use in controlling microorganisms associated with suchdegradation processes.The work undertaken by HydroQuébec and CIRAD involved two types of experiment: 1 in Petri dishes toassess and characterize the antagonistic capacity of Trichoderma against white rot and brown rot fungi; 2on pieces taken from untreated poles in order to study confrontation between the basidiomycete and theantagonistic strain in wood.This study investigated the antagonism of three ascomycetes of the genus Trichoderma against two whiterot basidiomycetes, Pycnoporus sanguineus and Coriolus versicolor, and two brown rot basidiomycetes,Antrodia sp. and Coniophora puteana, through direct confrontation in Petri dishes and in the wood ofHydroQuébec poles.The results obtained seemed to complete each other coherently. They revealed that the Trichodermagroup of fungi was not aggressive to wood and the results obtained after direct confrontation in Petri disheswere confirmed in wood.By directly exposing the different basidiomycetes and antagonists to each other in Petri dishes, two bytwo, we effectively revealed an antagonism effect for a large majority of the pairs. However, there wassubstantial variability in reactions from one pair to the next.

  12. Reconceptualizing synergism and antagonism among multiple stressors.

    Science.gov (United States)

    Piggott, Jeremy J; Townsend, Colin R; Matthaei, Christoph D

    2015-04-01

    The potential for complex synergistic or antagonistic interactions between multiple stressors presents one of the largest uncertainties when predicting ecological change but, despite common use of the terms in the scientific literature, a consensus on their operational definition is still lacking. The identification of synergism or antagonism is generally straightforward when stressors operate in the same direction, but if individual stressor effects oppose each other, the definition of synergism is paradoxical because what is synergistic to one stressor's effect direction is antagonistic to the others. In their highly cited meta-analysis, Crain et al. (Ecology Letters, 11, 2008: 1304) assumed in situations with opposing individual effects that synergy only occurs when the cumulative effect is more negative than the additive sum of the opposing individual effects. We argue against this and propose a new systematic classification based on an additive effects model that combines the magnitude and response direction of the cumulative effect and the interaction effect. A new class of "mitigating synergism" is identified, where cumulative effects are reversed and enhanced. We applied our directional classification to the dataset compiled by Crain et al. (Ecology Letters, 11, 2008: 1304) to determine the prevalence of synergistic, antagonistic, and additive interactions. Compared to their original analysis, we report differences in the representation of interaction classes by interaction type and we document examples of mitigating synergism, highlighting the importance of incorporating individual stressor effect directions in the determination of synergisms and antagonisms. This is particularly pertinent given a general bias in ecology toward investigating and reporting adverse multiple stressor effects (double negative). We emphasize the need for reconsideration by the ecological community of the interpretation of synergism and antagonism in situations where

  13. THREE-DIMENSIONAL MAPPING OF DIFFERENTIAL AMINO ACIDS OF HUMAN, MURINE, CANINE AND EQUINE TLR4/MD-2 RECEPTOR COMPLEXES CONFERRING ENDOTOXIC ACTIVATION BY LIPID A, ANTAGONISM BY ERITORAN AND SPECIES-DEPENDENT ACTIVITIES OF LIPID IVA IN THE MAMMALIAN LPS SENSOR SYSTEM

    Directory of Open Access Journals (Sweden)

    Thomas Scior

    2013-05-01

    Full Text Available A literature review concerning the unexpected species differences of the vertebrate innate immune response to lipid IVA was published in CSBJ prior to the present computational study to address the unpaired activity-sequence correlation of prototypic E. coli -type lipid A and its precursor lipid IVA regarding human, murine, equine and canine species. To this end, their sequences and structures of hitherto known Toll-like receptor 4 (TLR4 and myeloid differentiation factor 2 (MD-2 complexes were aligned and their differential side chain patterns studied. If required due to the lack of the corresponding X-ray crystallographic data, three-dimensional models of TLR4/MD-2/ligand complexes were generated using mono and dimeric crystal structures as templates and in silico docking of the prototypic ligands lipid A, lipid IVA and Eritoran. All differential amino acids were mapped to pinpoint species dependency on an atomic scale, i.e. the possible concert of mechanistically relevant side chains. In its most abstract and general form the three-dimensional (3D- models devise a triangular interface or “wedge” where molecular interactions between TLR4, MD-2 and ligand itself take place. This study identifies two areas in the wedge related to either agonism or antagonism reflecting why ligands like lipid IVA can possess a species dependent dual activity. Lipid IVA represents an imperfect (underacylated and backbone-flipped, low affinity ligand of mammalian TLR4/MD-2 complexes. Its specific but weak antagonistic activity in the human system is in particular due to the loss of phosphate attraction in the wedge-shaped region conferred by nonhomologous residue changes when compared to crystal and modeled structures of the corresponding murine and equine TLR4/MD-2 complexes. The counter-TLR4/MD-2 unit was also taken into account since agonist-mediated dimerization in a defined m-shaped complex composed of two TLR4/MD-2/agonist subunits triggers intracellular

  14. Evaluation of the antagonism of nicotine by mecamylamine and pempidine in the brain

    International Nuclear Information System (INIS)

    Martin, T.J.

    1989-01-01

    Antagonists have been crucial in the characterization of nicotine's pharmacology. Initial evidence for the existence of central nicotinic receptors was based on the fact that nicotine produced a number of behavioral effects that were antagonized by ganglionic blockers that crossed the blood-brain barrier, such as mecamylamine and pempidine. These compounds are thought to be noncompetitive antagonists due to the fact that they do not compete for agonist binding to brain homogenate in vitro. However, pharmacological evidence in support of noncompetitive antagonism is lacking. Dose-response curves for nicotine were determined in the presence of various doses of pempidine for depression of spontaneous activity and antinociception in mice. Pempidine was found to shift the dose response curves for these effects of nicotine in a manner consistent with noncompetitive antagonism. A number of mecamylamine analogs were investigated for antagonism of these central effects of nicotine as well. These studies revealed that the N-, 2-, and 3-methyls were crucial for optimal efficacy and potency and suggests that these compounds possess a specific mechanism of action, possibly involving a receptor. Furthermore, the structure-activity relationships for the mecamylamine analogs were found to be different than that previously reported for the agonists, suggesting that they do not act at the same site. The binding of [ 3 H]-L-nicotine and [ 3 H]-pempidine was studied in vitro to mouse brain homogentate and in situ to rat brain slices. The in situ binding of [ 3 H]-L-nicotine to rat brain slices was quantitated autoradiographically to discrete brain areas in the presence and absence of 1, 10 and 100 μM nicotine and pempidine. Pempidine did not effectively displace [ 3 H]-L-nicotine binding

  15. Forced Normalization: Antagonism Between Epilepsy and Psychosis.

    Science.gov (United States)

    Kawakami, Yasuhiko; Itoh, Yasuhiko

    2017-05-01

    The antagonism between epilepsy and psychosis has been discussed for a long time. Landolt coined the term "forced normalization" in the 1950s to describe psychotic episodes associated with the remission of seizures and disappearance of epileptiform activity on electroencephalograms in individuals with epilepsy. Since then, neurologists and psychiatrists have been intrigued by this phenomenon. However, although collaborative clinical studies and basic experimental researches have been performed, the mechanism of forced normalization remains unknown. In this review article, we present a historical overview of the concept of forced normalization, and discuss potential pathogenic mechanisms and clinical diagnosis. We also discuss the role of dopamine, which appears to be a key factor in the mechanism of forced normalization. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Characterization of novel non-clonal intrachromosomal rearrangements between the H4 and PTEN genes (H4/PTEN) in human thyroid cell lines and papillary thyroid cancer specimens

    International Nuclear Information System (INIS)

    Puxeddu, Efisio; Zhao Guisheng; Stringer, James R.; Medvedovic, Mario; Moretti, Sonia; Fagin, James A.

    2005-01-01

    The two main forms of RET rearrangement in papillary thyroid carcinomas (PTC) arise from intrachromosomal inversions fusing the tyrosine kinase domain of RET with either the H4 (RET/PTC1) or the ELE1/RFG genes (RET/PTC3). PTEN codes for a dual-specificity phosphatase and maps to chromosome 10q22-23. Germline mutations confer susceptibility to Cowden syndrome whereas somatic mutations or deletions are common in several sporadic human tumors. Decreased PTEN expression has been implicated in thyroid cancer development. We report the characterization of a new chromosome 10 rearrangement involving H4 and PTEN. The initial H4/PTEN rearrangement was discovered as a non-specific product of RT-PCR for RET/PTC1 in irradiated thyroid cell lines. Sequencing revealed a transcript consisting of exon 1 and 2 of H4 fused with exons 3-6 of PTEN. Nested RT-PCR with specific primers bracketing the breakpoints confirmed the H4/PTEN rearrangements in irradiated KAT-1 and KAT-50 cells. Additional H4/PTEN variants, generated by recombination of either exon 1 or exon 2 of H4 with exon 6 of PTEN, were found in non-irradiated KAK-1, KAT-50, ARO and NPA cells. Their origin through chromosomal recombination was confirmed by detection of the reciprocal PTEN/H4 product. H4/PTEN recombination was not a clonal event in any of the cell lines, as Southern blots with appropriate probes failed to demonstrate aberrant bands, and multicolor FISH of KAK1 cells with BAC probes for H4 and PTEN did not show a signal overlap in all cells. Based on PCR of serially diluted samples, the minimal frequency of spontaneous recombination between these loci was estimated to be approximately 1/10 6 cells. H4/PTEN products were found by nested RT-PCR in 4/14 normal thyroid tissues (28%) and 14/18 PTC (78%) (P < 0.01). H4/PTEN is another example of recombination involving the H4 locus, and points to the high susceptibility of thyroid cells to intrachromosomal gene rearrangements. As this also represents a plausible

  17. Characterization of novel non-clonal intrachromosomal rearrangements between the H4 and PTEN genes (H4/PTEN) in human thyroid cell lines and papillary thyroid cancer specimens

    Energy Technology Data Exchange (ETDEWEB)

    Puxeddu, Efisio [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Zhao Guisheng [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Stringer, James R. [Department of Molecular Genetics, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Medvedovic, Mario [Center for Biostatistic Service, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Moretti, Sonia [Dipartimento di Medicina Interna, Universita degli Studi di Perugia, Via E. dal Pozzo, Perugia 06126, (Italy); Fagin, James A. [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States)]. E-mail: james.fagin@uc.edu

    2005-02-15

    The two main forms of RET rearrangement in papillary thyroid carcinomas (PTC) arise from intrachromosomal inversions fusing the tyrosine kinase domain of RET with either the H4 (RET/PTC1) or the ELE1/RFG genes (RET/PTC3). PTEN codes for a dual-specificity phosphatase and maps to chromosome 10q22-23. Germline mutations confer susceptibility to Cowden syndrome whereas somatic mutations or deletions are common in several sporadic human tumors. Decreased PTEN expression has been implicated in thyroid cancer development. We report the characterization of a new chromosome 10 rearrangement involving H4 and PTEN. The initial H4/PTEN rearrangement was discovered as a non-specific product of RT-PCR for RET/PTC1 in irradiated thyroid cell lines. Sequencing revealed a transcript consisting of exon 1 and 2 of H4 fused with exons 3-6 of PTEN. Nested RT-PCR with specific primers bracketing the breakpoints confirmed the H4/PTEN rearrangements in irradiated KAT-1 and KAT-50 cells. Additional H4/PTEN variants, generated by recombination of either exon 1 or exon 2 of H4 with exon 6 of PTEN, were found in non-irradiated KAK-1, KAT-50, ARO and NPA cells. Their origin through chromosomal recombination was confirmed by detection of the reciprocal PTEN/H4 product. H4/PTEN recombination was not a clonal event in any of the cell lines, as Southern blots with appropriate probes failed to demonstrate aberrant bands, and multicolor FISH of KAK1 cells with BAC probes for H4 and PTEN did not show a signal overlap in all cells. Based on PCR of serially diluted samples, the minimal frequency of spontaneous recombination between these loci was estimated to be approximately 1/10{sup 6} cells. H4/PTEN products were found by nested RT-PCR in 4/14 normal thyroid tissues (28%) and 14/18 PTC (78%) (P < 0.01). H4/PTEN is another example of recombination involving the H4 locus, and points to the high susceptibility of thyroid cells to intrachromosomal gene rearrangements. As this also represents a

  18. Electric field effect on the emission rate of H4F and H4S hole traps in InP

    International Nuclear Information System (INIS)

    Darwich, R.; Alek, B.

    2010-01-01

    The electric field effect on the emission rate enhancement of the H4 F and H4 S hole trap in highly Zn-doped InP has been examined using the deep level transient spectroscopy (DLTS) and double correlation DLTS (DDLTS). The DLTS and DDLTS results have been found to be in good agreement for low and intermediate electric fields, but they disagree for large field effect. Comparing our emission data with the theory, we have found that H4 F obeys the quantum model of phonon-assisted tunneling while H4 S follows the Poole-Frenkel model employing a three-dimensional screening coulombic potential. Our results show that the H4 S defect can be attributed to a charged (V p - Zn) complex. (author)

  19. Alterations of global histone H4K20 methylation during prostate carcinogenesis

    Directory of Open Access Journals (Sweden)

    Behbahani Turang E

    2012-03-01

    Full Text Available Abstract Background Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3 at different stages of prostate cancer (PCA carcinogenesis. Methods Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113, non-malignant prostate disease (n = 27, metastatic hormone-naive PCA (mPCA, n = 30 and castration-resistant PCA (CRPC, n = 34. Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. Results Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. Conclusions H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.

  20. 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”.

  1. Characterization of the UV-crosslinked heterodimer of histones H2B and H4

    International Nuclear Information System (INIS)

    Johnson, E.R.; Brown, D.M.; DeLange, R.J.

    1986-01-01

    At relatively high salt concentrations (1.2 M), histone 2B (H2B) and histone 4 (H4) can be covalently crosslinked by irradiation with ultraviolet light to yield a mixture of the three possible dimers: H2B-H2B, H4-H4, and H2B-H4. The formation of the H2B-H4 heterodimer was found to be favored at lower histone concentrations (> 90% H2B-H4 at 0.1 mg/ml total histone protein). CNBr cleavage of the H2B-H4 dimer produced three fragments which were separated by reverse phase HPLC. These fragments were identified by amino acid compositional analysis to be H4(85-102), H2B(62-125), and the crosslinked N-terminal regions H2B(1-59)-H4(1-84). Amino acid sequence analysis of the crosslinked fragment indicated that tyrosine-40 of H2B is likely involved in the covalent crosslinkage which joins the histone monomers to form the heterodimer

  2. Nanoconfined NaAlH4 Conversion Electrodes for Li Batteries

    DEFF Research Database (Denmark)

    Huen, Priscilla; Peru, Filippo; Charalambopoulou, Georgia

    2017-01-01

    -Type anode in Li-ion batteries. Here, NaAlH4 nanoconfined in carbon scaffolds as an anode material for Li-ion batteries is reported for the first time. Nanoconfined NaAlH4 was prepared by melt infiltration into mesoporous carbon scaffolds. In the first cycle, the electrochemical reversibility of nanoconfined...

  3. 26 CFR 31.3402(h)(4)-1 - Other methods.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Other methods. 31.3402(h)(4)-1 Section 31.3402... Collection of Income Tax at Source § 31.3402(h)(4)-1 Other methods. (a) Maximum permissible deviations. An employer may use any other method of withholding under which the employer will deduct and withhold upon...

  4. Glucocorticoid receptor modulators.

    Science.gov (United States)

    Meijer, Onno C; Koorneef, Lisa L; Kroon, Jan

    2018-06-01

    The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects. Selective glucocorticoid receptor modulators are ligands that induce a receptor conformation that allows activation of only a subset of downstream signaling pathways. Such molecules thereby combine agonistic and antagonistic properties. Here we discuss the mechanisms underlying selective receptor modulation and their promise in treating diseases in several organ systems where cortisol signaling plays a role. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  5. Adsorption of Ti on LiAlH4 surfaces studied by band structure calculations

    International Nuclear Information System (INIS)

    Loevvik, O.M.

    2004-01-01

    LiAlH 4 is a potential light-weight hydrogen storage material if hydrogenation can be made reversible. In NaAlH 4 this may be done by adding small amounts of Ti, but the same effect has not yet been observed in LiAlH 4 . To understand these mechanisms, detailed studies of the materials with and without the additive are necessary. In this study, two-dimensional slabs representing the open (0 1 0) and densely packed (1 0 1) surfaces of LiAlH 4 have been used to model adsorption of titanium atoms on those surfaces. The results show that the Ti atom tends to move below the surface towards interstitial sites rather than binding to a Li ion or AlH 4 complex at the surface

  6. [Clinical significance of determination of serum B7-H4 in patients with malignant hematologic diseases].

    Science.gov (United States)

    Wang, Xiao-Mei; Hu, Guo-Yan; Liu, Wei; Zheng, Shu-Hua; Lv, Jing; Wang, Hong-Mei; Xu, Jun-Fa

    2010-09-01

    To study the clinical significance of determination of serum B7-H4 in patients with malignant hematologic diseases. Serum B7-H4 levels were determined in 65 patients with leucemia, 34 patients with lymphoma, 12 patients with multiple myeloma as well as in 50 healthy controls. The serum B7-H4 levels in patients with lymphoma [(38.81+/-10.34) kappag/L] were significantly higher than healthy controls [(31.62+/-9.850) kappag/L] (Pleucemia, patients with multiple myeloma and healthy controls. These results suggest that the B7-H4 may correlated with lymphoma, but uncorrelated with leucemia and multiple myeloma. Measurement of serum B7-H4 level provide useful information for distinctive diagnosis of different kinds of malignant hematologic diseases.

  7. Characterization of joining sites of a viral histone H4 on host insect chromosomes.

    Directory of Open Access Journals (Sweden)

    Sunil Kumar

    Full Text Available A viral histone H4 (CpBV-H4 is encoded in a polydnavirus, Cotesia plutellae bracovirus (CpBV. It plays a crucial role in parasitism of an endoparasitoid wasp, C. plutellae, against diamondback moth, Plutella xylostella, by altering host gene expression in an epigenetic mode by its N-terminal tail after joining host nucleosomes. Comparative transcriptomic analysis between parasitized and nonparasitized P. xylostella by RNA-Seq indicated that 1,858 genes were altered at more than two folds in expression levels at late parasitic stage, including 877 up-regulated genes and 981 down-regulated genes. Among parasitic factors altering host gene expression, CpBV-H4 alone explained 16.3% of these expressional changes. To characterize the joining sites of CpBV-H4 on host chromosomes, ChIP-Seq (chromatin immunoprecipitation followed by deep sequencing was applied to chromatins extracted from parasitized larvae. It identified specific 538 ChIP targets. Joining sites were rich (60.2% in AT sequence. Almost 40% of ChIP targets included short nucleotide repeat sequences presumably recognizable by transcriptional factors and chromatin remodeling factors. To further validate these CpBV-H4 targets, CpBV-H4 was transiently expressed in nonparasitized host at late larval stage and subjected to ChIP-Seq. Two kinds of ChIP-Seqs shared 51 core joining sites. Common targets were close (within 1 kb to genes regulated at expression levels by CpBV-H4. However, other host genes not close to CpBV-H4 joining sites were also regulated by CpBV-H4. These results indicate that CpBV-H4 joins specific chromatin regions of P. xylostella and controls about one sixth of the total host genes that were regulated by C. plutellae parasitism in an epigenetic mode.

  8. Molecular recognition of H3/H4 histone tails by the tudor domains of JMJD2A: a comparative molecular dynamics simulations study.

    Directory of Open Access Journals (Sweden)

    Musa Ozboyaci

    Full Text Available BACKGROUND: Histone demethylase, JMJD2A, specifically recognizes and binds to methylated lysine residues at histone H3 and H4 tails (especially trimethylated H3K4 (H3K4me3, trimethylated H3K9 (H3K9me3 and di,trimethylated H4K20 (H4K20me2, H4K20me3 via its tandem tudor domains. Crystal structures of JMJD2A-tudor binding to H3K4me3 and H4K20me3 peptides are available whereas the others are not. Complete picture of the recognition of the four histone peptides by the tandem tudor domains yet remains to be clarified. METHODOLOGY/PRINCIPAL FINDINGS: We report a detailed molecular dynamics simulation and binding energy analysis of the recognition of JMJD2A-tudor with four different histone tails. 25 ns fully unrestrained molecular dynamics simulations are carried out for each of the bound and free structures. We investigate the important hydrogen bonds and electrostatic interactions between the tudor domains and the peptide molecules and identify the critical residues that stabilize the complexes. Our binding free energy calculations show that H4K20me2 and H3K9me3 peptides have the highest and lowest affinity to JMJD2A-tudor, respectively. We also show that H4K20me2 peptide adopts the same binding mode with H4K20me3 peptide, and H3K9me3 peptide adopts the same binding mode with H3K4me3 peptide. Decomposition of the enthalpic and the entropic contributions to the binding free energies indicate that the recognition of the histone peptides is mainly driven by favourable van der Waals interactions. Residue decomposition of the binding free energies with backbone and side chain contributions as well as their energetic constituents identify the hotspots in the binding interface of the structures. CONCLUSION: Energetic investigations of the four complexes suggest that many of the residues involved in the interactions are common. However, we found two receptor residues that were related to selective binding of the H3 and H4 ligands. Modifications or mutations

  9. Effect of endothelin antagonism on apnea frequency following chronic intermittent hypoxia.

    Science.gov (United States)

    Donovan, Lucas M; Liu, Yuzhen; Weiss, J Woodrow

    2014-04-01

    Chronic hypoxia increases the hypoxic ventilatory response (HVR). Augmented HVR contributes to central apneas seen in heart failure and complex sleep apnea. Endothelin receptor (ETR) antagonism decreases carotid body afferent activity following chronic intermittent hypoxia (CIH). We speculated ETR antagonism would reduce HVR and apneas following CIH. HVR and apneas were measured after exposure to CIH and room air sham (SHAM). ETR blocker Ambrisentan was administered via the chow of CIH-exposed animals from days 1 to 12 of CIH (CIH/AMB). A separate crossover group was exposed to CIH and fed normal chow (placebo) days 1-6, and Ambrisentan days 7-12 (CIH/PLA-AMB). SHAM and CIH/PLA animals were fed placebo days 1-12. The CIH/AMB and CIH/PLA-AMB rats had reduced HVR compared to CIH/PLA, similar HVR compared to sham exposed animals, and reduced apnea frequency compared to CIH/PLA animals. The reduced HVR and post-hypoxic apneas resulting from Ambrisentan administration suggests ETR antagonists may have utility in reducing central apneas following CIH. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Fumonisin FB1 treatment acts synergistically with methyl donor deficiency during rat pregnancy to produce alterations of H3- and H4-histone methylation patterns in fetuses.

    Science.gov (United States)

    Pellanda, Hélène; Forges, Thierry; Bressenot, Aude; Chango, Abalo; Bronowicki, Jean-Pierre; Guéant, Jean-Louis; Namour, Fares

    2012-06-01

    Prenatal folate and methyl donor malnutrition lead to epigenetic alterations that could enhance susceptibility to disease. Methyl-deficient diet (MDD) and fumonisin FB1 are risk factors for neural tube defects and cancers. Evidence indicates that FB1 impairs folate metabolism. Folate receptors and four heterochromatin markers were investigated in rat fetuses liver derived from dams exposed to MDD and/or FB1 administered at a dose twice higher than the provisional maximum tolerable daily intake (PMTDI = 2 μg/kg/day). Even though folate receptors transcription seemed up-regulated by methyl depletion regardless of FB1 treatment, combined MDD/FB1 exposure might reverse this up-regulation since folate receptors transcripts were lower in the MDD/FB1 versus MDD group. Methyl depletion decreased H4K20me3. Combined MDD/FB1 decreased H4K20me3 even more and increased H3K9me3. The elevated H3K9me3 can be viewed as a defense mechanism inciting the cell to resist heterochromatin disorganization. H3R2me2 and H4K16Ac varied according to this mechanism even though statistical significance was not consistent. Considering that humans are exposed to FB1 levels above the PMTDI, this study is relevant because it suggests that low doses of FB1 interact with MDD thus contributing to disrupt the epigenetic landscape. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation*

    Science.gov (United States)

    Dudakovic, Amel; Evans, Jared M.; Li, Ying; Middha, Sumit; McGee-Lawrence, Meghan E.; van Wijnen, Andre J.; Westendorf, Jennifer J.

    2013-01-01

    Bone has remarkable regenerative capacity, but this ability diminishes during aging. Histone deacetylase inhibitors (HDIs) promote terminal osteoblast differentiation and extracellular matrix production in culture. The epigenetic events altered by HDIs in osteoblasts may hold clues for the development of new anabolic treatments for osteoporosis and other conditions of low bone mass. To assess how HDIs affect the epigenome of committed osteoblasts, MC3T3 cells were treated with suberoylanilide hydroxamic acid (SAHA) and subjected to microarray gene expression profiling and high-throughput ChIP-Seq analysis. As expected, SAHA induced differentiation and matrix calcification of osteoblasts in vitro. ChIP-Seq analysis revealed that SAHA increased histone H4 acetylation genome-wide and in differentially regulated genes, except for the 500 bp upstream of transcriptional start sites. Pathway analysis indicated that SAHA increased the expression of insulin signaling modulators, including Slc9a3r1. SAHA decreased phosphorylation of insulin receptor β, Akt, and the Akt substrate FoxO1, resulting in FoxO1 stabilization. Thus, SAHA induces genome-wide H4 acetylation and modulates the insulin/Akt/FoxO1 signaling axis, whereas it promotes terminal osteoblast differentiation in vitro. PMID:23940046

  12. Mechanism of plutonium metal dissolution in HNO3-HF-N2H4 solution

    International Nuclear Information System (INIS)

    Karraker, D.G.

    1985-01-01

    An oxidation-reduction balance of the products of the dissolution of plutonium metal and alloys in HNO 3 -HF-N 2 H 4 solution shows that the major reactions during dissolution are the reduction of nitrate to NH 3 , N 2 and N 2 O by the metal, and the oxidation of H free radicals to NH 3 by N 2 H 4 . Reactions between HNO 3 and N 2 H 4 produce varying amounts of HN 3 . The reaction rate is greater for delta-Pu than alpha-Pu, and is increased by higher concentrations of HF and HNO 3 . The low yield of reduced nitrogen species indicates that nitrate is reduced on the metal surface without producing a significant concentration of species that react with N 2 H 4 . It is conjectured that intermediate Pu valences and electron transfer within the metal are involved. 7 refs., 3 tabs

  13. Destabilized LiBH4-NaAlH4 Mixtures Doped with Titanium Based Catalysts

    DEFF Research Database (Denmark)

    Shi, Qing; Yu, Xuebin; Feidenhans'l, Robert

    2008-01-01

    We investigate the hydrogen storage properties of the mixed complex hydride LiBH4-NaAlH4 system, both undoped and doped with a TiCl3 additive. The mixed system is found to initiate a transformation to LiBH4-NaAlH4 after ball-milling, and the doped system is found to have a significant lower hydro...

  14. Synthesis and characterization of Ru(II) complexes with polyfunctional quinazoline-(3H)-4-ones

    International Nuclear Information System (INIS)

    Prabhakar, B.; Lingaiah, P.; Laxma Reddy, K.

    1991-01-01

    Few Ru(II) complexes of the type Ru(O-N-O) 2 with tridentate O-N-O donors and of the type RuCl 2 (O-N) 2 with bidentate O-O and O-N donors have been synthesized and characterized on the basis of analytical, conductivity, thermal, magnetic, IR, electronic and PMR spectral data. The IR and PMR spectral data of the metal complexes indicate that the lignads like 2-methyl/phenyl-3-(2'-hydroxybenzalamino) quinazoline-(3H)-4-one(MHBQ/PHBQ) act as uninegative tridentate, 2-methyl/phenyl-3-(carboxymethyl) quinazoline(3H)-4-one (MCMQ/PCMQ) as uninegative bidentate and 2-methyl/phenyl-3-(furfuralamino) quinazoline-(3H)-4-one (MFQ/PFQ), 2-methyl/phenyl-3-(acetamino) quinazoline-(3H)-4-one (MAQ/PAQ), 2-methyl/phenyl3-(uramino)quinazoline-(3H)-4-one (MUQ/PUQ) and 2-methyl/phenyl-3-thiouramino)quinazoline-(3H)-4-one-(MTUQ/PTUQ) as neutral bidentate ligands. The electronic spectral data of the complexes indicate that the arrangement around Ru(II) is octahedral. (author). 25 refs., 2 tabs

  15. Rhubarb Antagonizes Matrix Metalloproteinase-9-induced Vascular Endothelial Permeability

    Directory of Open Access Journals (Sweden)

    Yun-Liang Cui

    2016-01-01

    Conclusions: The rhubarb mixture of emodin, 3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid, 1-O-caffeoyl-2-(4-hydroxyl-O-cinnamoyl-β-D-glucose, daucosterol linoleate, and rhein, at a low concentration, antagonized the MMP9-induced HUVEC monolayer permeability by promoting HUVEC proliferation and reducing extracellular VE-cadherin concentrations.

  16. Analysis of Determinants in Filovirus Glycoproteins Required for Tetherin Antagonism

    Directory of Open Access Journals (Sweden)

    Kerstin Gnirß

    2014-04-01

    Full Text Available The host cell protein tetherin can restrict the release of enveloped viruses from infected cells. The HIV-1 protein Vpu counteracts tetherin by removing it from the site of viral budding, the plasma membrane, and this process depends on specific interactions between the transmembrane domains of Vpu and tetherin. In contrast, the glycoproteins (GPs of two filoviruses, Ebola and Marburg virus, antagonize tetherin without reducing surface expression, and the domains in GP required for tetherin counteraction are unknown. Here, we show that filovirus GPs depend on the presence of their authentic transmembrane domains for virus-cell fusion and tetherin antagonism. However, conserved residues within the transmembrane domain were dispensable for membrane fusion and tetherin counteraction. Moreover, the insertion of the transmembrane domain into a heterologous viral GP, Lassa virus GPC, was not sufficient to confer tetherin antagonism to the recipient. Finally, mutation of conserved residues within the fusion peptide of Ebola virus GP inhibited virus-cell fusion but did not ablate tetherin counteraction, indicating that the fusion peptide and the ability of GP to drive host cell entry are not required for tetherin counteraction. These results suggest that the transmembrane domains of filoviral GPs contribute to tetherin antagonism but are not the sole determinants.

  17. Antagonism in the carbon footprint between beef and dairy ...

    African Journals Online (AJOL)

    The higher increase in production (milk) of intensive dairy cows, compared to the increase in production (calf weight) of intensive beef cows, explains the antagonism in the carbon footprint between different beef and dairy production systems. Unfortunately, carbon sequestration estimates have been neglected and thus the ...

  18. GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations

    DEFF Research Database (Denmark)

    Deacon, Carolyn F; Plamboeck, Astrid; Rosenkilde, Mette M

    2006-01-01

    Glucose-dependent insulinotropic polypeptide [GIP-(1-42)] is degraded by dipeptidyl peptidase IV (DPP IV), forming GIP-(3-42). In mice, high concentrations of synthetic GIP-(3-42) may function as a GIP receptor antagonist, but it is unclear whether this occurs at physiological concentrations...... GIP, GIP-(3-42) behaved as a weak antagonist (IC(50), 92 and 731 nM for inhibition of cAMP accumulation elicited by 10 pM and 1 nM native GIP, respectively). In the isolated perfused rat pancreas, GIP-(3-42) alone had no effect on insulin output and only reduced the response to GIP (1 nM) when......-42) can weakly antagonize cAMP accumulation and insulin output in vitro, it does not behave as a physiological antagonist in vivo....

  19. Exploitative and hierarchical antagonism in a cooperative bacterium.

    Directory of Open Access Journals (Sweden)

    Francesca Fiegna

    2005-11-01

    Full Text Available Social organisms that cooperate with some members of their own species, such as close relatives, may fail to cooperate with other genotypes of the same species. Such noncooperation may take the form of outright antagonism or social exploitation. Myxococcus xanthus is a highly social prokaryote that cooperatively develops into spore-bearing, multicellular fruiting bodies in response to starvation. Here we have characterized the nature of social interactions among nine developmentally proficient strains of M. xanthus isolated from spatially distant locations. Strains were competed against one another in all possible pairwise combinations during starvation-induced development. In most pairings, at least one competitor exhibited strong antagonism toward its partner and a majority of mixes showed bidirectional antagonism that decreased total spore production, even to the point of driving whole populations to extinction. Differential response to mixing was the primary determinant of competitive superiority rather than the sporulation efficiencies of unmixed populations. In some competitive pairings, the dominant partner sporulated more efficiently in mixed populations than in clonal isolation. This finding represents a novel form of exploitation in bacteria carried out by socially competent genotypes and is the first documentation of social exploitation among natural bacterial isolates. Patterns of antagonistic superiority among these strains form a highly linear dominance hierarchy. At least some competition pairs construct chimeric, rather than segregated, fruiting bodies. The cooperative prokaryote M. xanthus has diverged into a large number of distinct social types that cooperate with clone-mates but exhibit intense antagonism toward distinct social types of the same species. Most lengthy migration events in nature may thus result in strong antagonism between migratory and resident populations, and this antagonism may have large effects on local

  20. Antagonism by supidimide of haloperidol-induced augmentation of [3H]-spiperone binding in rat striatum

    International Nuclear Information System (INIS)

    Hennies, H.H.; Hess, V.; Flohe, L.

    1984-01-01

    Rats were treated for two weeks with haloperidol alone or with additional test drugs and the D 2 receptor density in the striatum was investigated after a drug-free period of five days. The D 2 receptor system as analysed by [ 3 H]-spinerone binding was best characterized by a model with two binding sites of different affinity. Chronic haloperidol treatment substantially augmented the total binding capacity 2-(2-Oxo-3-piperidyl)-1,2-benzisothiazoline-3-one-1,1-dioxide (supidimide), a functional synergist of neuroleptics in acute experiments, surprisingly antagonized the haloperidol-induced receptor augmentation, whereas other CNS depressants (diazepam and phenobarbital) were ineffective. (orig./MG) [de

  1. Antagonism by supidimide of haloperidol-induced augmentation of (/sup 3/H)-spiperone binding in rat striatum

    Energy Technology Data Exchange (ETDEWEB)

    Hennies, H H; Hess, V; Flohe, L

    1984-01-01

    Rats were treated for two weeks with haloperidol alone or with additional test drugs and the D/sub 2/ receptor density in the striatum was investigated after a drug-free period of five days. The D/sub 2/ receptor system as analysed by (/sup 3/H)-spinerone binding was best characterized by a model with two binding sites of different affinity. Chronic haloperidol treatment substantially augmented the total binding capacity 2-(2-Oxo-3-piperidyl)-1,2-benzisothiazoline-3-one-1,1-dioxide (supidimide), a functional synergist of neuroleptics in acute experiments, surprisingly antagonized the haloperidol-induced receptor augmentation, whereas other CNS depressants (diazepam and phenobarbital) were ineffective.

  2. Hydrogen Storage Characteristics of CNT doped NaAlH4

    International Nuclear Information System (INIS)

    Pukazhselvan, D.; Sterlin Leo Hudson, M.; Bipin Kumar Gupta; Srivastava, O.N.

    2006-01-01

    The current Hydrogen based energy infrastructure required a high energy density consumer friendly hydrogen storage media. Although the desired goals for the hydrogen fueled vehicular transport has not yet met by any hydrogen storage material, complex Sodium Alanate is said to be a promising candidate under this demand due to its high hydrogen storage capacity and the thermodynamically permissible reversible hydrogen storage capacity. However its poor sorption behavior under moderate conditions (NaAlH 4 →Na 3 AlH 6 ; 3.7 wt % vs 50 hrs at ∼170 C and Na 3 AlH 6 →NaH; 1.85 wt % vs 30 hrs at ∼220 C) urges their limited uses in ages. But these limitations can be removed by using catalysts particularly transition elements but the location of catalyst in NaAlH 4 matrix and the possible mechanism is not yet clearly understood. The aim of the present investigation is to improve the overall sorption characteristics of NaAlH 4 by a new light weighted high surface area (1315 sq mtr/gm) material (CNT) admixing and to obtain a best doping level to NaAlH 4 . So far only Ti has been attempted as a suitable catalyst. It is believed that the high surface area of CNT can provide an additional solid-gas (H 2 ) surface/interface and it can produce thermal contact between grains (thermal conductivity Kth of MWCNT: 3000 w/k and Kth of NaAlH 4 : 0.32 w/k) for stimulating their thermally activated dissociation in NaAlH 4 . In parallel with this approach XRD of NaAlH 4 reveals that there was no change in lattice structure after doping by CNT, SEM picture depicts that CNT precipitation in grain surfaces. Catalytic concentration of various mole % of x values finds that x = 8 is the best doping level as it gives 3.3 wt % of hydrogen within 2 hrs. The comparative sorption behavior with Ti:NaAlH 4 also shows CNTs as an optimum alternative catalyst to NaAlH 4 and besides this CNT doped desorbed ingredients shown good re-hydrogenation behavior(3.7 wt % at 8. cycle and 4.2 wt % maximum at

  3. Mechanochemical transformations in Li(Na)AlH4-Li(Na)NH2 systems

    International Nuclear Information System (INIS)

    Dolotko, Oleksandr; Zhang Haiqiao; Ugurlu, Ozan; Wiench, Jerzy W.; Pruski, Marek; Scott Chumbley, L.; Pecharsky, Vitalij

    2007-01-01

    Mechanochemical transformations of tetrahydroaluminates and amides of lithium and sodium have been investigated using gas volumetric analysis, X-ray powder diffraction, solid-state nuclear magnetic resonance (NMR) and transmission electron microscopy. In a transformation of LiAlH 4 and LiNH 2 taken in an 1:1 molar ratio, the amount of released hydrogen (6.6 wt.% after 30 min ball milling) was higher than in any known one pot mechanochemical process involving a hydrogen-containing solid. A total of 4.3 wt.% of hydrogen is released by the NaAlH 4 -NaNH 2 system after 60 min ball milling; and 5.2 wt.% H 2 is released when LiAlH 4 and NaNH 2 or NaAlH 4 and LiNH 2 are ball milled for 90 min and 120 min, respectively. All transformations proceed at room temperature. The mechanism of the overall transformation MAlH 4 (s) + MNH 2 (s) → 2MH(s) + AlN(s) + 2H 2 (g) was identified based on detailed spectroscopic analysis of the intermediate (M 3 AlH 6 ) and final products of the ball milling process

  4. RPA binds histone H3-H4 and functions in DNA replication-coupled nucleosome assembly.

    Science.gov (United States)

    Liu, Shaofeng; Xu, Zhiyun; Leng, He; Zheng, Pu; Yang, Jiayi; Chen, Kaifu; Feng, Jianxun; Li, Qing

    2017-01-27

    DNA replication-coupled nucleosome assembly is essential to maintain genome integrity and retain epigenetic information. Multiple involved histone chaperones have been identified, but how nucleosome assembly is coupled to DNA replication remains elusive. Here we show that replication protein A (RPA), an essential replisome component that binds single-stranded DNA, has a role in replication-coupled nucleosome assembly. RPA directly binds free H3-H4. Assays using a synthetic sequence that mimics freshly unwound single-stranded DNA at replication fork showed that RPA promotes DNA-(H3-H4) complex formation immediately adjacent to double-stranded DNA. Further, an RPA mutant defective in H3-H4 binding exhibited attenuated nucleosome assembly on nascent chromatin. Thus, we propose that RPA functions as a platform for targeting histone deposition to replication fork, through which RPA couples nucleosome assembly with ongoing DNA replication. Copyright © 2017, American Association for the Advancement of Science.

  5. Muon Beam Studies in the H4 beam line and the Gamma Irradiation Facility (GIF++)

    CERN Document Server

    Margraf, Rachel; CERN. Geneva. EN Department

    2017-01-01

    In this report, I summarize my work of detailed study and optimization of the muon beam configuration of H4 beam line in SPS North Area. Using Monte-Carlo simulations, I studied the properties and behavior of the muon beam in combination with the field of the large, spectrometer “ GOLIATH” magnet at -1.5, -1.0, 0, 1.0 and 1.5 Tesla, which is shown to affect the central x position of the muon beam that is delivered to the Gamma Irradiation Facility (GIF++). I also studied the muon beam for different configurations of the two XTDV beam dumps upstream of GIF++ in the H4 beam line. I will also discuss my role in mapping the magnetic field of the GOLIATH magnet in the H4 beam line.

  6. Cerebral, spinal and peripheral inhibition of gastrointestinal transit by PI017: differential antagonism by naloxonazine

    Energy Technology Data Exchange (ETDEWEB)

    Williams, C.L.; Heyman, J.S.; Porreca, F.; Burks, T.F.

    1986-03-05

    The authors were interested in characterizing the relative importance of central (cerebral, spinal) and peripheral opioid receptors in inhibition of gastrointestinal transit. The mu-receptor selective agonist, (NMePhe/sup 3/,D-Pro/sup 4/)morphiceptin (PL017), was evaluated for its effectiveness in slowing gastrointestinal transit after subcutaneous, intracerebroventricular (i.c.v.) or intrathecal (i.th.) administration when given alone or after pretreatment with naloxonazine, an irreversible mu/sub 1/ selective opioid receptor antagonist. Male, ICR mice (20-25 g) were pretreated with saline, naloxone or naloxonazine (35 mg/kg, s.c.) 25 hr prior to testing. Gastrointestinal transit was evaluated in previously fasted (18 hr) mice by oral administration of a liquid radiolabelled marker (Na/sub 2//sup 51/CrO/sub 4/). I.th. PL017 (100-1000 ng) was effective in slowing transit, but was essentially insensitive to naloxone or naloxonazine pretreatment. PL017 produced a dose-related inhibition of transit when given by either the i.c.v. (100-1000 ng) or s.c.(1-10 mg/kg) route; this effect was not sensitive to naloxone pretreatment but was antagonized by naloxonazine. These results indicate that the opioid receptors mediating gastrointestinal transit in the brain and periphery may be mu/sub 1/. In contrast, the insensitivity to naloxonazine suggests that the gastrointestinal effects of PL017 in the spinal cord may be the result of activation of mu/sub 2/ or possibly delta opioid receptors.

  7. Zinc terephthalates ZnC_8H_4O_4 as anodes for lithium ion batteries

    International Nuclear Information System (INIS)

    Wang, Liping; Zou, Jian; Chen, Shulin; Yang, Jingyi; Qing, Fangzhu; Gao, Peng; Li, Jingze

    2017-01-01

    Graphical abstract: Both of well-crystalline and amorphous zinc terephthalates ZnC_8H_4O_4 are synthesized and amorphous structure demonstrates a higher capacity and better cycling performance. - Highlights: • Crystalline and amorphous ZnC_8H_4O_4 are obtained. • Both crystalline and amorphous ZnC_8H_4O_4 have σ_e of 10"−"7 S m"−"1. • Lithium ion diffusion is the rate-determine process. • Amorphous has a high capacity and durable performance. • Amorphous ZnC_8H_4O_4 has a high apparent lithium ion diffusion coefficient. - Abstract: Organic materials offer the advantages of cost-effective, environmental benignity, and molecular structural diversity as applications of electrode materials for lithium ion batteries. In fact, their lithium storage behaviors in terms of dynamics and kinetics intrinsically lie in ion migration in solids. Thus the solid forms including crystalline and amorphous states are crucial for the properties. In this study, a conventional carbonyl type organic material, namely zinc terephthalate (ZnC_8H_4O_4), is obtained in both well-crystalline and amorphous forms and applied as anodes for lithium ion batteries. ZnC_8H_4O_4 with amorphous structure shows higher lithium storage capacity and better capacity retention compared with that of crystalline one. It is ascribed that the amorphous phase provides a higher lithium ion diffusion coefficient than the crystalline one under the conditions of similar electronic conductivity.

  8. Fragmentation of C2H4 by charge-changing collisions of O2+ ions

    International Nuclear Information System (INIS)

    Sato, S.; Mizuno, T.; Yamada, T.; Imai, M.; Shibata, H.; Itoh, A.; Tsuchida, H.

    2009-01-01

    We investigated molecular fragmentation of C 2 H 4 in charge-changing collisions of 1.14MeV O 2+ ions. Branching ratios associated with decaying from temporary produced (C 2 H 4 ) r+ ions into various fragment channels were obtained. Dissociation via a C-C bond breaking is preferential in 1-electron loss collisions in comparison with 1-electron capture collisions. We confirmed that multiple ionization and dissociation rarely occur in electron capture collisions, while they occur rather strongly in electron loss collisions. (author)

  9. A perturbational h4 exponential finite difference scheme for the convective diffusion equation

    International Nuclear Information System (INIS)

    Chen, G.Q.; Gao, Z.; Yang, Z.F.

    1993-01-01

    A perturbational h 4 compact exponential finite difference scheme with diagonally dominant coefficient matrix and upwind effect is developed for the convective diffusion equation. Perturbations of second order are exerted on the convective coefficients and source term of an h 2 exponential finite difference scheme proposed in this paper based on a transformation to eliminate the upwind effect of the convective diffusion equation. Four numerical examples including one- to three-dimensional model equations of fluid flow and a problem of natural convective heat transfer are given to illustrate the excellent behavior of the present exponential schemes. Besides, the h 4 accuracy of the perturbational scheme is verified using double precision arithmetic

  10. Platformed antagonism: Racist discourses on fake Muslim Facebook pages

    DEFF Research Database (Denmark)

    Farkas, Johan; Schou, Jannick; Neumayer, Christina

    2018-01-01

    This research examines how fake identities on social media create and sustain antagonistic and racist discourses. It does so by analysing 11 Danish Facebook pages, disguised as Muslim extremists living in Denmark, conspiring to kill and rape Danish citizens. It explores how anonymous content...... producers utilize Facebook's socio-technical characteristics to construct, what we propose to term as, platformed antagonism. This term refers to socio-technical and discursive practices that produce new modes of antagonistic relations on social media platforms. Through a discourse-theoretical analysis...... of posts, images, 'about' sections and user comments on the studied Facebook pages, the article highlights how antagonism between ethno-cultural identities is produced on social media through fictitious social media accounts, prompting thousands of user reactions. These findings enhance our current...

  11. Interleukin-1 Antagonism Decreases Cortisol Levels in Obese Individuals

    OpenAIRE

    Urwyler, Sandrine Andrea; Schuetz, Philipp; Ebrahimi, Fahim; Donath, Marc Y.; Christ-Crain, Mirjam

    2017-01-01

    Increased cortisol levels in obesity may contribute to the associated metabolic syndrome. In obesity, the activated innate immune system leads to increased interleukin (IL)-1β, which is known to stimulate the release of adrenocorticotropin hormone (ACTH).; We hypothesized that in obesity IL-1 antagonism would result in downregulation of the hypothalamo-pituitary-adrenal axis, leading to decreased cortisol levels.; In this prospective intervention study, we included 73 patients with obesity (b...

  12. Antagonism of Innate Immunity by Paramyxovirus Accessory Proteins

    Directory of Open Access Journals (Sweden)

    Raychel Chambers

    2009-10-01

    Full Text Available Paramyxovirinae, a subfamily of Paramyxoviridae, are negative strand RNA viruses comprised of many important human and animal pathogens, which share a high degree of genetic and structural homology. The accessory proteins expressed from the P/V/C gene are major factors in the pathogenicity of the viruses, because of their ability to abrogate various facets of type I interferon (IFN induction and signaling. Most of the paramyxoviruses exhibit a commonality in their ability to antagonize innate immunity by blocking IFN induction and the Jak/STAT pathway. However, the manner in which the accessory proteins inhibit the pathway differs among viruses. Similarly, there are variations in the capability of the viruses to counteract intracellular detectors (RNA helicases, mda-5 and RIG-I. Furthermore, a functional specificity in the antagonism of the IFN response has been reported, suggesting that specificity in the circumvention of innate immunity restricts viral host range. Available evidence indicates that paramyxoviruses employ specific strategies to antagonize the IFN response of their specific hosts, which is one of the major factors that determine viral pathogenicity and host range.

  13. 14C2H4: distribution of 14C-labeled tissue metabolites in pea seedlings

    International Nuclear Information System (INIS)

    Giaquinta, R.; Beyer, E. Jr.

    1977-01-01

    The 14 C-metabolite distribution pattern following 14 C 2 H 4 metabolism in intact pea seedlings (Pisum sativum L.) was determined under various conditions. After a 24 hr exposure to 14 C 2 H 4 , the majority of 14 C-metabolites were water-soluble (60-70%) with lesser amounts in the protein (10-15%), lipid (1%), and insoluble (1-2%) fractions. Ion exchange chromatography of the water-soluble components into basic, neutral, and acidic fractions revealed a 50:40:10 distribution, respectively. Chromatography of the neutral fraction revealed two regions of radioactivity (Rf=0.38) and 0.63 which did not cochromatograph with twenty-two known sugars or neutral metabolites. Chromatograms of the basic fraction contained 3 regions of radioactivity. Similar distribution patterns were noted when 14 C 2 H 4 exposure was followed by a 6 hr air chase or when 5% CO 2 , an antagonist of ethylene action, was present during the exposure. Marked differences in the 14 C-metabolite distribution patterns were obtained when 14 CO 2 was substituted for 14 C 2 H 4 . These results indicate that the metabolic pathway involved in ethylene metabolism is different from that involved in intermediately carbon metabolism. (auth.)

  14. Thyroid epithelial cell hyperplasia in IFN-gamma deficient NOD.H-2h4 mice.

    Science.gov (United States)

    Yu, Shiguang; Sharp, Gordon C; Braley-Mullen, Helen

    2006-01-01

    The role of inflammatory cells in thyroid epithelial cell (thyrocyte) hyperplasia is unknown. Here, we demonstrate that thyrocyte hyperplasia in IFN-gamma-/- NOD.H-2h4 mice has an autoimmune basis. After chronic exposure to increased dietary iodine, 60% of IFN-gamma-/- mice had severe thyrocyte hyperplasia with minimal or moderate lymphocyte infiltration, and thyroid dysfunction with reduced serum T4. All mice produced anti-thyroglobulin autoantibody. Some wild-type NOD.H-2h4 mice had isolated areas of thyrocyte hyperplasia with predominantly lymphocytic infiltration, whereas IL-4-/- and 50% of wild-type NOD.H-2h4 mice developed lymphocytic thyroiditis but no thyrocyte hyperplasia. Both thyroid infiltrating inflammatory cells and environmental factors (iodine) were required to induce thyrocyte hyperplasia. Splenocytes from IFN-gamma-/- mice with thyrocyte hyperplasia, but not splenocytes from naïve IFN-gamma-/- mice, induced hyperplasia in IFN-gamma-/- NOD.H-2h4.SCID mice. These results may provide clues for understanding the mechanisms underlying development of epithelial cell hyperplasia not only in thyroids but also in other tissues and organs.

  15. Nucleotide sequences of the genes encoding fructosebisphosphatase and phosphoribulokinase from Xanthobacter flavus H4-14

    NARCIS (Netherlands)

    Meijer, Wilhelmus; Enequist, H.G.; Terpstra, Peter; Dijkhuizen, L.

    The genes encoding fructosebisphosphatase and phosphoribulokinase present on a 2.5 kb SalI fragment from Xanthobacter flavus H4-14 were sequenced. Two large open reading frames (ORFs) were identified, preceded by plausible ribosome-binding sites. The ORFs were transcribed in the same direction and

  16. Structural studies of disordered Mg2NiH4 formed by mechanical grinding

    DEFF Research Database (Denmark)

    Rönnebro, Ewa; Jensen, Jens Oluf; Noréus, Dag

    1999-01-01

    The low temperature phase of Mg2NiH4 was mechanically ground in argon atmosphere. The ordered monoclinic structure was destroyed to form the disordered cubic structure, previously only found above 510 K. With a Guinier-Hagg X-ray camera the cell parameter was determined to be a=6.492(3) Angstrom....

  17. O(3P) + C2H4 Potential Energy Surface: Study at the Multireference Level

    Czech Academy of Sciences Publication Activity Database

    West, A. C.; Kretchmer, J. S.; Sellner, B.; Park, K.; Hase, W. L.; Lischka, Hans; Windus, T. L.

    2009-01-01

    Roč. 113, č. 45 (2009), s. 12663-12674 ISSN 1089-5639 Institutional research plan: CEZ:AV0Z40550506 Keywords : hydrogen combustion * multireference methods * O(3P)+C2H4 reaction Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 2.899, year: 2009

  18. Direct formation of LiAlH4 by a mechanochemical reaction

    International Nuclear Information System (INIS)

    Kojima, Yoshitsugu; Kawai, Yasuaki; Haga, Tetsuya; Matsumoto, Mitsuru; Koiwai, Akihiko

    2007-01-01

    A small amount of lithium tetrahydridoaluminate (LiAlH 4 ) was directly synthesized by ball-milling of lithium hydride LiH and aluminum Al in a H 2 atmosphere (1 MPa) at room temperature. Concomitant formation of lithium hexahydridoaluminate Li 3 AlH 6 was confirmed

  19. Antifungal properties of wheat histones (H1-H4) and purified wheat histone H1

    Science.gov (United States)

    Wheat (Triticum sp.) histones H1, H2, H3, and H4 were extracted. H1 was further purified. Their activities against fungi with varying degrees of wheat pathogenicity were determined. They included Aspergillus flavus, A. fumigatus, A. niger, F. oxysporum, F. verticillioides, F. solani, F. graminearu...

  20. Interview with Kortney Ryan Ziegler of the Trans*H4CK Project

    DEFF Research Database (Denmark)

    Raun, Tobias

    2014-01-01

    TSQ New Media editor Tobias Raun interviews Kortney Ryan Ziegler, the organizer of the Trans*H4CK hackathon, which took place in Oakland, California, in September 2013. The hackathon brought forty transgender, gender nonconforming, cisgender, and queer people together to create digital tools...

  1. A GIF++ Gamma Irradiation Facility at the SPS H4 Beam Line

    CERN Document Server

    Capéans-Garrido, M; Linssen, L; Moll, M; Rembser, C

    2009-01-01

    The current document describes a proposal to implement a new gamma irradiation facility, combined with a high-energy particle beam in the SPS H4 beam line in hall EHN1. This new GIF++ facility is motivated by strong needs from the LHC and sLHC detector and accelerator communities for the tests of LHC components and systems.

  2. File list: His.PSC.50.H4K16ac.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.PSC.50.H4K16ac.AllCell mm9 Histone H4K16ac Pluripotent stem cell SRX212325,SRX2...98193,SRX212326,SRX298194 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.PSC.50.H4K16ac.AllCell.bed ...

  3. File list: His.PSC.20.H4K16ac.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.PSC.20.H4K16ac.AllCell mm9 Histone H4K16ac Pluripotent stem cell SRX298193,SRX2...12325,SRX212326,SRX298194 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.PSC.20.H4K16ac.AllCell.bed ...

  4. Deacetylation of H4-K16Ac and heterochromatin assembly in senescence

    Directory of Open Access Journals (Sweden)

    Contrepois Kévin

    2012-08-01

    Full Text Available Abstract Background Cellular senescence is a stress response of mammalian cells leading to a durable arrest of cell proliferation that has been implicated in tumor suppression, wound healing, and aging. The proliferative arrest is mediated by transcriptional repression of genes essential for cell division by the retinoblastoma protein family. This repression is accompanied by varying degrees of heterochromatin assembly, but little is known regarding the molecular mechanisms involved. Results We found that both deacetylation of H4-K16Ac and expression of HMGA1/2 can contribute to DNA compaction during senescence. SIRT2, an NAD-dependent class III histone deacetylase, contributes to H4-K16Ac deacetylation and DNA compaction in human fibroblast cell lines that assemble striking senescence-associated heterochromatin foci (SAHFs. Decreased H4-K16Ac was observed in both replicative and oncogene-induced senescence of these cells. In contrast, this mechanism was inoperative in a fibroblast cell line that did not assemble extensive heterochromatin during senescence. Treatment of senescent cells with trichostatin A, a class I/II histone deacetylase inhibitor, also induced rapid and reversible decondensation of SAHFs. Inhibition of DNA compaction did not significantly affect the stability of the senescent state. Conclusions Variable DNA compaction observed during senescence is explained in part by cell-type specific regulation of H4 deacetylation and HMGA1/2 expression. Deacetylation of H4-K16Ac during senescence may explain reported decreases in this mark during mammalian aging and in cancer cells.

  5. SB-224289 Antagonizes the Antifungal Mechanism of the Marine Depsipeptide Papuamide A.

    Directory of Open Access Journals (Sweden)

    Chelsi D Cassilly

    Full Text Available In order to expand the repertoire of antifungal compounds a novel, high-throughput phenotypic drug screen targeting fungal phosphatidylserine (PS synthase (Cho1p was developed based on antagonism of the toxin papuamide A (Pap-A. Pap-A is a cyclic depsipeptide that binds to PS in the membrane of wild-type Candida albicans, and permeabilizes its plasma membrane, ultimately causing cell death. Organisms with a homozygous deletion of the CHO1 gene (cho1ΔΔ do not produce PS and are able to survive in the presence of Pap-A. Using this phenotype (i.e. resistance to Pap-A as an indicator of Cho1p inhibition, we screened over 5,600 small molecules for Pap-A resistance and identified SB-224289 as a positive hit. SB-224289, previously reported as a selective human 5-HT1B receptor antagonist, also confers resistance to the similar toxin theopapuamide (TPap-A, but not to other cytotoxic depsipeptides tested. Structurally similar molecules and truncated variants of SB-224289 do not confer resistance to Pap-A, suggesting that the toxin-blocking ability of SB-224289 is very specific. Further biochemical characterization revealed that SB-224289 does not inhibit Cho1p, indicating that Pap-A resistance is conferred by another undetermined mechanism. Although the mode of resistance is unclear, interaction between SB-224289 and Pap-A or TPap-A suggests this screening assay could be adapted for discovering other compounds which could antagonize the effects of other environmentally- or medically-relevant depsipeptide toxins.

  6. The effects of conformational constraints and steric bulk in the amino acid moiety of philanthotoxins on AMPAR antagonism

    DEFF Research Database (Denmark)

    Jørgensen, Malene; Olsen, Christian A; Mellor, Ian R

    2005-01-01

    , establishing general protocols for philanthotoxin solution- and solid-phase synthesis (39-90% and 42-54% overall yields, respectively). The analogues were tested for their ability to antagonize kainate-induced currents of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazoyl)propanoic acid receptors (AMPAR) expressed...... in Xenopus oocytes from rat brain mRNA. This showed that steric bulk in the amino acid moiety is well tolerated and suggests that binding to AMPAR does not involve the alpha-NHCO group as a donor in hydrogen bonding.......Philanthotoxin-343 (PhTX-343), a synthetic analogue of wasp toxin PhTX-433, is a noncompetitive antagonist at ionotropic receptors (e.g., AChR or iGluR). To determine possible effects of variations of the amino acid side chain, a library consisting of seventeen PhTX-343 analogues was prepared. Thus...

  7. Effect of blockage of the endocannabinoid system by CB(1) antagonism on cardiovascular risk.

    Science.gov (United States)

    Mach, François; Montecucco, Fabrizio; Steffens, Sabine

    2009-01-01

    The endocannabinoid system is a crucial player in the inflammatory processes underlying atherosclerosis. Recently, basic research studies and animal models have strongly supported the role of the endocannabinoid system not only in the regulation of classical cardiovascular risk factors (including lipid profile and glucose homeostasis), but also in the activation of immune cells and inflammatory mediators. Clinical trials investigating treatment with rimonabant (a selective antagonist of the cannabinoid type 1 receptor) have suggested a beneficial effect of this drug in the management of obesity. Further studies are needed to explore a possible use for rimonabant in treating type 2 diabetes and acute and chronic cardiovascular disease. Despite the slight increase in adverse events (mainly psychiatric), which has led to the recent withdrawal of rimonabant from the market, CB(1) receptor antagonism might represent a very promising therapeutic strategy to reduce the cardiovascular risk. In the present review, we focused on the most important experimental investigations into the role of the endocannabinoid system in atherosclerosis and cardiovascular risk.

  8. Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology.

    Science.gov (United States)

    Fuxe, K; Marcellino, D; Rivera, A; Diaz-Cabiale, Z; Filip, M; Gago, B; Roberts, D C S; Langel, U; Genedani, S; Ferraro, L; de la Calle, A; Narvaez, J; Tanganelli, S; Woods, A; Agnati, L F

    2008-08-01

    representing a compensatory up-regulation to counteract the cocaine-induced increases in dopamine D(2) and D(3) signaling. Therefore, A(2A) agonists, through antagonizing D(2) and D(3) signaling within A(2A)/D(2) and A(2A)/D(3) RM heteromers in the nucleus accumbens, may be found useful as a treatment for cocaine dependence. Furthermore, antagonistic cannabinoid CB(1)/D(2) interactions requiring A(2A) receptors have also been discovered and possibly operate in CB(1)/D(2)/A(2A) RM located principally on striatal glutamate terminals but also on some ventral striato-pallidal GABA neurons, thereby opening up a new mechanism for the integration of endocannabinoid, DA and adenosine mediated signals. Thus, A(2A), mGluR5 and/or CB(1) receptors can form integrative units with D(2) receptors within RM displaying different compositions, topography and localization. Also galaninR/5-HT(1A) RM probably participates in the transmission of the ascending 5-hydroxytryptamine neurons, where galanin receptors antagonize 5-HT(1A) recognition and signaling. Subtype specific galanin receptor antagonists may therefore represent novel antidepressant drugs. These results suggest the importance of a complete understanding of the function of these RM with regard to disease. Ultimately receptor-receptor interactions within RM that modify dopaminergic and serotonergic signaling may give new strategies for treatment of a wide range of diseases associated with altered dopaminergic and serotonergic signaling.

  9. Experimental and kinetic modeling study of C2H4 oxidation at high pressure

    DEFF Research Database (Denmark)

    Lopez, Jorge Gimenez; Rasmussen, Christian Lund; Alzueta, Maria

    2009-01-01

    of conditions (0.003-100 bar, 200-3000 K). The results indicate that at 60 bar and medium temperatures vinyl peroxide, rather than CH2O and HCO, is the dominant product. The experiments, involving C2H4/O-2 mixtures diluted in N-2, were carried out in a high pressure flow reactor at 600-900 K and 60 bar, varying......A detailed chemical kinetic model for oxidation of C2H4 in the intermediate temperature range and high pressure has been developed and validated experimentally. New ab initio calculations and RRKM analysis of the important C2H3 + O-2 reaction was used to obtain rate coefficients over a wide range...

  10. High Density Hydrogen Storage System Demonstration Using NaAlH4 Based Complex Compound Hydrides

    Energy Technology Data Exchange (ETDEWEB)

    Daniel A. Mosher; Xia Tang; Ronald J. Brown; Sarah Arsenault; Salvatore Saitta; Bruce L. Laube; Robert H. Dold; Donald L. Anton

    2007-07-27

    This final report describes the motivations, activities and results of the hydrogen storage independent project "High Density Hydrogen Storage System Demonstration Using NaAlH4 Based Complex Compound Hydrides" performed by the United Technologies Research Center under the Department of Energy Hydrogen Program, contract # DE-FC36-02AL67610. The objectives of the project were to identify and address the key systems technologies associated with applying complex hydride materials, particularly ones which differ from those for conventional metal hydride based storage. This involved the design, fabrication and testing of two prototype systems based on the hydrogen storage material NaAlH4. Safety testing, catalysis studies, heat exchanger optimization, reaction kinetics modeling, thermochemical finite element analysis, powder densification development and material neutralization were elements included in the effort.

  11. Monitoring the effect of belinostat in solid tumors by H4 acetylation

    DEFF Research Database (Denmark)

    Marquard, L.; Petersen, K.D.; Persson, M.

    2008-01-01

    after treatment with HDAC inhibitors, and could thus be used as a marker for monitoring cellular response to HDAC inhibitor treatment. Here we describe the utility of a newly described monoclonal antibody against acetylated H4 for immunohistochemistry on paraffin-embedded fine needle biopsies from nude...... acetylation in fine needle biopsies using the T25 antibody may prove useful in monitoring HDAC inhibitor efficacy in clinical trials involving humans with solid tumors Udgivelsesdato: 2008/5...

  12. Tungsten chemical vapor deposition characteristics using SiH4 in a single wafer system

    International Nuclear Information System (INIS)

    Rosler, R.S.; Mendonca, J.; Rice, M.J. Jr.

    1988-01-01

    Several workers have recently begun using silane as a high-rate, low-temperature alternative to hydrogen for the reduction of WF 6 in the chemical vapor deposition of W. The deposition and film characteristics of both selective and blanket W using this new chemistry are explored in a radiantly heated single wafer system using closed-loop temperature control with a thermocouple in direct contact with the backside of the wafer. Selective W deposition rates of up to 1.5 μm/min were measured over the temperature range 250--550 0 C with blanket W rates typically 2--5 x lower. Resistivity is in the 10--15 μΩcm range at 300 0 C for SiH 4 /WF 6 ratios of 0.2 to 1.0, while above 400 0 C the range is 7.5--8.5 μΩcm. Si content in the W films is quite low at 10 16 to 10 17 atoms/cm 3 . Adhesion to silicon is excellent at temperatures of 350 0 C and above. Selective W using SiH 4 reduction for doped silicon contact fill shows none of the consumption or encroachment problems common to H 2 reduction, although selectivity is more sensitive. Contact resistance for p + and n + silicon contacts are comparable to aluminum controls and to previously published data. Blanket deposition into narrow geometries gives ≥0% step coverage and without keyholes in the 250--450 0 C deposition temperature range. For low-SiH 4 flows, deposition at 500 0 C causes small keyholes, while at 550 0 C even larger keyholes result. At higher SiH 4 flows, keyholes are typically not seen from 250 to 550 0 C

  13. Valproic acid promotes neuronal differentiation by induction of proneural factors in association with H4 acetylation.

    Science.gov (United States)

    Yu, In Tag; Park, Jin-Yong; Kim, Sung Hyun; Lee, Jeong-Sik; Kim, Yong-Seok; Son, Hyeon

    2009-02-01

    Valproate (VPA) influences the proliferation and differentiation of neuronal cells. However, little is known about the downstream events, such as alterations in gene transcription, that are associated with cell fate choice. To determine whether VPA plays an instructive role in cell fate choice during hippocampal neurogenesis, the expression of genes involved in the cell cycle and neuronal differentiation was investigated. Treatment with VPA during the progenitor stages resulted in strong inhibition of cell proliferation and induction of neuronal differentiation, accompanied by increases in the expression of proneural transcription factors and in neuronal cell numbers. The increased expression of Ngn1, Math1 and p15 points to a shift towards neuronal fate in response to histone deacetylase inhibitors (HDACi). Chromatin immunoprecipitation (ChIP) analysis showed that acetylated histone H4 (Ac-H4) was associated with the Ngn1, Math1 and p15 promoters in cultured hippocampal neural progenitor cells. VPA-induced hippocampal neurogenesis was also accompanied by association of Ac-H4 with the Ngn1 promoter in hippocampal extracts. The discovery of an association between HDACi and the Ngn1, Math1 and p15 promoters extends the importance of HDAC inhibition as a key regulator of neuronal differentiation at the transcriptional level.

  14. Structure-based nuclear import mechanism of histones H3 and H4 mediated by Kap123

    Energy Technology Data Exchange (ETDEWEB)

    An, Sojin [Department of Biological Chemistry, University of Michigan Medical School, Michigan, United States; Yoon, Jungmin [Structural Biology Laboratory of Epigenetics, Department of Biological Sciences, Graduate school of Nanoscience and Technology (World Class University), KI for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon, South Korea; Kim, Hanseong [Department of Biological Chemistry, University of Michigan Medical School, Michigan, United States; Song, Ji-Joon [Structural Biology Laboratory of Epigenetics, Department of Biological Sciences, Graduate school of Nanoscience and Technology (World Class University), KI for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon, South Korea; Cho, Uhn-soo [Department of Biological Chemistry, University of Michigan Medical School, Michigan, United States

    2017-10-16

    Kap123, a major karyopherin protein of budding yeast, recognizes the nuclear localization signals (NLSs) of cytoplasmic histones H3 and H4 and translocates them into the nucleus during DNA replication. Mechanistic questions include H3- and H4-NLS redundancy toward Kap123 and the role of the conserved diacetylation of cytoplasmic H4 (K5ac and K12ac) in Kap123-mediated histone nuclear translocation. Here, we report crystal structures of full-length Kluyveromyces lactis Kap123 alone and in complex with H3- and H4-NLSs. Structures reveal the unique feature of Kap123 that possesses two discrete lysine-binding pockets for NLS recognition. Structural comparison illustrates that H3- and H4-NLSs share at least one of two lysine-binding pockets, suggesting that H3- and H4-NLSs are mutually exclusive. Additionally, acetylation of key lysine residues at NLS, particularly H4-NLS diacetylation, weakens the interaction with Kap123. These data support that cytoplasmic histone H4 diacetylation weakens the Kap123-H4-NLS interaction thereby facilitating histone Kap123-H3-dependent H3:H4/Asf1 complex nuclear translocation.

  15. The histamine H-4 receptor is a potent inhibitor of adhesion-dependent degranulation in human neutrophils

    Czech Academy of Sciences Publication Activity Database

    Dib, K.; Perečko, Tomáš; Jenei, V.

    2014-01-01

    Roč. 96, č. 3 (2014), s. 411-418 ISSN 0741-5400 R&D Projects: GA MŠk(CZ) EE2.3.30.0030 Institutional support: RVO:68081707 Keywords : inflammation * signaling * innate immunity Subject RIV: BO - Biophysics Impact factor: 4.289, year: 2014

  16. Pancreatic Transdifferentiation and Glucose-Regulated Production of Human Insulin in the H4IIE Rat Liver Cell Line

    Directory of Open Access Journals (Sweden)

    Binhai Ren

    2016-04-01

    Full Text Available Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat NeuroD1 gene alone, or the human insulin gene and rat NeuroD1 genes together, to the rat liver cell line, H4IIE, to determine if storage of insulin and pancreatic transdifferentiation occurred. Stable clones were selected and expanded into cell lines: H4IIEins (insulin gene alone, H4IIE/ND (NeuroD1 gene alone, and H4IIEins/ND (insulin and NeuroD1 genes. The H4IIEins cells did not store insulin; however, H4IIE/ND and H4IIEins/ND cells stored 65.5 ± 5.6 and 1475.4 ± 171.8 pmol/insulin/5 × 106 cells, respectively. Additionally, several β cell transcription factors and pancreatic hormones were expressed in both H4IIE/ND and H4IIEins/ND cells. Electron microscopy revealed insulin storage vesicles in the H4IIE/ND and H4IIEins/ND cell lines. Regulated secretion of insulin to glucose (0–20 mmol/L was seen in the H4IIEins/ND cell line. The H4IIEins/ND cells were transplanted into diabetic immunoincompetent mice, resulting in normalization of blood glucose. This data shows that the expression of NeuroD1 and insulin in liver cells may be a useful strategy for inducing islet neogenesis and reversing diabetes.

  17. A prototypical Sigma-1 receptor antagonist protects against brain ischemia

    OpenAIRE

    Schetz, John A.; Perez, Evelyn; Liu, Ran; Chen, Shiuhwei; Lee, Ivan; Simpkins, James W.

    2007-01-01

    Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this s...

  18. Procion Green H-4G immobilized poly(hydroxyethylmethacrylate/chitosan) composite membranes for heavy metal removal

    International Nuclear Information System (INIS)

    Genc, Oe.; Soysal, L.; Bayramoglu, G.; Arica, M.Y.; Bektas, S.

    2003-01-01

    The effective removal of toxic heavy metals from environmental samples still remains a major topic of present research. Metal-chelating membranes are very promising materials as adsorbents when compared with conventional beads because they are not compressible, and they eliminate internal diffusion limitations. The purpose of this study was to evaluate the performance of a novel adsorbent, Procion Green H-4G immobilized poly(hydroxyethylmethacrylate (HEMA)/chitosan) composite membranes, for the removal of three toxic heavy metal ions, namely, Cd(II), Pb(II) and Hg(II) from aquatic systems. The Procion Green H-4G immobilized poly(hydroxyethylmethacrylate/chitosan) composite membranes were characterized by elemental analysis, scanning electron microscopy and Fourier transform infrared (FTIR) spectroscopy. The immobilized amount of the Procion Green H-4G was calculated as 0.018±0.003 μmol/cm 2 from the nitrogen and sulphur stoichiometry. The adsorption capacity of Procion Green H-4G immobilized poly(hydroxyethylmethacrylate/chitosan) composite membranes for selected heavy metal ions from aqueous media containing different amounts of these ions (30-400 mg/l) and at different pH values (2.0-6.0) was investigated. The amount of Cd(II), Pb(II) and Hg(II) adsorbed onto the membranes measured at equilibrium, increased with time during the first 45 min and then remained unchanged toward the equilibrium adsorption. The maximum amounts of heavy metal ions adsorbed were 43.60±1.74, 68.81±2.75 and 48.22±1.92 mg/g for Cd(II), Pb(II) and Hg(II), respectively. The heavy metal ion adsorption on the pHEMA/chitosan membranes (carrying no dye) were relatively low, 6.31±0.13 mg/g for Cd(II), 18.73±0.37 mg/g for Pb(II) and 18.82±0.38 mg/g for Hg(II). Competitive adsorption of the metal ions was also studied. When the metal ions competed with each other, the adsorbed amounts were 12.74±0.38 mg Cd(II)/g, 28.80±0.86 mg Pb(II)/g and 18.41±0.54 mg Hg(II)/g. Procion Green H-4G

  19. Carbon K-shell photoionization of fixed-in-space C2H4

    International Nuclear Information System (INIS)

    Osipov, T.; Belkacem, A.; Schoeffler, M.; Weber, Th.; Prior, M. H.; Stener, M.; Schmidt, L.; Doerner, R.; Landers, A.; Cocke, C. L.

    2010-01-01

    Measurements of the photoelectron angular distributions in the body-fixed frame (MFPAD) have been carried out for 290- to 320-eV photons (just above the carbon K-shell ionization threshold) on C 2 H 4 using an approach based on cold-target recoil-ion momentum spectroscopy (COLTRIMS). The results are compared with a theoretical calculation and excellent agreement is found. A direct verification of the 'f-wave shape resonance' is accomplished by obtaining the complex amplitude of the l=3 partial wave, which shows a peak in its absolute value and a relative phase change of π as the energy is scanned across the resonance.

  20. Spread of avian pathogenic Escherichia coli ST117 O78:H4 in Nordic broiler production

    DEFF Research Database (Denmark)

    Ronco, Troels; Stegger, Marc; Olsen, Rikke Heidemann

    2017-01-01

    and have in general been characterized as being a genetically diverse population. In the Nordic countries, poultry farmers depend on import of Swedish broiler breeders which are part of a breeding pyramid. During 2014 to 2016, an increased occurrence of colibacillosis on Nordic broiler chicken farms...... nucleotide polymorphisms. In general, the characterized poultry isolates constituted a genetically diverse population. However, the phylogenetic analyses revealed a major clade of 47 closely related ST117 O78:H4 isolates. The isolates in this clade were collected from broiler chickens and breeders...

  1. TDPAC study of the order-disorder transition in HfV2H4

    International Nuclear Information System (INIS)

    Forker, M.; Herz, W.; Simon, D.

    1989-01-01

    The static and dynamic electric quadrupole interaction at highly dilute 111 Cd nuclei on V sites of the intermetallic hydride HfV 2 H 4 , investigated by time differential perturbed angular correlations (TDPAC), reflects the existence of an order-disorder transition at T=305 K, in agreement with neutron diffraction measurements. The asymmetry of the electric field gradient tensor indicates a gradually increasing order of hydrogen on the 2/2 tetrahedral interstices towards lower temperatures. Full order is reached at about 200 K. (orig.)

  2. Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset.

    Science.gov (United States)

    Cabrera, Susanne M; Wang, Xujing; Chen, Yi-Guang; Jia, Shuang; Kaldunski, Mary L; Greenbaum, Carla J; Mandrup-Poulsen, Thomas; Hessner, Martin J

    2016-04-01

    It was hypothesized that IL-1 antagonism would preserve β-cell function in new onset Type 1 diabetes (T1D). However, the Anti-Interleukin-1 in Diabetes Action (AIDA) and TrialNet Canakinumab (TN-14) trials failed to show efficacy of IL-1 receptor antagonist (IL-1Ra) or canakinumab, as measured by stimulated C-peptide response. Additional measures are needed to define immune state changes associated with therapeutic responses. Here, we studied these trial participants with plasma-induced transcriptional analysis. In blinded analyses, 70.2% of AIDA and 68.9% of TN-14 participants were correctly called to their treatment arm. While the transcriptional signatures from the two trials were distinct, both therapies achieved varying immunomodulation consistent with IL-1 inhibition. On average, IL-1 antagonism resulted in modest normalization relative to healthy controls. At endpoint, signatures were quantified using a gene ontology-based inflammatory index, and an inverse relationship was observed between measured inflammation and stimulated C-peptide response in IL-1Ra- and canakinumab-treated patients. Cytokine neutralization studies showed that IL-1α and IL-1β additively contribute to the T1D inflammatory state. Finally, analyses of baseline signatures were indicative of later therapeutic response. Despite the absence of clinical efficacy by IL-1 antagonist therapy, transcriptional analysis detected immunomodulation and may yield new insight when applied to other clinical trials. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Mdm2 is a novel activator of ApoCIII promoter which is antagonized by p53 and SHP inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Zhihong; Zhang, Yuxia [Departments of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132 (United States); Wang, Li, E-mail: l.wang@hsc.utah.edu [Departments of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132 (United States)

    2012-01-13

    Highlights: Black-Right-Pointing-Pointer Mdm2 enhances HNF4{alpha} activation of the ApoCIII promoter via interaction with HNF4{alpha}. Black-Right-Pointing-Pointer p53 antagonizes the effect of Mdm2 activation of the ApoCIII promoter. Black-Right-Pointing-Pointer SHP strengthens p53 inhibition but abolishes Mdm2 activation of the ApoCIII promoter. Black-Right-Pointing-Pointer Mdm2 alters the enrichment of HNF4{alpha}, p53 and SHP to the ApoCIII promoter. -- Abstract: We examined the effect of Mdm2 on regulation of the ApoCIII promoter and its cross-talk with p53 and nuclear receptor SHP. Overexpression of Mdm2 markedly enhanced ApoCIII promoter activity by HNF4{alpha}. A direct association of Mdm2 protein with the HNF4{alpha} protein was observed by co-immunoprecipitation. Ectopic expression of p53 decreased HNF4{alpha} activation of the ApoCIII promoter and antagonized the effect of Mdm2. Co-expression of SHP further strengthened p53 inhibition and abolished Mdm2 activation of the ApoCIII promoter. Mdm2 inhibited p53-mediated enrichment of HNF4{alpha} to the ApoCIII promoter while simultaneously reducing p53 binding and increasing recruitment of SHP to the ApoCIII promoter. The results from this study implicate a potentially important function of Mdm2 in regulation of lipoprotein metabolism.

  4. Mdm2 is a novel activator of ApoCIII promoter which is antagonized by p53 and SHP inhibition

    International Nuclear Information System (INIS)

    Yang, Zhihong; Zhang, Yuxia; Wang, Li

    2012-01-01

    Highlights: ► Mdm2 enhances HNF4α activation of the ApoCIII promoter via interaction with HNF4α. ► p53 antagonizes the effect of Mdm2 activation of the ApoCIII promoter. ► SHP strengthens p53 inhibition but abolishes Mdm2 activation of the ApoCIII promoter. ► Mdm2 alters the enrichment of HNF4α, p53 and SHP to the ApoCIII promoter. -- Abstract: We examined the effect of Mdm2 on regulation of the ApoCIII promoter and its cross-talk with p53 and nuclear receptor SHP. Overexpression of Mdm2 markedly enhanced ApoCIII promoter activity by HNF4α. A direct association of Mdm2 protein with the HNF4α protein was observed by co-immunoprecipitation. Ectopic expression of p53 decreased HNF4α activation of the ApoCIII promoter and antagonized the effect of Mdm2. Co-expression of SHP further strengthened p53 inhibition and abolished Mdm2 activation of the ApoCIII promoter. Mdm2 inhibited p53-mediated enrichment of HNF4α to the ApoCIII promoter while simultaneously reducing p53 binding and increasing recruitment of SHP to the ApoCIII promoter. The results from this study implicate a potentially important function of Mdm2 in regulation of lipoprotein metabolism.

  5. Two-dimensional simulations of multi-hollow VHF SiH4/H2 plasma

    Directory of Open Access Journals (Sweden)

    Li-Wen Su

    2018-02-01

    Full Text Available A triode multi-hollow VHF SiH4/H2 plasma (60 MHz was examined at a pressure of 20 Pa by two-dimensional simulations using the fluid model. In this study, we considered the effect of the rate constant of reaction, SiH3 + SiH3→SiH2 + SiH4, on the plasma characteristics. A typical VHF plasma of a high-electron density with a low-electron temperature was obtained between two discharge electrodes. Spatial profiles of SiH3+, SiH2+, SiH3- and SiH3 densities were similar to that of the electron density while the electron temperature had a maximum value near the two discharge electrodes. It was found that the SiH3 radical density did not decrease rapidly near the substrate and the electron temperature was lower than 1 eV, suggesting that the triode multi-hollow plasma source can provide high quality amorphous silicon with a high deposition rate.

  6. Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

    Science.gov (United States)

    Stante, Maria; Minopoli, Giuseppina; Passaro, Fabiana; Raia, Maddalena; Vecchio, Luigi Del; Russo, Tommaso

    2009-01-01

    Fe65 is a binding partner of the Alzheimer's β-amyloid precursor protein APP. The possible involvement of this protein in the cellular response to DNA damage was suggested by the observation that Fe65 null mice are more sensitive to genotoxic stress than WT counterpart. Fe65 associated with chromatin under basal conditions and its involvement in DNA damage repair requires this association. A known partner of Fe65 is the histone acetyltransferase Tip60. Considering the crucial role of Tip60 in DNA repair, we explored the hypothesis that the phenotype of Fe65 null cells depended on its interaction with Tip60. We demonstrated that Fe65 knockdown impaired recruitment of Tip60-TRRAP complex to DNA double strand breaks and decreased histone H4 acetylation. Accordingly, the efficiency of DNA repair was decreased upon Fe65 suppression. To explore whether APP has a role in this mechanism, we analyzed a Fe65 mutant unable to bind to APP. This mutant failed to rescue the phenotypes of Fe65 null cells; furthermore, APP/APLP2 suppression results in the impairment of recruitment of Tip60-TRRAP complex to DNA double strand breaks, decreased histone H4 acetylation and repair efficiency. On these bases, we propose that Fe65 and its interaction with APP play an important role in the response to DNA damage by assisting the recruitment of Tip60-TRRAP to DNA damage sites. PMID:19282473

  7. Quaternionic representation of the Coxeter group W(H4) and the polyhedra

    International Nuclear Information System (INIS)

    Koca, Mehmet; Al-Ajmi, Mudhahir; Koc, Ramazan

    2006-01-01

    The vertices of the four-dimensional polytope {3, 3, 5} and its dual {5, 3, 3} admitting the symmetry of the non-crystallographic Coxeter group W(H 4 ) of order 14,400 are represented in terms of quaternions with unit norm where the polytope {3, 3, 5} is represented by the elements of the binaryicosahedral group of quaternions of order 120. We projected the polytopes to three-dimensional Euclidean space where the quaternionic vertices are the orbits of the Coxeter group W(H 3 ), icosahedral group with inversion, where W(H 3 ) x Z 2 is one of the maximal subgroups of the Coxeter group W(H 4 ). The orbits of the icosahedral group W(H 3 ) in the polytope {3, 3, 5} are the conjugacy classes of the binary icosahedral group and represent a number of icosahedrons, dodecahedrons and one icosidodecahedron in three dimensions. The 15 orbits of the icosahedral group W(H 3 ) in the polytope {5, 3, 3} represent the dodecahedrons, icosidodecahedrons, small rhombicosidodecahedrons and some convex solids possessing the icosahedral symmetry. One of the convex solids with 60 vertices is very similar to the truncated icosahedron (soccer ball) but with two different edge lengths which can be taken as a realistic model of the C 60 molecule at extreme temperature and pressure

  8. A combined crossed molecular beams and theoretical study of the reaction CN + C2H4

    International Nuclear Information System (INIS)

    Balucani, Nadia; Leonori, Francesca; Petrucci, Raffaele; Wang, Xingan; Casavecchia, Piergiorgio; Skouteris, Dimitrios; Albernaz, Alessandra F.; Gargano, Ricardo

    2015-01-01

    Highlights: • The CN + C 2 H 4 reaction was investigated in crossed beam experiments. • Electronic structure calculations of the potential energy surface were performed. • RRKM estimates qualitatively reproduce the experimental C 2 H 3 NC yield. - Abstract: The CN + C 2 H 4 reaction has been investigated experimentally, in crossed molecular beam (CMB) experiments at the collision energy of 33.4 kJ/mol, and theoretically, by electronic structure calculations of the relevant potential energy surface and Rice–Ramsperger–Kassel–Marcus (RRKM) estimates of the product branching ratio. Differently from previous CMB experiments at lower collision energies, but similarly to a high energy study, we have some indication that a second reaction channel is open at this collision energy, the characteristics of which are consistent with the channel leading to CH 2 CHNC + H. The RRKM estimates using M06L electronic structure calculations qualitatively support the experimental observation of C 2 H 3 NC formation at this and at the higher collision energy of 42.7 kJ/mol of previous experiments

  9. ExoMol molecular line lists - XXVII: spectra of C2H4

    Science.gov (United States)

    Mant, Barry P.; Yachmenev, Andrey; Yurchenko, Jonathan Tennyson Sergei N.

    2018-05-01

    A new line list for ethylene, 12C21H4 is presented. The line list is based on high level ab initiopotential energy and dipole moment surfaces. The potential energy surface is refined by fitting to experimental energies. The line list covers the range up to 7000 cm-1(1.43 μm) with all ro-vibrational transitions (50 billion) with the lower state below 5000 cm-1included and thus should be applicable for temperatures up to 700 K. A technique for computing molecular opacities from vibrational band intensities is proposed and used to provide temperature dependent cross sections of ethylene for shorter wavelength and higher temperatures. When combined with realistic band profiles (such as the proposed three-band model), the vibrational intensity technique offers a cheap but reasonably accurate alternative to the full ro-vibrational calculations at high temperatures and should be reliable for representing molecular opacities. The C2H4 line list, which is called MaYTY, is rmade available in electronic form from the CDS (http://cdsarc.u-strasbg.fr) and ExoMol (www.exomol.com) databases.

  10. TRPV1 Antagonism by Capsazepine Modulates Innate Immune Response in Mice Infected with Plasmodium berghei ANKA

    Directory of Open Access Journals (Sweden)

    Elizabeth S. Fernandes

    2014-01-01

    Full Text Available Thousands of people suffer from severe malaria every year. The innate immune response plays a determinant role in host’s defence to malaria. Transient receptor potential vanilloid 1 (TRPV1 modulates macrophage-mediated responses in sepsis, but its role in other pathogenic diseases has never been addressed. We investigated the effects of capsazepine, a TRPV1 antagonist, in malaria. C57BL/6 mice received 105 red blood cells infected with Plasmodium berghei ANKA intraperitoneally. Noninfected mice were used as controls. Capsazepine or vehicle was given intraperitoneally for 6 days. Mice were culled on day 7 after infection and blood and spleen cell phenotype and activation were evaluated. Capsazepine decreased circulating but not spleen F4/80+Ly6G+ cell numbers as well as activation of both F4/80+and F4/80+Ly6G+ cells in infected animals. In addition, capsazepine increased circulating but not spleen GR1+ and natural killer (NK population, without interfering with natural killer T (NKT cell numbers and blood NK and NKT activation. However, capsazepine diminished CD69 expression in spleen NKT but not NK cells. Infection increased lipid peroxidation and the release of TNFα and IFNγ, although capsazepine-treated group exhibited lower levels of lipid peroxidation and TNFα. Capsazepine treatment did not affect parasitaemia. Overall, TRPV1 antagonism modulates the innate immune response to malaria.

  11. Glucocorticoid Antagonism Reduces Insulin Resistance and Associated Lipid Abnormalities in High-Fructose-Fed Mice.

    Science.gov (United States)

    Priyadarshini, Emayavaramban; Anuradha, Carani Venkatraman

    2017-02-01

    High intake of dietary fructose causes perturbation in lipid metabolism and provokes lipid-induced insulin resistance. A rise in glucocorticoids (GCs) has recently been suggested to be involved in fructose-induced insulin resistance. The objective of the study was to investigate the effect of GC blockade on lipid abnormalities in insulin-resistant mice. Insulin resistance was induced in mice by administering a high-fructose diet (HFrD) for 60 days. Mifepristone (RU486), a GC antagonist, was administered to HFrD-fed mice for the last 18 days, and the intracellular and extracellular GC levels, the glucocorticoid receptor (GR) activation and the expression of GC-regulated genes involved in lipid metabolism were examined. HFrD elevated the intracellular GC content in both liver and adipose tissue and enhanced the GR nuclear translocation. The plasma GC level remained unchanged. The levels of free fatty acids and triglycerides in plasma were elevated, accompanied by increased plasma insulin and glucose levels and decreased hepatic glycogen content. Treatment with RU486 reduced plasma lipid levels, tissue GC levels and the expression of GC-targeted genes involved in lipid accumulation, and it improved insulin sensitivity. This study demonstrated that HFrD-induced lipid accumulation and insulin resistance are mediated by enhanced GC in liver and adipose tissue and that GC antagonism might reduce fructose-induced lipid abnormalities and insulin resistance. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  12. Endocannabinoid antagonism: blocking the excess in the treatment of high-risk abdominal obesity.

    Science.gov (United States)

    Duffy, Danielle; Rader, Daniel

    2007-02-01

    Abdominal obesity is a prevalent, worldwide problem linked to cardiometabolic comorbidities and an increased risk of coronary heart disease. First-line therapy to reduce such risk revolves around diet and exercise; however, such changes are often difficult to implement and unsuccessful. Understanding the underlying pathophysiology of underlying metabolic derangements could provide new targets for pharmacologic therapy. One system that has gained recent attention is the endocannabinoid system. The endocannabinoid system has a significant role in central appetite control and peripheral lipogenesis and is up-regulated in diet-induced obesity. Rimonabant is a selective cannabinoid-1 receptor antagonist and is the first compound of its type to test the hypothesis that down-regulating an overactive endocannabinoid system could have therapeutic benefit not only for weight loss but also for the atherogenic dyslipidemia and insulin resistance that cluster with abdominal obesity in particular. Animal models have been critical for elucidating the role of the endocannabinoid system in obesity and in demonstrating that antagonism with rimonabant can induce loss of visceral fat and improve insulin sensitivity. Early human trials with rimonabant have confirmed significant reductions in weight, as well as favorable changes in atherogenic dyslipidemia, insulin resistance, and markers of inflammation. Interestingly, some of these beneficial metabolic effects are partially weight-loss-independent, confirming the importance of peripheral endocannabinoid system effects in addition to central effects.

  13. Calcitonin gene-related peptide antagonism and cluster headache

    DEFF Research Database (Denmark)

    Ashina, Håkan; Newman, Lawrence; Ashina, Sait

    2017-01-01

    Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact...... role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials.gov . The search term used was "cluster headache and calcitonin gene related peptide......" and "primary headaches and calcitonin gene related peptide." Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play...

  14. Extinction antagonizes olfactory memory at the subcellular level.

    Science.gov (United States)

    Schwaerzel, Martin; Heisenberg, Martin; Zars, Troy

    2002-08-29

    Memory loss occurs by diverse mechanisms, as different time constants of performance decrement and sensitivities to experimental manipulations suggest. While the phenomena of memory decay, interference, and extinction are well established behaviorally, little is known about them at the circuit or molecular level. In Drosophila, odorant memories lasting up to 3 hr can be localized to mushroom body Kenyon cells, a single neuronal level in the olfactory pathway. The plasticity underlying this memory trace can be induced without Kenyon cell synaptic output. Experimental extinction, i.e., presentation of the conditioned stimulus without the reinforcer, reduces memory performance and does so at the same circuit level as memory formation. Thus, unreinforced presentation of learned odorants antagonizes intracellularly the signaling cascade underlying memory formation.

  15. Revisiting 26Al-26Mg systematics of plagioclase in H4 chondrites

    Science.gov (United States)

    Telus, M.; Huss, G. R.; Nagashima, K.; Ogliore, R. C.

    2014-06-01

    Zinner and Göpel found clear evidence for the former presence of 26Al in the H4 chondrites Ste. Marguerite and Forest Vale. They assumed that the 26Al-26Mg systematics of these chondrites date "metamorphic cooling of the H4 parent body." Plagioclase in these chondrites can have very high Al/Mg ratios and low Mg concentrations, making these ion probe analyses susceptible to ratio bias, which is inversely proportional to the number of counts of the denominator isotope (Ogliore et al.). Zinner and Göpel used the mean of the ratios to calculate the isotope ratios, which exacerbates this problem. We analyzed the Al/Mg ratios and Mg isotopic compositions of plagioclase grains in thin sections of Ste. Marguerite, Forest Vale, Beaver Creek, and Sena to evaluate the possible influence of ratio bias on the published initial 26Al/27Al ratios for these meteorites. We calculated the isotope ratios using total counts, a less biased method of calculating isotope ratios. The results from our analyses are consistent with those from Zinner and Göpel, indicating that ratio bias does not significantly affect 26Al-26Mg results for plagioclase in these chondrites. Ste. Marguerite has a clear isochron with an initial 26Al/27Al ratio indicating that it cooled to below 450 °C 5.2 ± 0.2 Myr after CAIs. The isochrons for Forest Vale and Beaver Creek also show clear evidence that 26Al was alive when they cooled, but the initial 26Al/27Al ratios are not well constrained. Sena does not show evidence that 26Al was alive when it cooled to below the Al-Mg closure temperature. Given that metallographic cooling rates for Ste. Marguerite, Forest Vale, and Beaver Creek are atypical (>5000 °C/Myr at 500 °C) compared with most H4s, including Sena, which have cooling rates of 10-50 °C/Myr at 500 °C (Scott et al.), we conclude that the Al-Mg systematics for Ste. Marguerite, Forest Vale, and Beaver Creek are the result of impact excavation of these chondrites and cooling at the surface of the

  16. Confined NaAlH4 nanoparticles inside CeO2 hollow nanotubes towards enhanced hydrogen storage.

    Science.gov (United States)

    Gao, Qili; Xia, Guanglin; Yu, Xuebin

    2017-10-05

    NaAlH 4 has been widely regarded as a potential hydrogen storage material due to its favorable thermodynamics and high energy density. The high activation energy barrier and high dehydrogenation temperature, however, significantly hinder its practical application. In this paper, CeO 2 hollow nanotubes (HNTs) prepared by a simple electrospinning technique are adopted as functional scaffolds to support NaAlH 4 nanoparticles (NPs) towards advanced hydrogen storage performance. The nanoconfined NaAlH 4 inside CeO 2 HNTs, synthesized via the infiltration of molten NaAlH 4 into the CeO 2 HNTs under high hydrogen pressure, exhibited significantly improved dehydrogenation properties compared with both bulk and ball-milled CeO 2 HNTs-catalyzed NaAlH 4 . The onset dehydrogenation temperature of the NaAlH 4 @CeO 2 composite was reduced to below 100 °C, with only one main dehydrogenation peak appearing at 130 °C, which is 120 °C and 50 °C lower than for its bulk counterpart and for the ball-milled CeO 2 HNTs-catalyzed NaAlH 4 , respectively. Moreover, ∼5.09 wt% hydrogen could be released within 30 min at 180 °C, while only 1.6 wt% hydrogen was desorbed from the ball-milled NaAlH 4 under the same conditions. This significant improvement is mainly attributed to the synergistic effects contributed by the CeO 2 HNTs, which could act as not only a structural scaffold to fabricate and confine the NaAlH 4 NPs, but also as an effective catalyst to enhance the hydrogen storage performance of NaAlH 4 .

  17. Improved hydrogen storage properties of LiAlH4 by mechanical milling with TiF3

    International Nuclear Information System (INIS)

    Zang, Lei; Cai, Jiaxing; Zhao, Lipeng; Gao, Wenhong; Liu, Jian; Wang, Yijing

    2015-01-01

    Dehydrogenation behavior of LiAlH 4 (lithium alanate) admixed with TiF 3 is investigated by pressure-composition-temperature (PCT), fourier transform infrared spectroscopy (FTIR), X-ray Diffraction (XRD), differential scanning calorimetry (DSC) and temperature programmed desorption (TPD). The TiF 3 addition enhances kinetics of LiAlH 4 and decreases the decomposition temperature. The LiAlH 4 -2 mol % TiF 3 sample starts to release hydrogen at about 35 °C and the dehydrogenation rate reaches a maximum value at 108.4 °C, compared with 145 °C and 179.9 °C for the as-received LiAlH 4 . As for the dehydrogenation kinetics, the LiAlH 4 -2 mol % TiF 3 sample releases about 7.0 wt % H 2 at 140 °C within 80 min. In comparison, the as-received LiAlH 4 sample releases only 0.8 wt % hydrogen under the same conditions. The existence of proposed catalyst, Al 3 Ti formed in-situ in the process of dehydrogenation, has been confirmed experimentally by XRD measurements. The activation energy of LiAlH 4 -2 mol % TiF 3 composite is deduced to be 66.76 kJ mol −1 and 88.21 kJ mol −1 for the first and second reaction stages of LiAlH 4 dehydrogenation. - Highlights: • TiF 3 considerably enhances the dehydrogenation kinetics of LiAlH 4 . • TiF 3 -doped LiAlH 4 dehydrogenates even at room temperature. • Low activation energy of the dehydrogenation reaction. • Al 3 Ti formed in-situ helps to explain the dehydrogenation mechanism

  18. Muon-flux measurements for SHiP at H4

    CERN Document Server

    van Herwijnen, E

    2017-01-01

    A major concern for the design of the SHiP experiment is the lack of a precise knowledge of the muon flux. This is a proposal to measure the expected muon flux in the SHiP experiment by installing a replica of the SHiP target in a 400 GeV/c proton beam at H4. We intend building a spectrometer using the drift tube prototypes that were constructed for OPERA. A muon tagger will be built using RPCs, which will also serve as a module-0 for SHiP. We propose to do this measurement in early 2018. Accumulating $\\sim 10^{11}$ 400 GeV/c POT will enable us to make a more realistic design of the muon shield. With some modifications, this setup can also be used to measure the charm cross section (including the cascade production). We intend to test this setup after the measurement of the muon flux.

  19. Theoretical analysis of factors controlling the nonalternating CO/C(2)H(4) copolymerization.

    Science.gov (United States)

    Haras, Alicja; Michalak, Artur; Rieger, Bernhard; Ziegler, Tom

    2005-06-22

    A [P-O]Pd catalyst based on o-alkoxy derivatives of diphenylphosphinobenzene sulfonic acid (I) has recently been shown by Drent et al. to perform nonalternating CO/C(2)H(4) copolymerization with subsequent incorporation of ethylene units into the polyketone chain. The origin of the nonalternation is investigated in a theoretical study of I, where calculated activation barriers and reaction heats of all involved elementary steps are used to generate a complete kinetic model. The kinetic model is able to account for the observed productivity and degree of nonalternation as a function of temperature. Consistent with the energy changes obtained for the real catalyst model, the selectivity toward a nonalternating distribution of both comonomers appears to be mainly a result of a strong destabilization of the Pd-acyl complex.

  20. Apparent violation of isospin symmetry in the 3H(3He,2H)4He reaction

    International Nuclear Information System (INIS)

    Rai, G.; Blyth, C.O.; England, J.B.A.; Farooq, A.; Karban, O.; Rawas, E.; Roman, S.; Vlastou, R.

    1988-01-01

    Angular distributions of the vector analyzing powers for the 3 H( 3 He, 2 H) 4 He reaction have been measured over the incident energy range 18--33 MeV. The measurements centered about 18 MeV display a deviation from the antisymmetric shape expected from isospin symmetry. Concentrating on the explanation of the 90 0 analyzing powers, we report the results of a distorted-wave Born approximation (DWBA) analysis which includes the direct and exchange processes and the spin-orbit potential. It is shown that the anomalous behavior of the 90 0 vector analyzing powers can be largely explained by the effect of a single F-wave potential resonance which leads to the magnification of the short-range differences between the 3 He and 3 H wave functions

  1. Spatial Positioning of RET and H4 Following Radiation Exposure Leads to Tumor Development

    Directory of Open Access Journals (Sweden)

    Yuri E. Nikiforov

    2001-01-01

    Full Text Available Exposure to ionizing radiation is a well-known risk factor for a number of human cancers, including leukemia, thyroid cancer, soft tissue sarcomas, and many others. Although it has been known for a long time that radiation exposure to the cell results in extensive DNA damage, including double strand DNA breaks, the exact mechanisms of radiation-induced carcinogenesis remain unknown. Recently, a large increase in incidence of thyroid cancer was observed in children exposed to radiation after the Chernobyl nuclear accident [1]. A high prevalence of chromosomal rearrangements involving the RET gene was found among these radiation-induced thyroid tumors [2,3]. As a result of such rearrangement, a portion of the RET gene is fused with another gene, typically with the H4 or ELE1. However, since the DNA targets of ionizing radiation are randomly distributed throughout the cell nucleus, the reason for predilection for the RET rearrangements in thyroid cells was unclear.

  2. Spread of avian pathogenic Escherichia coli ST117 O78:H4 in Nordic broiler production

    DEFF Research Database (Denmark)

    Ronco, Troels; Stegger, Marc; Olsen, Rikke Heidemann

    2017-01-01

    Escherichia coli infections known as colibacillosis constitute a considerable challenge to poultry farmers worldwide, in terms of decreased animal welfare and production economy. Colibacillosis is caused by avian pathogenic E. coli (APEC). APEC strains are extraintestinal pathogenic E. coli...... of isolates were collected from poultry with colibacillosis on Nordic farms. Subsequently, comparative genomic analyses were carried out. This included in silico typing (sero- and multi-locus sequence typing), identification of virulence and resistance genes and phylogenetic analyses based on single...... diseased broilers and breeders. The data indicate that the closely related ST117 O78:H4 strains have been transferred vertically through the broiler breeding pyramid into distantly located farms across the Nordic countries....

  3. A combined crossed molecular beams and theoretical study of the reaction CN + C2H4

    Science.gov (United States)

    Balucani, Nadia; Leonori, Francesca; Petrucci, Raffaele; Wang, Xingan; Casavecchia, Piergiorgio; Skouteris, Dimitrios; Albernaz, Alessandra F.; Gargano, Ricardo

    2015-03-01

    The CN + C2H4 reaction has been investigated experimentally, in crossed molecular beam (CMB) experiments at the collision energy of 33.4 kJ/mol, and theoretically, by electronic structure calculations of the relevant potential energy surface and Rice-Ramsperger-Kassel-Marcus (RRKM) estimates of the product branching ratio. Differently from previous CMB experiments at lower collision energies, but similarly to a high energy study, we have some indication that a second reaction channel is open at this collision energy, the characteristics of which are consistent with the channel leading to CH2CHNC + H. The RRKM estimates using M06L electronic structure calculations qualitatively support the experimental observation of C2H3NC formation at this and at the higher collision energy of 42.7 kJ/mol of previous experiments.

  4. Life-finding detector development at NASA GSFC using a custom H4RG test bed

    Science.gov (United States)

    Mosby, Gregory; Rauscher, Bernard; Kutyrev, Alexander

    2018-01-01

    Chemical species associated with life, called biosignatures, should be visible in exoplanet atmospheres with larger space telescopes. These signals will be faint and require very low noise (~e-) detectors to robustly measure. At NASA Goddard we are developing a single detector H4RG test bed to characterize and identify potential technology developments needed for the next generation's large space telescopes. The vacuum and cryogenic test bed will include near infrared light sources from integrating spheres using a motorized shutter. The detector control and readout will be handled by a Leach controller. Detector cables have been manufactured and test planning has begun. Planned tests include testing minimum read noise capabilities, persistence mitigation strategies using long wavelength light, and measuring intrapixel variation which might affect science goals of future missions. In addition to providing a means to identify areas of improvement in detector technology, we hope to use this test bed to probe some fundamental physics of these infrared arrays.

  5. Teledyne H1RG, H2RG, and H4RG Noise Generator

    Science.gov (United States)

    Rauscher, Bernard J.

    2015-01-01

    This paper describes the near-infrared detector system noise generator (NG) that we wrote for the James Webb Space Telescope (JWST) Near Infrared Spectrograph (NIRSpec). NG simulates many important noise components including; (1) white "read noise", (2) residual bias drifts, (3) pink 1/f noise, (4) alternating column noise, and (5) picture frame noise. By adjusting the input parameters, NG can simulate noise for Teledyne's H1RG, H2RG, and H4RG detectors with and without Teledyne's SIDECAR ASIC IR array controller. NG can be used as a starting point for simulating astronomical scenes by adding dark current, scattered light, and astronomical sources into the results from NG. NG is written in Python-3.4.

  6. Muon Beam Studies in the H4 beam line and the Gamma Irradiation Facility (GIF++)

    CERN Document Server

    Margraf, Rachel; CERN. Geneva. ATS Department

    2018-01-01

    In this note, we present detailed simulation results for the trajectory of a muon beam, traversing beam zones PPE-134 and PPE-154, produced by a 150 GeV positive hadron beam incident on collimators 9 & 10 in the H4 beam line when these collimators are placed off-beam axis to stop all hadrons and electrons. Using G4Beamline, a GEANT-4 based Monte-Carlo program, the trajectory of the muon beam has been studied for several field strengths of the GOLIATH magnet, as well as for different polarities. The position of the beam at the Gamma Irradiation Facility (GIF++), located downstream the PPE-144 area, is also presented. In addition, two configurations of the two XTDV’s present in the line (XTDV.022.520 and XTDV.022.610) have been studied, with the purpose to simulate the pion contamination of the beam both in PPE134 and GIF++.

  7. Growth Processes of Particles up to Nanometer in High-Frequency SiH4 Plasmas

    International Nuclear Information System (INIS)

    Watanabe, Y.; Shiratani, M.; Fukuzawa, T.; Koga, K.

    2000-01-01

    Growth processes of particles in high-frequency SiH 4 discharges have been understood fairly well in a size range above 10 nm. Recently, we have developed two in situ particle detection methods to study those of particles (clusters) in a size range below ∼ 10 nm. The studies have clarified time evolution of their density and size and revealed the following facts: the cluster density amounts to ∼ 10 11 cm -3 under the device quality low-power and low-pressure conditions: the discharge modulation, substrate heating and H 2 dilution are quite effective in suppressing the cluster growth. We have proposed the cluster growth model explaining reasonably the obtained results. (author)

  8. Microbial sulfate reduction and metal attenuation in pH 4 acid mine water

    Directory of Open Access Journals (Sweden)

    Alpers Charles N

    2007-10-01

    Full Text Available Abstract Sediments recovered from the flooded mine workings of the Penn Mine, a Cu-Zn mine abandoned since the early 1960s, were cultured for anaerobic bacteria over a range of pH (4.0 to 7.5. The molecular biology of sediments and cultures was studied to determine whether sulfate-reducing bacteria (SRB were active in moderately acidic conditions present in the underground mine workings. Here we document multiple, independent analyses and show evidence that sulfate reduction and associated metal attenuation are occurring in the pH-4 mine environment. Water-chemistry analyses of the mine water reveal: (1 preferential complexation and precipitation by H2S of Cu and Cd, relative to Zn; (2 stable isotope ratios of 34S/32S and 18O/16O in dissolved SO4 that are 2–3 ‰ heavier in the mine water, relative to those in surface waters; (3 reduction/oxidation conditions and dissolved gas concentrations consistent with conditions to support anaerobic processes such as sulfate reduction. Scanning electron microscope (SEM analyses of sediment show 1.5-micrometer, spherical ZnS precipitates. Phospholipid fatty acid (PLFA and denaturing gradient gel electrophoresis (DGGE analyses of Penn Mine sediment show a high biomass level with a moderately diverse community structure composed primarily of iron- and sulfate-reducing bacteria. Cultures of sediment from the mine produced dissolved sulfide at pH values near 7 and near 4, forming precipitates of either iron sulfide or elemental sulfur. DGGE coupled with sequence and phylogenetic analysis of 16S rDNA gene segments showed populations of Desulfosporosinus and Desulfitobacterium in Penn Mine sediment and laboratory cultures.

  9. Microbial sulfate reduction and metal attenuation in pH 4 acid mine water

    Science.gov (United States)

    Church, C.D.; Wilkin, R.T.; Alpers, Charles N.; Rye, R.O.; Blaine, R.B.

    2007-01-01

    Sediments recovered from the flooded mine workings of the Penn Mine, a Cu-Zn mine abandoned since the early 1960s, were cultured for anaerobic bacteria over a range of pH (4.0 to 7.5). The molecular biology of sediments and cultures was studied to determine whether sulfate-reducing bacteria (SRB) were active in moderately acidic conditions present in the underground mine workings. Here we document multiple, independent analyses and show evidence that sulfate reduction and associated metal attenuation are occurring in the pH-4 mine environment. Water-chemistry analyses of the mine water reveal: (1) preferential complexation and precipitation by H2S of Cu and Cd, relative to Zn; (2) stable isotope ratios of 34S/32S and 18O/16O in dissolved SO4 that are 2-3 ??? heavier in the mine water, relative to those in surface waters; (3) reduction/oxidation conditions and dissolved gas concentrations consistent with conditions to support anaerobic processes such as sulfate reduction. Scanning electron microscope (SEM) analyses of sediment show 1.5-micrometer, spherical ZnS precipitates. Phospholipid fatty acid (PLFA) and denaturing gradient gel electrophoresis (DGGE) analyses of Penn Mine sediment show a high biomass level with a moderately diverse community structure composed primarily of iron- and sulfate-reducing bacteria. Cultures of sediment from the mine produced dissolved sulfide at pH values near 7 and near 4, forming precipitates of either iron sulfide or elemental sulfur. DGGE coupled with sequence and phylogenetic analysis of 16S rDNA gene segments showed populations of Desulfosporosinus and Desulfitobacterium in Penn Mine sediment and laboratory cultures. ?? 2007 Church et al; licensee BioMed Central Ltd.

  10. PP32 and SET/TAF-Iβ proteins regulate the acetylation of newly synthesized histone H4.

    Science.gov (United States)

    Saavedra, Francisco; Rivera, Carlos; Rivas, Elizabeth; Merino, Paola; Garrido, Daniel; Hernández, Sergio; Forné, Ignasi; Vassias, Isabelle; Gurard-Levin, Zachary A; Alfaro, Iván E; Imhof, Axel; Almouzni, Geneviève; Loyola, Alejandra

    2017-11-16

    Newly synthesized histones H3 and H4 undergo a cascade of maturation steps to achieve proper folding and to establish post-translational modifications prior to chromatin deposition. Acetylation of H4 on lysines 5 and 12 by the HAT1 acetyltransferase is observed late in the histone maturation cascade. A key question is to understand how to establish and regulate the distinct timing of sequential modifications and their biological significance. Here, we perform proteomic analysis of the newly synthesized histone H4 complex at the earliest time point in the cascade. In addition to known binding partners Hsp90 and Hsp70, we also identify for the first time two subunits of the histone acetyltransferase inhibitor complex (INHAT): PP32 and SET/TAF-Iβ. We show that both proteins function to prevent HAT1-mediated H4 acetylation in vitro. When PP32 and SET/TAF-Iβ protein levels are down-regulated in vivo, we detect hyperacetylation on lysines 5 and 12 and other H4 lysine residues. Notably, aberrantly acetylated H4 is less stable and this reduces the interaction with Hsp90. As a consequence, PP32 and SET/TAF-Iβ depleted cells show an S-phase arrest. Our data demonstrate a novel function of PP32 and SET/TAF-Iβ and provide new insight into the mechanisms regulating acetylation of newly synthesized histone H4. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  11. The evolution of reduced antagonism--A role for host-parasite coevolution.

    Science.gov (United States)

    Gibson, A K; Stoy, K S; Gelarden, I A; Penley, M J; Lively, C M; Morran, L T

    2015-11-01

    Why do some host-parasite interactions become less antagonistic over evolutionary time? Vertical transmission can select for reduced antagonism. Vertical transmission also promotes coevolution between hosts and parasites. Therefore, we hypothesized that coevolution itself may underlie transitions to reduced antagonism. To test the coevolution hypothesis, we selected for reduced antagonism between the host Caenorhabditis elegans and its parasite Serratia marcescens. This parasite is horizontally transmitted, which allowed us to study coevolution independently of vertical transmission. After 20 generations, we observed a response to selection when coevolution was possible: reduced antagonism evolved in the copassaged treatment. Reduced antagonism, however, did not evolve when hosts or parasites were independently selected without coevolution. In addition, we found strong local adaptation for reduced antagonism between replicate host/parasite lines in the copassaged treatment. Taken together, these results strongly suggest that coevolution was critical to the rapid evolution of reduced antagonism. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

  12. 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...

  13. Cooperation, Trust, and Antagonism: How Public Goods Are Promoted.

    Science.gov (United States)

    Parks, Craig D; Joireman, Jeff; Van Lange, Paul A M

    2013-12-01

    One of the most continually vexing problems in society is the variability with which citizens support endeavors that are designed to help a great number of people. In this article, we examine the twin roles of cooperative and antagonistic behavior in this variability. We find that each plays an important role, though their contributions are, understandably, at odds. It is this opposition that produces seeming unpredictability in citizen response to collective need. In fact, we suggest that careful consideration of the research allows one to often predict when efforts to provide a collectively beneficial good will succeed and when they will fail. To understand the dynamics of participation in response to collective need, it is necessary to distinguish between the primary types of need situations. A public good is an entity that relies in whole or in part on contributions to be provided. Examples of public goods are charities and public broadcasting. Public goods require that citizens experience a short-term loss (of their contribution) in order to realize a long-term gain (of the good). However, because everyone can use the good once it is provided, there is also an incentive to not contribute, let others give, and then take advantage of their efforts. This state of affairs introduces a conflict between doing what is best for oneself and what is best for the group. In a public goods situation, cooperation and antagonism impact how one resolves this conflict. The other major type of need situation is a common-pool resource problem. Here, a good is fully provided at the outset, and citizens may sample from it. The resource is usually, but not necessarily, partially replenished. Examples of replenished resources are drinking water and trees; examples of resources that are functionally not replenished are oil and minerals. Common-pool resources allow citizens to experience a short-term gain (by getting what they want in the early life of the resource) but also present

  14. H2 dilution effect in the Cat-CVD processes of the SiH4/NH3 system

    International Nuclear Information System (INIS)

    Ansari, S.G.; Umemoto, Hironobu; Morimoto, Takashi; Yoneyama, Koji; Izumi, Akira; Masuda, Atsushi; Matsumura, Hideki

    2006-01-01

    Gas-phase diagnostics in the catalytic chemical vapor deposition processes of the SiH 4 /NH 3 /H 2 system were carried out to examine the effect of H 2 dilution. The decomposition efficiency of NH 3 showed a sharp decrease with the introduction of a small amount of SiH 4 , but this decrease was recovered by the addition of H 2 when the NH 3 pressure was low. On the other hand, at higher NH 3 pressures, the decomposition efficiency showed a minor dependence on the H 2 partial pressure. The addition of SiH 4 to the NH 3 system decreases the H-atom density by one order of magnitude, but this decrease is also recovered by H 2 addition. H atoms produced from H 2 must re-activate the catalyzer surfaces poisoned by SiH 4 when the NH 3 pressure is low

  15. Histone H4 hyperacetylation and rapid turnover of its acetyl groups in transcriptionally inactive rooster testis spermatids.

    Science.gov (United States)

    Oliva, R; Mezquita, C

    1982-01-01

    In order to study the relationship between acetylation of histones, chromatin structure and gene activity, the distribution and turnover of acetyl groups among nucleosomal core histones and the extent of histone H4 acetylation were examined in rooster testis cell nuclei at different stages of spermatogenesis. Histone H4 was the predominant acetylated histone in mature testes. Hyperacetylation of H4 and rapid turnover of its acetyl groups are not univocally correlated with transcriptional activity since they were detected in both genetically active testicular cells and genetically inactive elongated spermatids. During the transition from nucleohistone to nucleoprotamine in elongated spermatids the chromatin undergoes dramatic structural changes with exposition of binding sites on DNA (1). Hyperacetylation of H4 and rapid turnover of its acetyl groups could be correlated with the particular conformation of chromatin in elongated spermatids and might represent a necessary condition for binding of chromosomal proteins to DNA. Images PMID:7162988

  16. Functional relevance of G-protein-coupled-receptor-associated proteins, exemplified by receptor-activity-modifying proteins (RAMPs).

    Science.gov (United States)

    Fischer, J A; Muff, R; Born, W

    2002-08-01

    The calcitonin (CT) receptor (CTR) and the CTR-like receptor (CRLR) are close relatives within the type II family of G-protein-coupled receptors, demonstrating sequence identity of 50%. Unlike the interaction between CT and CTR, receptors for the related hormones and neuropeptides amylin, CT-gene-related peptide (CGRP) and adrenomedullin (AM) require one of three accessory receptor-activity-modifying proteins (RAMPs) for ligand recognition. An amylin/CGRP receptor is revealed when CTR is co-expressed with RAMP1. When complexed with RAMP3, CTR interacts with amylin alone. CRLR, initially classed as an orphan receptor, is a CGRP receptor when co-expressed with RAMP1. The same receptor is specific for AM in the presence of RAMP2. Together with human RAMP3, CRLR defines an AM receptor, and with mouse RAMP3 it is a low-affinity CGRP/AM receptor. CTR-RAMP1, antagonized preferentially by salmon CT-(8-32) and not by CGRP-(8-37), and CRLR-RAMP1, antagonized by CGRP-(8-37), are two CGRP receptor isotypes. Thus amylin and CGRP interact specifically with heterodimeric complexes between CTR and RAMP1 or RAMP3, and CGRP and AM interact with complexes between CRLR and RAMP1, RAMP2 or RAMP3.

  17. A new epigenetic marker: The replication-coupled, cell cycle-dependent, dual modification of the histone H4 tail

    Czech Academy of Sciences Publication Activity Database

    Fidlerová, Helena; Kalinová, Jana; Blechová, Miroslava; Velek, Jiří; Raška, Ivan

    2009-01-01

    Roč. 167, č. 1 (2009), s. 76-82 ISSN 1047-8477 R&D Projects: GA ČR(CZ) GA304/06/1691 Grant - others:GA MŠk(CZ) LC535 Program:LC Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z40550506 Keywords : epigenetics * H4K16 * H4K20 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.673, year: 2009

  18. Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106

    Energy Technology Data Exchange (ETDEWEB)

    Su, Dan; Hu, Qi; Li, Qing; Thompson, James R; Cui, Gaofeng; Fazly, Ahmed; Davies, Brian A; Botuyan, Maria Victoria; Zhang, Zhiguo; Mer, Georges [Mayo

    2013-04-08

    Dynamic variations in the structure of chromatin influence virtually all DNA-related processes in eukaryotes and are controlled in part by post-translational modifications of histones. One such modification, the acetylation of lysine 56 (H3K56ac) in the amino-terminal α-helix (αN) of histone H3, has been implicated in the regulation of nucleosome assembly during DNA replication and repair, and nucleosome disassembly during gene transcription. In Saccharomyces cerevisiae, the histone chaperone Rtt106 contributes to the deposition of newly synthesized H3K56ac-carrying H3-H4 complex on replicating DNA, but it is unclear how Rtt106 binds H3-H4 and specifically recognizes H3K56ac as there is no apparent acetylated lysine reader domain in Rtt106. Here, we show that two domains of Rtt106 are involved in a combinatorial recognition of H3-H4. An N-terminal domain homodimerizes and interacts with H3-H4 independently of acetylation while a double pleckstrin-homology (PH) domain binds the K56-containing region of H3. Affinity is markedly enhanced upon acetylation of K56, an effect that is probably due to increased conformational entropy of the αN helix of H3. Our data support a mode of interaction where the N-terminal homodimeric domain of Rtt106 intercalates between the two H3-H4 components of the (H3-H4)2 tetramer while two double PH domains in the Rtt106 dimer interact with each of the two H3K56ac sites in (H3-H4)2. We show that the Rtt106-(H3-H4)2 interaction is important for gene silencing and the DNA damage response.

  19. [The EHEC O104:H4 outbreak in Germany 2011 - lessons learned?!].

    Science.gov (United States)

    Rissland, J; Kielstein, J T; Stark, K; Wichmann-Schauer, H; Stümpel, F; Pulz, M

    2013-04-01

    The EHEC O104:H4 outbreak 2011 in Germany provided numerous insights into the recognition and control of such epidemic situations. Food-borne outbreaks and their related dynamics may lead to a critical burden of disease and an eventual capacity overload of the medical care system. Possible difficulties in the microbiological diagnostics of new or significantly altered infectious agents may result in a delayed detection of the outbreak as well as the launching of interventional measures. Besides an early notification of the local public health office by the affected institutions, in which a complete electronic procedure and additional sentinel or surveillance instruments (e. g., in emergency departments of hospitals) may be of great help, an interdisciplinary cooperation of the local public health and food safety agencies is the key to an effective outbreak control. Corresponding organizations on the state and federal level should support the investigation process by microbiological diagnostics and advanced epidemiological analysis as well as examination of the food chains. Finally, successful crisis communication relies on "speaking with one voice" (not necessarily one person). Immediate, transparent, appropriate and honest information of the general public concerning the reasons, consequences and (counter-) measures of a crisis are the best means to keep the trust of the population and to counteract the otherwise inevitable speculations. © Georg Thieme Verlag KG Stuttgart · New York.

  20. Hybrid Simulation of Duty Cycle Influences on Pulse Modulated RF SiH4/Ar Discharge

    Science.gov (United States)

    Wang, Xifeng; Song, Yuanhong; Zhao, Shuxia; Dai, Zhongling; Wang, Younian

    2016-04-01

    A one-dimensional fluid/Monte-Carlo (MC) hybrid model is developed to describe capacitively coupled SiH4/Ar discharge, in which the lower electrode is applied by a RF source and pulse modulated by a square-wave, to investigate the modulation effects of the pulse duty cycle on the discharge mechanism. An electron Monte Carlo simulation is used to calculate the electron energy distribution as a function of position and time phase. Rate coefficients in chemical reactions can then be obtained and transferred to the fluid model for the calculation of electron temperature and densities of different species, such as electrons, ions, and radicals. The simulation results show that, the electron energy distribution f(ɛ) is modulated evidently within a pulse cycle, with its tail extending to higher energies during the power-on period, while shrinking back promptly in the afterglow period. Thus, the rate coefficients could be controlled during the discharge, resulting in modulation of the species composition on the substrate compared with continuous excitation. Meanwhile, more negative ions, like SiH-3 and SiH-2, may escape to the electrodes owing to the collapse of ambipolar electric fields, which is beneficial to films deposition. Pulse modulation is thus expected to provide additional methods to customize the plasma densities and components. supported by National Natural Science Foundation of China (No. 11275038)

  1. Pro-apoptotic effects of the flavonoid luteolin in rat H4IIE cells

    International Nuclear Information System (INIS)

    Michels, G.; Waetjen, W.; Niering, P.; Steffan, B.; Thi, Q.-H. Tran; Chovolou, Y.; Kampkoetter, A.; Bast, A.; Proksch, P.; Kahl, R.

    2005-01-01

    Polyphenols are ubiquitous substances in the diet. Their anti-oxidative, anti-inflammatory and anti-viral effects are of interest for human health, and polyphenols such as luteolin are used at high concentrations in food supplements. The aim of this project was to determine the intrinsic effects of luteolin in H4IIE rat hepatoma cells. Luteolin is relatively toxic, cell death was caused via induction of apoptosis as detected by DNA-ladder formation, by nuclear fragmentation and activation of apoptotic enzymes (caspase-2, -3/7, -9 and -8/10). Luteolin (250 μM, 24 h) increased the caspase-3/7 activity four-fold and the caspase-9 activity six-fold. In a time course experiment caspase-9 is activated after 6 h, while caspase-2 and -3/7 are activated after 12 h. After 24 h, caspase-8/10 also displays activation. We found a concentration-dependent increase in malondialdehyde release suggesting a prooxidative effect of luteolin. Furthermore, we analysed DNA strand break formation by luteolin and found a distinct increase of DNA strand breaks after incubation for 3 h with 100 μM luteolin, a concentration which induces oligonucleosomal DNA cleavage at 24 h. In conclusion, the sequence of events is compatible with the assumption that luteolin triggers the mitochondrial pathway of apoptosis, probably by inducing DNA damage

  2. Genomic epidemiology of the Escherichia coli O104:H4 outbreaks in Europe, 2011

    DEFF Research Database (Denmark)

    Grad, Yonatan H; Lipsitch, Marc; Feldgarden, Michael

    2012-01-01

    The degree to which molecular epidemiology reveals information about the sources and transmission patterns of an outbreak depends on the resolution of the technology used and the samples studied. Isolates of Escherichia coli O104:H4 from the outbreak centered in Germany in May-July 2011, and the ...... that purged diversity in the German isolates, variation in mutation rates in the two E. coli outbreak populations, or uneven distribution of diversity in the seed populations that led to each outbreak....... remarkably little diversity, with only two single nucleotide polymorphisms (SNPs) found in isolates from four individuals. Surprisingly, we found much greater diversity (19 SNPs) in isolates from seven individuals infected in the French outbreak. The German isolates form a clade within the more diverse...... French outbreak strains. Moreover, five isolates derived from a single infected individual from the French outbreak had extremely limited diversity. The striking difference in diversity between the German and French outbreak samples is consistent with several hypotheses, including a bottleneck...

  3. Gas-phase nitrosation of ethylene and related events in the C2H4NO+ landscape.

    Science.gov (United States)

    Gerbaux, Pascal; Dechamps, Noemie; Flammang, Robert; Nam, Pham Cam; Nguyen, Minh Tho; Djazi, Fayçal; Berruyer, Florence; Bouchoux, Guy

    2008-06-19

    The C2H4NO(+) system has been examined by means of quantum chemical calculations using the G2 and G3B3 approaches and tandem mass spectrometry experiments. Theoretical investigation of the C2H4NO(+) potential-energy surface includes 19 stable C2H4NO(+) structures and a large set of their possible interconnections. These computations provide insights for the understanding of the (i) addition of the nitrosonium cation NO(+) to the ethylene molecule, (ii) skeletal rearrangements evidenced in previous experimental studies on comparable systems, and (iii) experimental identification of new C2H4NO(+) structures. It is predicted from computation that gas-phase nitrosation of ethylene may produce C2H4(*)NO(+) adducts, the most stable structure of which is a pi-complex, 1, stabilized by ca. 65 kJ/mol with respect to its separated components. This complex was produced in the gas phase by a transnitrosation process involving as reactant a complex between water and NO(+) (H2O.NO(+)) and the ethylene molecule and fully characterized by collisional experiments. Among the other C 2H 4NO (+) structures predicted by theory to be protected against dissociation or isomerization by significant energy barriers, five were also experimentally identified. These finding include structures CH3CHNO(+) (5), CH 3CNOH (+) ( 8), CH3NHCO(+) (18), CH3NCOH(+) (19), and an ion/neutral complex CH2O...HCNH(+) (12).

  4. H4 replication-dependent diacetylation and Hat1 promote S-phase chromatin assembly in vivo

    Science.gov (United States)

    Ejlassi-Lassallette, Aïda; Mocquard, Eloïse; Arnaud, Marie-Claire; Thiriet, Christophe

    2011-01-01

    While specific posttranslational modification patterns within the H3 and H4 tail domains are associated with the S-phase, their actual functions in replication-dependent chromatin assembly have not yet been defined. Here we used incorporation of trace amounts of recombinant proteins into naturally synchronous macroplasmodia of Physarum polycephalum to examine the function of H3 and H4 tail domains in replication-coupled chromatin assembly. We found that the H3/H4 complex lacking the H4 tail domain was not efficiently recovered in nuclei, whereas depletion of the H3 tail domain did not impede nuclear import but chromatin assembly failed. Furthermore, our results revealed that the proper pattern of acetylation on the H4 tail domain is required for nuclear import and chromatin assembly. This is most likely due to binding of Hat1, as coimmunoprecipitation experiments showed Hat1 associated with predeposition histones in the cytoplasm and with replicating chromatin. These results suggest that the type B histone acetyltransferase assists in shuttling the H3/H4 complex from cytoplasm to the replication forks. PMID:21118997

  5. Kefiran antagonizes cytopathic effects of Bacillus cereus extracellular factors.

    Science.gov (United States)

    Medrano, Micaela; Pérez, Pablo Fernando; Abraham, Analía Graciela

    2008-02-29

    Kefiran, the polysaccharide produced by microorganisms present in kefir grains, is a water-soluble branched glucogalactan containing equal amounts of D-glucose and D-galactose. In this study, the effect of kefiran on the biological activity of Bacillus cereus strain B10502 extracellular factors was assessed by using cultured human enterocytes (Caco-2 cells) and human erythrocytes. In the presence of kefiran concentrations ranging from 300 to 1000 mg/L, the ability of B. cereus B10502 spent culture supernatants to detach and damage cultured human enterocytes was significantly abrogated. In addition, mitochondrial dehydrogenase activity was higher when kefiran was present during the cell toxicity assays. Protection was also demonstrated in hemolysis and apoptosis/necrosis assays. Scanning electron microscopy showed the protective effect of kefiran against structural cell damages produced by factors synthesized by B. cereus strain B10502. Protective effect of kefiran depended on strain of B. cereus. Our findings demonstrate the ability of kefiran to antagonize key events of B. cereus B10502 virulence. This property, although strain-specific, gives new perspectives for the role of bacterial exopolysaccharides in functional foods.

  6. Heterodimerization of Msx and Dlx homeoproteins results in functional antagonism.

    Science.gov (United States)

    Zhang, H; Hu, G; Wang, H; Sciavolino, P; Iler, N; Shen, M M; Abate-Shen, C

    1997-05-01

    Protein-protein interactions are known to be essential for specifying the transcriptional activities of homeoproteins. Here we show that representative members of the Msx and Dlx homeoprotein families form homo- and heterodimeric complexes. We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. In particular, we show that Msx and Dlx proteins interact independently and noncooperatively with homeodomain DNA binding sites and that dimerization is specifically blocked by the presence of such DNA sites. We further demonstrate that the transcriptional properties of Msx and Dlx proteins display reciprocal inhibition. Specifically, Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. Finally, we show that the expression patterns of representative Msx and Dlx genes (Msx1, Msx2, Dlx2, and Dlx5) overlap in mouse embryogenesis during limb bud and craniofacial development, consistent with the potential for their protein products to interact in vivo. Based on these observations, we propose that functional antagonism through heterodimer formation provides a mechanism for regulating the transcriptional actions of Msx and Dlx homeoproteins in vivo.

  7. Requirements within the Ebola Viral Glycoprotein for Tetherin Antagonism

    Directory of Open Access Journals (Sweden)

    Nathan H. Vande Burgt

    2015-10-01

    Full Text Available Tetherin is an interferon-induced, intrinsic cellular response factor that blocks release of numerous viruses, including Ebola virus, from infected cells. As with many viruses targeted by host factors, Ebola virus employs a tetherin antagonist, the viral glycoprotein (EboGP, to counteract restriction and promote virus release. Unlike other tetherin antagonists such as HIV-1 Vpu or KSHV K5, the features within EboGP needed to overcome tetherin are not well characterized. Here, we describe sequences within the EboGP ectodomain and membrane spanning domain (msd as necessary to relieve tetherin restriction of viral particle budding. Fusing the EboGP msd to a normally secreted form of the glycoprotein effectively promotes Ebola virus particle release. Cellular protein or lipid anchors could not substitute for the EboGP msd. The requirement for the EboGP msd was not specific for filovirus budding, as similar results were seen with HIV particles. Furthermore trafficking of chimeric proteins to budding sites did not correlate with an ability to counter tetherin. Additionally, we find that a glycoprotein construct, which mimics the cathepsin-activated species by proteolytic removal of the EboGP glycan cap and mucin domains, is unable to counteract tetherin. Combining these results suggests an important role for the EboGP glycan cap and msd in tetherin antagonism.

  8. Antagonism of rice phylloplane fungi against Cercospora oryzae

    Science.gov (United States)

    Mardani, A.; Hadiwiyono

    2018-03-01

    Narrow brown leaf spot (NBLS) caused by Cercospora oryzae Miyake is one of the important obstacle in rice cultivation that can decrease the productivity up to 40%. It has been known well that some phylloplane fungi are antagonistic to some leaf diseases. Phylloplane fungi of rice however haven’t been studied much and poorly understood as biological control agent of rice pathogen such C. oryzae. The research aimed to study the antagonism of some phylloplane fungi of rice against C. oryzae. At least 14 isolates of phylloplane fungi were collected which consisted of six pathogenic and eight nonpathogenic variants. All of nonpathogenic isolates were antagonistic against C. oryzae both in vitro and only one isolate could not inhibit the infection of the pathogen in vivo. Some isolates were identified as Aspergillus, Mucor, Penicillium, Fusarium, and Trichoderma. The isolate of Mucor and Fusarium could inhibit the highest growth of pathogen on potato dextrose medium that were at 36.0% and 35.5% respectively. Whereas on artificial inoculation on rice, some isolates such Penicillium and Fusarium could inhibit most effectively and were significantly different to Mencozeb application with dosage 5g L-1.

  9. Caffeine antagonism of alcohol-induced driving impairment.

    Science.gov (United States)

    Liguori, A; Robinson, J H

    2001-07-01

    The extent to which caffeine antagonizes alcohol-induced impairment of simulated automobile driving at the current lowest legal American limit (0.08% BrAC) was the focus of this study. Fifteen adults swallowed a capsule (0, 200, or 400 mg caffeine) then drank a beverage (0.0 or 0.6 g/kg ethanol) in a within-subject, double-blind, randomized procedure. Forty-five minutes later, participants completed a test battery of subjective effects scales, dynamic posturography, critical flicker fusion (CFF), choice reaction time (CRT), divided attention (Stroop test), and simulated driving. Alcohol alone increased ratings of 'dizzy', 'drug effect', and 'high', slowed CRT and brake latency, and increased body sway. Caffeine alone increased ratings of 'alert' and 'jittery', but did not significantly affect body sway or psychomotor performance. Both caffeine doses comparably counteracted alcohol impairment of brake latency but not CRT or body sway. Brake latency with either alcohol-caffeine combination remained significantly longer than that with placebo. Stroop and CFF performance were unaffected by any drug condition. The results suggest that caffeine may increase alertness and improve reaction time after alcohol use but will not completely counteract alcohol impairment in a driver.

  10. Notch pathway signaling in the skin antagonizes Merkel cell development.

    Science.gov (United States)

    Logan, Gregory J; Wright, Margaret C; Kubicki, Adam C; Maricich, Stephen M

    2018-02-15

    Merkel cells are mechanosensitive skin cells derived from the epidermal lineage whose development requires expression of the basic helix-loop-helix transcription factor Atoh1. The genes and pathways involved in regulating Merkel cell development during embryogenesis are poorly understood. Notch pathway signaling antagonizes Atoh1 expression in many developing body regions, so we hypothesized that Notch signaling might inhibit Merkel cell development. We found that conditional, constitutive overexpression of the Notch intracellular domain (NICD) in mouse epidermis significantly decreased Merkel cell numbers in whisker follicles and touch domes of hairy skin. Conversely, conditional deletion of the obligate NICD binding partner RBPj in the epidermis significantly increased Merkel cell numbers in whisker follicles, led to the development of ectopic Merkel cells outside of touch domes in hairy skin epidermis, and altered the distribution of Merkel cells in touch domes. Deletion of the downstream Notch effector gene Hes1 also significantly increased Merkel cell numbers in whisker follicles. Together, these data demonstrate that Notch signaling regulates Merkel cell production and patterning. Copyright © 2018 Elsevier Inc. All rights reserved.

  11. [The value of B7-H4 and carcinoembryonic antigen in diagnosing the benign and malignant pleural effusion].

    Science.gov (United States)

    Wei, F; Wei, Y; Li, L F; Li, G L; Wang, G J

    2017-07-23

    Objective: To evaluate the value of combined detection of negative costimulatory molecule B7-H4 and carcinoembryonic antigen (CEA) in diagnosing malignant and benign pleural effusion. Methods: Ninety-seven pleural effusion specimen were collected, 55 of which were diagnosed as malignant pleural effusion and 42 were benign pleural effusion. Enzyme-linked immunosorbent assay(ELISA) was used to examine the concentration of B7-H4 and CEA in pleural effusion. Electro-chemiluminescence immunoassay was used to detect the CEA level in pleural effusion. Receiver operating characteristic (ROC) curve was established to analyze and evaluate the single or combined detection of B7-H4 and CEA in diagnosing malignant and benign pleural effusion. Results: The concentrations of B7-H4 and CEA in malignant pleural effusion (MPE) group were (60.08±35.04) ng/ml and (41.49±37.16) ng/ml, respectively, obviously higher than (27.26±9.55) ng/ml and (2.41±0.94) ng/ml of benign pleural effusion (BPE) group (both P 37.25 ng/ml or CEA>4.18 ng/ml, the sensitivity of diagnosis as MPE was down-regulated to 90.9% and the specificity was elevated to 88.1%. When B7-H4 >37.25 ng/ml and CEA>4.18 ng/ml, the sensitivity of diagnosis as MPE was down-regulated to 78.2% and the specificity was elevated to 97.6%. The sensitivity and specificity of combined detection of B7-H4 and CEA to diagnose MPE were elevated to 90.9% and 97.6%, respectively. The level of B7-H4 in MPE and BPE were both positively correlated with CEA ( r =0.670, P =0.001 in MPE and r =0.002, P =0.001 in BEP). Conclusions: B7-H4 is a potential tumor marker in diagnosing the benign and malignant pleural effusion. Although the diagnostic value of B7-H4 may not precede to CEA, the combined detection of B7-H4 and CEA can improve the diagnostic sensitivity and specificity of MPE.

  12. Increased NMDA receptor inhibition at an increased Sevoflurane MAC

    Directory of Open Access Journals (Sweden)

    Brosnan Robert J

    2012-06-01

    Full Text Available Abstract Background Sevoflurane potently enhances glycine receptor currents and more modestly decreases NMDA receptor currents, each of which may contribute to immobility. This modest NMDA receptor antagonism by sevoflurane at a minimum alveolar concentration (MAC could be reciprocally related to large potentiation of other inhibitory ion channels. If so, then reduced glycine receptor potency should increase NMDA receptor antagonism by sevoflurane at MAC. Methods Indwelling lumbar subarachnoid catheters were surgically placed in 14 anesthetized rats. Rats were anesthetized with sevoflurane the next day, and a pre-infusion sevoflurane MAC was measured in duplicate using a tail clamp method. Artificial CSF (aCSF containing either 0 or 4 mg/mL strychnine was then infused intrathecally at 4 μL/min, and the post-infusion baseline sevoflurane MAC was measured. Finally, aCSF containing strychnine (either 0 or 4 mg/mL plus 0.4 mg/mL dizocilpine (MK-801 was administered intrathecally at 4 μL/min, and the post-dizocilpine sevoflurane MAC was measured. Results Pre-infusion sevoflurane MAC was 2.26%. Intrathecal aCSF alone did not affect MAC, but intrathecal strychnine significantly increased sevoflurane requirement. Addition of dizocilpine significantly decreased MAC in all rats, but this decrease was two times larger in rats without intrathecal strychnine compared to rats with intrathecal strychnine, a statistically significant (P  Conclusions Glycine receptor antagonism increases NMDA receptor antagonism by sevoflurane at MAC. The magnitude of anesthetic effects on a given ion channel may therefore depend on the magnitude of its effects on other receptors that modulate neuronal excitability.

  13. Numerical modeling of soot formation in a turbulent C2H4/air diffusion flame

    Directory of Open Access Journals (Sweden)

    Manedhar Reddy Busupally

    2016-06-01

    Full Text Available Soot formation in a lifted C2H4-Air turbulent diffusion flame is studied using two different paths for soot nucleation and oxidation; by a 2D axisymmetric RANS simulation using ANSYS FLUENT 15.0. The turbulence-chemistry interactions are modeled using two different approaches: steady laminar flamelet approach and flamelet-generated manifold. Chemical mechanism is represented by POLIMI to study the effect of species concentration on soot formation. P1 approximation is employed to approximate the radiative transfer equation into truncated series expansion in spherical harmonics while the weighted sum of gray gases is invoked to model the absorption coefficient while the soot model accounts for nucleation, coagulation, surface growth, and oxidation. The first route for nucleation considers acetylene concentration as a linear function of soot nucleation rate, whereas the second route considers two and three ring aromatic species as function of nucleation rate. Equilibrium-based and instantaneous approach has been used to estimate the OH concentration for soot oxidation. Lee and Fenimore-Jones soot oxidation models are studied to shed light on the effect of OH on soot oxidation. Moreover, the soot-radiation interactions are also included in terms of absorption coefficient of soot. Furthermore, the soot-turbulence interactions have been invoked using a temperature/mixture fraction-based single variable PDF. Both the turbulence-chemistry interaction models are able to accurately predict the flame liftoff height, and for accurate prediction of flame length, radiative heat loss should be accounted in an accurate way. The soot-turbulence interactions are found sensitive to the PDF used in present study.

  14. THE NATURE OF EXTREMELY RED H - [4.5] > 4 GALAXIES REVEALED WITH SEDS AND CANDELS

    Energy Technology Data Exchange (ETDEWEB)

    Caputi, K. I.; Dunlop, J. S.; McLure, R. J.; Cirasuolo, M. [SUPA, Institute for Astronomy, The University of Edinburgh, Royal Observatory, Edinburgh EH9 3HJ (United Kingdom); Huang, J.-S.; Fazio, G. G.; Ashby, M. L. N. [Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States); Castellano, M.; Fontana, A. [INAF-Osservatorio Astronomico di Roma, Via Frascati 33, I-00040 Monteporzio (Italy); Almaini, O. [School of Physics and Astronomy, University of Nottingham, University Park, Nottingham NG7 2RD (United Kingdom); Bell, E. F. [Department of Astronomy, University of Michigan, 500 Church Street, Ann Arbor, MI 48109 (United States); Dickinson, M. [National Optical Astronomy Observatory, 950 North Cherry Avenue, Tucson, AZ 85719 (United States); Donley, J. L.; Ferguson, H. C.; Grogin, N. A.; Koekemoer, A. M. [Space Telescope Science Institute, 3700 San Martin Drive, Baltimore, MD 21218 (United States); Faber, S. M.; Kocevski, D. D.; Koo, D. C. [University of California Observatories/Lick Observatory, University of California, Santa Cruz, CA 95064 (United States); Giavalisco, M., E-mail: karina@astro.rug.nl [Department of Astronomy, University of Massachusetts, Amherst, MA 01003 (United States); and others

    2012-05-01

    We have analyzed a sample of 25 extremely red H - [4.5] > 4 galaxies, selected using 4.5 {mu}m data from the Spitzer SEDS survey and deep H-band data from the Hubble Space Telescope CANDELS survey, over {approx}180 arcmin{sup 2} of the UKIDSS Ultra-Deep Survey field. Our aim is to investigate the nature of this rare population of mid-infrared (mid-IR) sources that display such extreme near-to-mid-IR colors. Using up to 17-band photometry (U through 8.0 {mu}m), we have studied in detail their spectral energy distributions, including possible degeneracies in the photometric redshift/internal extinction (z{sub phot}-A{sub V} ) plane. Our sample appears to include sources of very different nature. Between 45% and 75% of them are dust-obscured, massive galaxies at 3 < z{sub phot} < 5. All of the 24 {mu}m detected sources in our sample are in this category. Two of these have S(24 {mu}m)>300 {mu}Jy, which at 3 < z{sub phot} < 5 suggests that they probably host a dust-obscured active galactic nucleus. Our sample also contains four highly obscured (A{sub V} > 5) sources at z{sub phot} < 1. Finally, we analyze in detail two z{sub phot} {approx} 6 galaxy candidates, and discuss their plausibility and implications. Overall, our red galaxy sample contains the tip of the iceberg of a larger population of z > 3 galaxies to be discovered with the future James Webb Space Telescope.

  15. Dwarfism and insulin resistance in male offspring caused by α1-adrenergic antagonism during pregnancy.

    Science.gov (United States)

    Oelkrug, Rebecca; Herrmann, Beate; Geissler, Cathleen; Harder, Lisbeth; Koch, Christiane; Lehnert, Hendrik; Oster, Henrik; Kirchner, Henriette; Mittag, Jens

    2017-10-01

    Maternal and environmental factors control the epigenetic fetal programming of the embryo, thereby defining the susceptibility for metabolic or endocrine disorders in the offspring. Pharmacological interventions required as a consequence of gestational problems, e.g. hypertension, can potentially interfere with correct fetal programming. As epigenetic alterations are usually only revealed later in life and not detected in studies focusing on early perinatal outcomes, little is known about the long-term epigenetic effects of gestational drug treatments. We sought to test the consequences of maternal α1-adrenergic antagonism during pregnancy, which can occur e.g. during hypertension treatment, for the endocrine and metabolic phenotype of the offspring. We treated C57BL/6NCrl female mice with the α1-adrenergic antagonist prazosin during pregnancy and analyzed the male and female offspring for endocrine and metabolic abnormalities. Our data revealed that maternal α1-adrenergic blockade caused dwarfism, elevated body temperature, and insulin resistance in male offspring, accompanied by reduced IGF-1 serum concentrations as the result of reduced hepatic growth hormone receptor (Ghr) expression. We subsequently identified increased CpG DNA methylation at the transcriptional start site of the alternative Ghr promotor caused by the maternal treatment, which showed a strong inverse correlation to hepatic Ghr expression. Our results demonstrate that maternal α1-adrenergic blockade can constitute an epigenetic cause for dwarfism and insulin resistance. The findings are of immediate clinical relevance as combined α/β-adrenergic blockers are first-line treatment of maternal hypertension. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

  16. The Netrin-related domain of Sfrp1 interacts with Wnt ligands and antagonizes their activity in the anterior neural plate

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    Esteve Pilar

    2008-08-01

    Full Text Available Abstract Background Secreted frizzled related proteins (SFRPs are multifunctional modulators of Wnt and BMP (Bone Morphogenetic Protein signalling necessary for the development of most organs and the homeostasis of different adult tissues. SFRPs fold in two independent domains: the cysteine rich domain (SfrpCRD related to the extracellular portion of Frizzled (Fz, Wnt receptors and the Netrin module (SfrpNTR defined by homologies with molecules such as Netrin-1, inhibitors of metalloproteinases and complement proteins. Due to its structural relationship with Fz, it is believed that SfrpCRD interferes with Wnt signalling by binding and sequestering the ligand. In contrast, the functional relevance of the SfrpNTR has been barely addressed. Results Here, we combine biochemical studies, mutational analysis and functional assays in cell culture and medaka-fish embryos to show that the Sfrp1NTR mimics the function of the entire molecule, binds to Wnt8 and antagonizes Wnt canonical signalling. This activity requires intact tertiary structure and is shared by the distantly related Netrin-1NTR. In contrast, the Sfrp1CRD cannot mirror the function of the entire molecule in vivo but interacts with Fz receptors and antagonizes Wnt8-mediated β-catenin transcriptional activity. Conclusion On the basis of these results, we propose that SFRP modulation of Wnt signalling may involve multiple and differential interactions among Wnt, Fz and SFRPs.

  17. A family of photoswitchable NMDA receptors

    Science.gov (United States)

    Berlin, Shai; Szobota, Stephanie; Reiner, Andreas; Carroll, Elizabeth C; Kienzler, Michael A; Guyon, Alice; Xiao, Tong; Trauner, Dirk; Isacoff, Ehud Y

    2016-01-01

    NMDA receptors, which regulate synaptic strength and are implicated in learning and memory, consist of several subtypes with distinct subunit compositions and functional properties. To enable spatiotemporally defined, rapid and reproducible manipulation of function of specific subtypes, we engineered a set of photoswitchable GluN subunits ('LiGluNs'). Photo-agonism of GluN2A or GluN2B elicits an excitatory drive to hippocampal neurons that can be shaped in time to mimic synaptic activation. Photo-agonism of GluN2A at single dendritic spines evokes spine-specific calcium elevation and expansion, the morphological correlate of LTP. Photo-antagonism of GluN2A alone, or in combination with photo-antagonism of GluN1a, reversibly blocks excitatory synaptic currents, prevents the induction of long-term potentiation and prevents spine expansion. In addition, photo-antagonism in vivo disrupts synaptic pruning of developing retino-tectal projections in larval zebrafish. By providing precise and rapidly reversible optical control of NMDA receptor subtypes, LiGluNs should help unravel the contribution of specific NMDA receptors to synaptic transmission, integration and plasticity. DOI: http://dx.doi.org/10.7554/eLife.12040.001 PMID:26929991

  18. Impact of histone H4 lysine 20 methylation on 53BP1 responses to chromosomal double strand breaks.

    Directory of Open Access Journals (Sweden)

    Andrea J Hartlerode

    Full Text Available Recruitment of 53BP1 to chromatin flanking double strand breaks (DSBs requires γH2AX/MDC1/RNF8-dependent ubiquitination of chromatin and interaction of 53BP1 with histone H4 methylated on lysine 20 (H4K20me. Several histone methyltransferases have been implicated in 53BP1 recruitment, but their quantitative contributions to the 53BP1 response are unclear. We have developed a multi-photon laser (MPL system to target DSBs to subfemtoliter nuclear volumes and used this to mathematically model DSB response kinetics of MDC1 and of 53BP1. In contrast to MDC1, which revealed first order kinetics, the 53BP1 MPL-DSB response is best fitted by a Gompertz growth function. The 53BP1 MPL response shows the expected dependency on MDC1 and RNF8. We determined the impact of altered H4K20 methylation on 53BP1 MPL response kinetics in mouse embryonic fibroblasts (MEFs lacking key H4K20 histone methyltransferases. This revealed no major requirement for the known H4K20 dimethylases Suv4-20h1 and Suv4-20h2 in 53BP1 recruitment or DSB repair function, but a key role for the H4K20 monomethylase, PR-SET7. The histone methyltransferase MMSET/WHSC1 has recently been implicated in 53BP1 DSB recruitment. We found that WHSC1 homozygous mutant MEFs reveal an alteration in balance of H4K20 methylation patterns; however, 53BP1 DSB responses in these cells appear normal.

  19. On-site SiH4 generator using hydrogen plasma generated in slit-type narrow gap

    Science.gov (United States)

    Takei, Norihisa; Shinoda, Fumiya; Kakiuchi, Hiroaki; Yasutake, Kiyoshi; Ohmi, Hiromasa

    2018-06-01

    We have been developing an on-site silane (SiH4) generator based on use of the chemical etching reaction between solid silicon (Si) and the high-density H atoms that are generated in high-pressure H2 plasma. In this study, we have developed a slit-type plasma source for high-efficiency SiH4 generation. High-density H2 plasma was generated in a narrow slit-type discharge gap using a 2.45 GHz microwave power supply. The plasma’s optical emission intensity distribution along the slit was measured and the resulting distribution was reflected by both the electric power distribution and the hydrogen gas flow. Because the Si etching rate strongly affects the SiH4 generation rate, the Si etching behavior was investigated with respect to variations in the experimental parameters. The weight etch rate increased monotonically with increasing input microwave power. However, the weight etch rate decreased with increasing H2 pressure and an increasing plasma gap. This reduction in the etch rate appears to be related to shrinkage of the plasma generation area because increased input power is required to maintain a constant plasma area with increasing H2 pressure and the increasing plasma gap. Additionally, the weight etch rate also increases with increasing H2 flow rate. The SiH4 generation rate of the slit-type plasma source was also evaluated using gas-phase Fourier transform infrared absorption spectroscopy and the material utilization efficiencies of both Si and the H2 gas for SiH4 gas formation were discussed. The main etch product was determined to be SiH4 and the developed plasma source achieved a SiH4 generation rate of 10 sccm (standard cubic centimeters per minute) at an input power of 900 W. In addition, the Si utilization efficiency exceeded 60%.

  20. Development of mechanical hypersensitivity in rats during heroin and ethanol dependence: alleviation by CRF₁ receptor antagonism.

    Science.gov (United States)

    Edwards, Scott; Vendruscolo, Leandro F; Schlosburg, Joel E; Misra, Kaushik K; Wee, Sunmee; Park, Paula E; Schulteis, Gery; Koob, George F

    2012-02-01

    Animal models of drug dependence have described both reductions in brain reward processes and potentiation of stress-like (or anti-reward) mechanisms, including a recruitment of corticotropin-releasing factor (CRF) signaling. Accordingly, chronic exposure to opiates often leads to the development of mechanical hypersensitivity. We measured paw withdrawal thresholds (PWTs) in male Wistar rats allowed limited (short access group: ShA) or extended (long access group: LgA) access to heroin or cocaine self-administration, or in rats made dependent on ethanol via ethanol vapor exposure (ethanol-dependent group). In heroin self-administering animals, after transition to LgA conditions, thresholds were reduced to around 50% of levels observed at baseline, and were also significantly lower than thresholds measured in animals remaining on the ShA schedule. In contrast, thresholds in animals self-administering cocaine under either ShA (1 h) or LgA (6 h) conditions were unaltered. Similar to heroin LgA rats, ethanol-dependent rats also developed mechanical hypersensitivity after eight weeks of ethanol vapor exposure compared to non-dependent animals. Systemic administration of the CRF1R antagonist MPZP significantly alleviated the hypersensitivity observed in rats dependent on heroin or ethanol. The emergence of mechanical hypersensitivity with heroin and ethanol dependence may thus represent one critical drug-associated negative emotional state driving dependence on these substances. These results also suggest a recruitment of CRF-regulated nociceptive pathways associated with escalation of intake and dependence. A greater understanding of relationships between chronic drug exposure and pain-related states may provide insight into mechanisms underlying the transition to drug addiction, as well as reveal new treatment opportunities. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. IL-1 receptor antagonism and muscle gene expression in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Berchtold, L. A.; Larsen, C. M.; Vaag, A.

    2009-01-01

    ). To investigate the effects of IL-1Ra in insulin-sensitive tissue, gene expression levels in skeletal muscle from type 2 diabetic patients treated with IL-1Ra were analysed. Methods. Gene expression profiles in vastus lateralis muscle biopsies from five obese patients (BMI>27) were determined before and after 13......RT-PCR, were significantly altered when comparing the number of transcripts before and after treatment for each individual. Conclusion. Treatment with IL-1Ra did not significantly affect gene expression levels in skeletal muscle in this limited and selected sample of obese patients with type 2 diabetes. Larger...

  2. SPINAL ANTINOCICEPTION BY MORPHINE IN RATS IS ANTAGONIZED BY GALANIN RECEPTOR ANTAGONISTS

    NARCIS (Netherlands)

    REIMANN, W; ENGLBERGER, W; FRIDERICHS, E; SELVE, N; WILFFERT, B

    1994-01-01

    Galanin, a 29 amino acid peptide, has been reported to possess antinociceptive properties at the spinal site and to potentiate opioid-induced antinociception. Our aim was to investigate whether also endogenous galanin interacts with an exogenously administered opioid, morphine, in the rat spinal

  3. Loss of Nat4 and its associated histone H4 N-terminal acetylation mediates calorie restriction-induced longevity.

    Science.gov (United States)

    Molina-Serrano, Diego; Schiza, Vassia; Demosthenous, Christis; Stavrou, Emmanouil; Oppelt, Jan; Kyriakou, Dimitris; Liu, Wei; Zisser, Gertrude; Bergler, Helmut; Dang, Weiwei; Kirmizis, Antonis

    2016-12-01

    Changes in histone modifications are an attractive model through which environmental signals, such as diet, could be integrated in the cell for regulating its lifespan. However, evidence linking dietary interventions with specific alterations in histone modifications that subsequently affect lifespan remains elusive. We show here that deletion of histone N-alpha-terminal acetyltransferase Nat4 and loss of its associated H4 N-terminal acetylation (N-acH4) extend yeast replicative lifespan. Notably, nat4Δ-induced longevity is epistatic to the effects of calorie restriction (CR). Consistent with this, (i) Nat4 expression is downregulated and the levels of N-acH4 within chromatin are reduced upon CR, (ii) constitutive expression of Nat4 and maintenance of N-acH4 levels reduces the extension of lifespan mediated by CR, and (iii) transcriptome analysis indicates that nat4Δ largely mimics the effects of CR, especially in the induction of stress-response genes. We further show that nicotinamidase Pnc1, which is typically upregulated under CR, is required for nat4Δ-mediated longevity. Collectively, these findings establish histone N-acH4 as a regulator of cellular lifespan that links CR to increased stress resistance and longevity. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  4. A modern and versatile data-acquisition package for calorimeter prototypes test-beams H4DAQ

    CERN Document Server

    Marini, Andrea Carlo

    2017-01-01

    The upgrade of the calorimeters for the HL-LHC or for future colliders requires an extensive programme of tests to qualify different detector prototypes with dedicated test beams. A common data-acquisition system (called H4DAQ) was developed for the H4 test beam line at the North Area of the CERN SPS in 2014 and it has since been adopted by an increasing number of teams involved in the CMS experiment and AIDA groups. Several different calorimeter prototypes and precision timing detectors have used H4DAQ from 2014 to 2017, and it has proved to be a versatile application, portable to many other beam test environments (the CERN beam lines EA-T9 at the PS, H2 and H4 at the SPS, and at the INFN Frascati Beam Test Facility).The H4DAQ is fast, simple, modular and can be configured to support different setups. The different functionalities of the DAQ core software are split into three configurable finite state machines the data readout, run control, and event builder. The distribution of information and data betw...

  5. Cloning and Molecular Characterization of the Schistosoma mansoni Genes RbAp48 and Histone H4

    Directory of Open Access Journals (Sweden)

    Patrícia P Souza

    2002-10-01

    Full Text Available The human nuclear protein RbAp48 is a member of the tryptophan/aspartate (WD repeat family, which binds to the retinoblastoma (Rb protein. It also corresponds to the smallest subunit of the chromatin assembly factor and is able to bind to the helix 1 of histone H4, taking it to the DNA in replication. A cDNA homologous to the human gene RbAp48 was isolated from a Schistosoma mansoni adult worm library and named SmRbAp48. The full length sequence of SmRbAp48 cDNA is 1036 bp long, encoding a protein of 308 amino acids. The transcript of SmRbAp48 was detected in egg, cercariae and schistosomulum stages. The protein shows 84% similarity with the human RbAp48, possessing four WD repeats on its C-terminus. A hypothetical tridimensional structure for the SmRbAp48 C-terminal domain was constructed by computational molecular modeling using the b-subunit of the G protein as a model. To further verify a possible interaction between SmRbAp48 and S. mansoni histone H4, the histone H4 gene was amplified from adult worm genomic DNA using degenerated primers. The gene fragment of SmH4 is 294 bp long, encoding a protein of 98 amino acids which is 100% identical to histone H4 from Drosophila melanogaster.

  6. Semiconducting perovskites (2-XC6H4C2H4NH3)2SnI4 (X = F, Cl, Br): steric interaction between the organic and inorganic layers.

    Science.gov (United States)

    Xu, Zhengtao; Mitzi, David B; Dimitrakopoulos, Christos D; Maxcy, Karen R

    2003-03-24

    Two new semiconducting hybrid perovskites based on 2-substituted phenethylammonium cations, (2-XC(6)H(4)C(2)H(4)NH(3))(2)SnI(4) (X = Br, Cl), are characterized and compared with the previously reported X = F compound, with a focus on the steric interaction between the organic and inorganic components. The crystal structure of (2-ClC(6)H(4)C(2)H(4)NH(3))(2)SnI(4) is solved in a disordered subcell [C2/m, a = 33.781(7) A, b = 6.178(1) A, c = 6.190(1) A, beta = 90.42(3)(o), and Z = 2]. The structure is similar to the known (2-FC(6)H(4)C(2)H(4)NH(3))(2)SnI(4) structure with regard to both the conformation of the organic cations and the bonding features of the inorganic sheet. The (2-BrC(6)H(4)C(2)H(4)NH(3))(2)SnI(4) system adopts a fully ordered monoclinic cell [P2(1)/c, a = 18.540(2) A, b = 8.3443(7) A, c = 8.7795(7) A, beta = 93.039(1)(o), and Z = 2]. The organic cation adopts the anti conformation, instead of the gauche conformation observed in the X = F and Cl compounds, apparently because of the need to accommodate the additional volume of the bromo group. The steric effect of the bromo group also impacts the perovskite sheet, causing notable distortions, such as a compressed Sn-I-Sn bond angle (148.7(o), as compared with the average values of 153.3 and 154.8(o) for the fluoro and chloro compounds, respectively). The optical absorption features a substantial blue shift (lowest exciton peak: 557 nm, 2.23 eV) relative to the spectra of the fluoro and chloro compounds (588 and 586 nm, respectively). Also presented are transport properties for thin-film field-effect transistors (TFTs) based on spin-coated films of the two hybrid semiconductors.

  7. Novel anti-HER2 monoclonal antibodies: synergy and antagonism with tumor necrosis factor-α

    Directory of Open Access Journals (Sweden)

    Ceran Ceyhan

    2012-10-01

    Full Text Available Abstract Background One-third of breast cancers display amplifications of the ERBB2 gene encoding the HER2 kinase receptor. Trastuzumab, a humanized antibody directed against an epitope on subdomain IV of the extracellular domain of HER2 is used for therapy of HER2-overexpressing mammary tumors. However, many tumors are either natively resistant or acquire resistance against Trastuzumab. Antibodies directed to different epitopes on the extracellular domain of HER2 are promising candidates for replacement or combinatorial therapy. For example, Pertuzumab that binds to subdomain II of HER2 extracellular domain and inhibits receptor dimerization is under clinical trial. Alternative antibodies directed to novel HER2 epitopes may serve as additional tools for breast cancer therapy. Our aim was to generate novel anti-HER2 monoclonal antibodies inhibiting the growth of breast cancer cells, either alone or in combination with tumor necrosis factor-α (TNF-α. Methods Mice were immunized against SK-BR-3 cells and recombinant HER2 extracellular domain protein to produce monoclonal antibodies. Anti-HER2 antibodies were characterized with breast cancer cell lines using immunofluorescence, flow cytometry, immunoprecipitation, western blot techniques. Antibody epitopes were localized using plasmids encoding recombinant HER2 protein variants. Antibodies, either alone or in combination with TNF-α, were tested for their effects on breast cancer cell proliferation. Results We produced five new anti-HER2 monoclonal antibodies, all directed against conformational epitope or epitopes restricted to the native form of the extracellular domain. When tested alone, some antibodies inhibited modestly but significantly the growth of SK-BR-3, BT-474 and MDA-MB-361 cells displaying ERBB2 amplification. They had no detectable effect on MCF-7 and T47D cells lacking ERBB2 amplification. When tested in combination with TNF-α, antibodies acted synergistically on SK-BR-3 cells

  8. 5-HT4 receptors mediating enhancement of contractility in canine stomach; an in vitro and in vivo study

    NARCIS (Netherlands)

    Prins, NH; van der Grijn, A; Lefebvre, RA; Akkermans, LMA; Schuurkes, JAJ

    1 We aimed to study 5-HT4 receptors in canine stomach contractility both in vivo and in vitro. 2 In anaesthetized Beagle dogs, the selective 5-HT4 receptor agonist prucalopride (i.v.) induced dose-dependent tonic stomach contractions under isobaric conditions, an effect that was antagonized by the

  9. Diagnostic value of soluble B7-H4 and carcinoembryonic antigen in distinguishing malignant from benign pleural effusion.

    Science.gov (United States)

    Jing, Xiaogang; Wei, Fei; Li, Jing; Dai, Lingling; Wang, Xi; Jia, Liuqun; Wang, Huan; An, Lin; Yang, Yuanjian; Zhang, Guojun; Cheng, Zhe

    2018-03-01

    To explore the diagnostic value of joint detection of soluble B7-H4 (sB7-H4) and carcinoembryonic antigen (CEA) in identifying malignant pleural effusion (MPE) from benign pleural effusion (BPE). A total of 97 patients with pleural effusion specimens were enrolled from The First Affiliated Hospital of Zhengzhou University between June 2014 and December 2015. All cases were categorized into malignant pleural effusion group (n = 55) and benign pleural effusion group (n = 42) according to etiologies. Enzyme-linked immunosorbent assay was applied to examine the levels of sB7-H4 in pleural effusion and meanwhile CEA concentrations were detected by electro-chemiluminescence immunoassays. Receiver operating characteristic (ROC) curve was established to assess the diagnostic value of sB7-H4 and CEA in pleural effusion. The correlation between sB7-H4 and CEA levels was analyzed by Pearson's product-moment. The concentrations of sB7-H4 and CEA in MPE exhibited obviously higher than those of BPE ([60.08 ± 35.04] vs. [27.26 ± 9.55] ng/ml, P = .000; [41.49 ± 37.16] vs. [2.41 ± 0.94] ng/ml, P = .000). The AUC area under ROC curve of sB7-H4 and CEA was 0.884 and 0.954, respectively. Two cutoff values by ROC curve analysis of sB7-H4 36.5 ng/ml and CEA 4.18 ng/ml were obtained, with a corresponding sensitivity (81.82%, 87.28%), specificity (90.48%, 95.24%), accuracy (85.57%, 90.72%), positive predictive value (PPV) (91.84%, 96.0%), negative predictive value (NPV) (79.17%, 85.11%), positive likelihood ratio (PLR) (8.614, 18.327), and negative likelihood ratio (NLR) (0.201, 0.134). When sB7-H4 and CEA were combined to detect pleural effusion, it obtained a higher sensitivity 90.91% and specificity 97.62%. Furthermore, correlation analysis result showed that the level of sB7-H4 was correlated with CEA level (r = .770, P = .000). sB7-H4 was a potentially valuable tumor marker in the differentiation between BPE and MPE. The combined detection of sB7-H4 and

  10. Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Brier, Tim J; Mellor, Ian R; Tikhonov, Denis B

    2003-01-01

    Whole-cell recordings and outside-out patch recordings from TE671 cells were made to investigate antagonism of human muscle nicotinic acetylcholine receptors (nAChR) by the philanthotoxins, PhTX-343 and PhTX-(12). When coapplied with acetylcholine (ACh), PhTX-343 caused activation-dependent, nonc......Whole-cell recordings and outside-out patch recordings from TE671 cells were made to investigate antagonism of human muscle nicotinic acetylcholine receptors (nAChR) by the philanthotoxins, PhTX-343 and PhTX-(12). When coapplied with acetylcholine (ACh), PhTX-343 caused activation...

  11. Facile Oxidative Desulfurisation of Benzothiophene Using Polyoxometalate H4[α-SiW12O40]/Zr Catalyst

    Directory of Open Access Journals (Sweden)

    Aldes Lesbani

    2015-07-01

    Full Text Available A highly active catalyst H4[α-SiW12O40]/Zr based polyoxometalete Keggin type was prepared by wet impregnation method and was characterized by FTIR spectroscopy, X-ray diffractometer, surface textural property by SEM, and analysis of porosity by BET method. H4[α-SiW12O40]/Zr was successfully synthesized and showed uniform properties with block solid structure which was applied as heterogeneous stable catalyst for oxidative desulfurization of benzothiophene under simple and mild condition using H2O2 as oxidant. Facile conversion of benzothiophene to sulfone by using heterogeneus                    H4[α-SiW12O40]/Zr catalyst up to 99% was observed to show the active catalytically. Keggin             H4[α-SiW12O40]/Zr cage structure after reaction was different from fresh catalyst which was indicated by the instability of H4[α-SiW12O40]/Zr  under reaction condition. © 2015 BCREC UNDIP. All rights reservedReceived: 9th November 2014; Revised: 31st March 2015; Accepted: 23rd April 2015How to Cite: Lesbani, A., Agnes, A., Saragih, R.O., Verawaty, M., Mohadi, R., Zulkifli, H. (2015.    Facile Oxidative Desulfurisation of Benzothiophen Using Polyoxometalate H4[α-SiW12O40]/Zr Catalyst. Bulletin of Chemical Reaction Engineering & Catalysis, 10 (2, 185-191. (doi:10.9767/bcrec.10.2.7734.185-191 Permalink/DOI: http://dx.doi.org/10.9767/bcrec.10.2.7734.185-191 

  12. Core Histones H2B and H4 Are Mobilized during Infection with Herpes Simplex Virus 1 ▿

    Science.gov (United States)

    Conn, Kristen L.; Hendzel, Michael J.; Schang, Luis M.

    2011-01-01

    The infecting genomes of herpes simplex virus 1 (HSV-1) are assembled into unstable nucleosomes soon after nuclear entry. The source of the histones that bind to these genomes has yet to be addressed. However, infection inhibits histone synthesis. The histones that bind to HSV-1 genomes are therefore most likely those previously bound in cellular chromatin. In order for preexisting cellular histones to associate with HSV-1 genomes, however, they must first disassociate from cellular chromatin. Consistently, we have shown that linker histones are mobilized during HSV-1 infection. Chromatinization of HSV-1 genomes would also require the association of core histones. We therefore evaluated the mobility of the core histones H2B and H4 as measures of the mobilization of H2A-H2B dimers and the more stable H3-H4 core tetramer. H2B and H4 were mobilized during infection. Their mobilization increased the levels of H2B and H4 in the free pools and decreased the rate of H2B fast chromatin exchange. The histones in the free pools would then be available to bind to HSV-1 genomes. The mobilization of H2B occurred independently from HSV-1 protein expression or DNA replication although expression of HSV-1 immediate-early (IE) or early (E) proteins enhanced it. The mobilization of core histones H2B and H4 supports a model in which the histones that associate with HSV-1 genomes are those that were previously bound in cellular chromatin. Moreover, this mobilization is consistent with the assembly of H2A-H2B and H3-H4 dimers into unstable nucleosomes with HSV-1 genomes. PMID:21994445

  13. H4DAQ: a modern and versatile data-acquisition package for calorimeter prototypes test-beams

    Science.gov (United States)

    Marini, A. C.

    2018-02-01

    The upgrade of the particle detectors for the HL-LHC or for future colliders requires an extensive program of tests to qualify different detector prototypes with dedicated test beams. A common data-acquisition system, H4DAQ, was developed for the H4 test beam line at the North Area of the CERN SPS in 2014 and it has since been adopted in various applications for the CMS experiment and AIDA project. Several calorimeter prototypes and precision timing detectors have used our system from 2014 to 2017. H4DAQ has proven to be a versatile application and has been ported to many other beam test environments. H4DAQ is fast, simple, modular and can be configured to support various kinds of setup. The functionalities of the DAQ core software are split into three configurable finite state machines: data readout, run control, and event builder. The distribution of information and data between the various computers is performed using ZEROMQ (0MQ) sockets. Plugins are available to read different types of hardware, including VME crates with many types of boards, PADE boards, custom front-end boards and beam instrumentation devices. The raw data are saved as ROOT files, using the CERN C++ ROOT libraries. A Graphical User Interface, based on the python gtk libraries, is used to operate the H4DAQ and an integrated data quality monitoring (DQM), written in C++, allows for fast processing of the events for quick feedback to the user. As the 0MQ libraries are also available for the National Instruments LabVIEW program, this environment can easily be integrated within H4DAQ applications.

  14. Phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H4 R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis.

    Science.gov (United States)

    Murata, Yoko; Song, Michael; Kikuchi, Hisayuki; Hisamichi, Katsuya; Xu, Xie L; Greenspan, Andrew; Kato, Mai; Chiou, Chiun-Fang; Kato, Takeshi; Guzzo, Cynthia; Thurmond, Robin L; Ohtsuki, Mamitaro; Furue, Masutaka

    2015-02-01

    This trial was conducted to evaluate the safety and efficacy of the H4 R-antagonist JNJ-39758979 in adult Japanese patients with moderate atopic dermatitis (AD). Eligible patients were randomly assigned to JNJ-39758979 300 mg, 100 mg or placebo once daily for 6 weeks in this phase 2a, double-blind, multicenter, placebo-controlled study. Primary efficacy was assessed via week-6 Eczema Area and Severity Index (EASI) scores. Secondary efficacy assessments included Investigator's Global Assessment (IGA) and patient-reported outcome (PRO) pruritus assessments (Pruritus Categorical Response Scale [PCRS], Pruritus Numeric Rating Scales [PNRS], Pruritus Interference Numeric Rating Scale [PINRS] and Subject's Global Impressions of Change in Pruritus [SGICP]). Eighty-eight of 105 planned patients were randomized before the study was stopped and unblinded for safety reasons. The study did not meet the primary end-point. However, numerical improvements (i.e. decreases) in median EASI were observed with JNJ-39758979 100 mg (-3.7) and 300 mg (-3.0) versus placebo (-1.3) at week 6. Nominally significant improvements across PRO PCRS, PNRS and SGICP assessments were consistently observed, particularly with JNJ-39758979 300 mg. Safety, including adverse events (AE), was comparable between JNJ-39758979 and placebo with the exception of two patients (both receiving JNJ-39758979 300 mg) with serious AE of neutropenia, leading to premature study discontinuation. No deaths were reported. Except for neutropenia, no clinically relevant changes in laboratory values were observed. Although not conclusive, findings suggest H4 R-antagonism may be beneficial for AD, particularly in controlling pruritus. JNJ-39758979 appears to be associated with drug-induced agranulocytosis, likely an off-target effect. © 2014 Japanese Dermatological Association.

  15. Facile Oxidative Desulfurisation of Benzothiophene Using Polyoxometalate H4[α-SiW12O40]/Zr Catalyst

    OpenAIRE

    Aldes Lesbani; A. Agnes; Randi O. Saragih; Mariska Verawaty; Risfidian Mohadi; Hilda Zulkifli

    2015-01-01

    A highly active catalyst H4[α-SiW12O40]/Zr based polyoxometalete Keggin type was prepared by wet impregnation method and was characterized by FTIR spectroscopy, X-ray diffractometer, surface textural property by SEM, and analysis of porosity by BET method. H4[α-SiW12O40]/Zr was successfully synthesized and showed uniform properties with block solid structure which was applied as heterogeneous stable catalyst for oxidative desulfurization of benzothiophene under simple and mild condition using...

  16. Characteristics of N-Acylhomoserine Lactones Produced by Hafnia alvei H4 Isolated from Spoiled Instant Sea Cucumber

    Directory of Open Access Journals (Sweden)

    Hong-Man Hou

    2017-04-01

    Full Text Available This study aimed to identify N-acylhomoserine lactone (AHL produced by Hafnia alvei H4, which was isolated from spoiled instant sea cucumber, and to investigate the effect of AHLs on biofilm formation. Two biosensor strains, Chromobacterium violaceum CV026 and Agrobacterium tumefaciens KYC55, were used to detect the quorum sensing (QS activity of H. alvei H4 and to confirm the existence of AHL-mediated QS system. Thin layer chromatography (TLC and high resolution triple quadrupole liquid chromatography/mass spectrometry (LC/MS analysis of the AHLs extracted from the culture supernatant of H. alvei H4 revealed the existence of at least three AHLs: N-hexanoyl-l-homoserine lactone (C6-HSL, N-(3-oxo-octanoyl-l-homoserine lactone (3-oxo-C8-HSL, and N-butyryl-l-homoserine lactone (C4-HSL. This is the first report of the production of C4-HSL by H. alvei. In order to determine the relationship between the production of AHL by H. alvei H4 and bacterial growth, the β-galactosidase assay was employed to monitor AHL activity during a 48-h growth phase. AHLs production reached a maximum level of 134.6 Miller unites at late log phase (after 18 h and then decreased to a stable level of about 100 Miller unites. AHL production and bacterial growth displayed a similar trend, suggesting that growth of H. alvei H4 might be regulated by QS. The effect of AHLs on biofilm formation of H. alvei H4 was investigated by adding exogenous AHLs (C4-HSL, C6-HSL and 3-oxo-C8-HSL to H. alvei H4 culture. Biofilm formation was significantly promoted (p < 0.05 by 5 and 10 µM C6-HSL, inhibited (p < 0.05 by C4-HSL (5 and 10 µM and 5 µM 3-oxo-C8-HSL, suggesting that QS may have a regulatory role in the biofilm formation of H. alvei H4.

  17. Reversible hydrogen storage by NaAlH4 confined within a titanium-functionalized MOF-74(Mg) nanoreactor.

    Science.gov (United States)

    Stavila, Vitalie; Bhakta, Raghunandan K; Alam, Todd M; Majzoub, Eric H; Allendorf, Mark D

    2012-11-27

    We demonstrate that NaAlH(4) confined within the nanopores of a titanium-functionalized metal-organic framework (MOF) template MOF-74(Mg) can reversibly store hydrogen with minimal loss of capacity. Hydride-infiltrated samples were synthesized by melt infiltration, achieving loadings up to 21 wt %. MOF-74(Mg) possesses one-dimensional, 12 Å channels lined with Mg atoms having open coordination sites, which can serve as sites for Ti catalyst stabilization. MOF-74(Mg) is stable under repeated hydrogen desorption and hydride regeneration cycles, allowing it to serve as a "nanoreactor". Confining NaAlH(4) within these pores alters the decomposition pathway by eliminating the stable intermediate Na(3)AlH(6) phase observed during bulk decomposition and proceeding directly to NaH, Al, and H(2), in agreement with theory. The onset of hydrogen desorption for both Ti-doped and undoped nano-NaAlH(4)@MOF-74(Mg) is ∼50 °C, nearly 100 °C lower than bulk NaAlH(4). However, the presence of titanium is not necessary for this increase in desorption kinetics but enables rehydriding to be almost fully reversible. Isothermal kinetic studies indicate that the activation energy for H(2) desorption is reduced from 79.5 kJ mol(-1) in bulk Ti-doped NaAlH(4) to 57.4 kJ mol(-1) for nanoconfined NaAlH(4). The structural properties of nano-NaAlH(4)@MOF-74(Mg) were probed using (23)Na and (27)Al solid-state MAS NMR, which indicates that the hydride is not decomposed during infiltration and that Al is present as tetrahedral AlH(4)(-) anions prior to desorption and as Al metal after desorption. Because of the highly ordered MOF structure and monodisperse pore dimensions, our results allow key template features to be identified to ensure reversible, low-temperature hydrogen storage.

  18. Water exposure assessment of aryl hydrocarbon receptor agonists in Three Gorges Reservoir, China using SPMD-based virtual organisms.

    Science.gov (United States)

    Wang, Jingxian; Bernhöft, Silke; Pfister, Gerd; Schramm, Karl-Werner

    2014-10-15

    SPMD-based virtual organisms (VOs) were deployed at five to eight sites in the Three Gorges Reservoir (TGR), China for five periods in 2008, 2009 and 2011. The water exposure of aryl hydrocarbon receptor (AhR) agonists was assessed by the VOs. The chosen bioassay response for the extracts of the VOs, the induction of 7-ethoxyresorufin-O-deethylase (EROD) was assayed using a rat hepatoma cell line (H4IIE). The results show that the extracts from the VOs could induce AhR activity significantly, whereas the chemically derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQcal) accounted for water level reached a maximum of 175 m. Although the aqueous concentration of AhR agonists of 0.8-4.8 pg TCDDL(-1) in TGR was not alarming, the tendency of accumulating high concentration of AhR agonists in VO lipid and existence of possible synergism or antagonism in the water may exhibit a potential hazard to local biota being exposed to AhR agonists. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Magnetic measurements and neutron diffraction study of the layered hybrid compounds Mn(C8H4O4)(H2O)2 and Mn2(OH)2(C8H4O4)

    International Nuclear Information System (INIS)

    Sibille, Romain; Mesbah, Adel; Mazet, Thomas; Malaman, Bernard; Capelli, Silvia; François, Michel

    2012-01-01

    Mn(C 8 H 4 O 4 )(H 2 O) 2 and Mn 2 (OH) 2 (C 8 H 4 O 4 ) layered organic–inorganic compounds based on manganese(II) and terephthalate molecules (C 8 H 4 O 4 2− ) have been studied by DC and AC magnetic measurements and powder neutron diffraction. The dihydrated compound behaves as a 3D antiferromagnet below 6.5 K. The temperature dependence of its χT product is typical of a 2D Heisenberg system and allows determining the in-plane exchange constant J≈−7.4 K through the carboxylate bridges. The magnetic structure confirms the in-plane nearest neighbor antiferromagnetic interactions and the 3D ordering. The hydroxide based compound also orders as a 3D antiferromagnet with a higher Néel temperature (38.5 K). Its magnetic structure is described from two antiferromagnetically coupled ferromagnetic sublattices, in relation with the two independent metallic sites. The isothermal magnetization data at 2 K are consistent with the antiferromagnetic ground-state of these compounds. However, in both cases, a slope change points to field-induced modification of the magnetic structure. - Graphical abstract: The macroscopic magnetic properties and magnetic structures of two metal-organic frameworks based on manganese (II) and terephthalate molecules are presented. Highlights: ► Magnetic study of Mn(C 8 H 4 O 4 )(H 2 O) 2 and Mn 2 (OH) 2 (C 8 H 4 O 4 ). ► Two compounds with common features (interlayer linker/distance, S=5/2 spin). ► Magnetic measurements quantitatively analyzed to deduce exchange constants. ► Magnetic structures determined from neutron powder diffraction experiments.

  20. APETALA 2-domain-containing transcription factors: focusing on abscisic acid and gibberellins antagonism.

    Science.gov (United States)

    Shu, Kai; Zhou, Wenguan; Yang, Wenyu

    2018-02-01

    The phytohormones abscisic acid (ABA) and gibberellin (GA) antagonistically mediate diverse plant developmental processes including seed dormancy and germination, root development, and flowering time control, and thus the optimal balance between ABA and GA is essential for plant growth and development. Although more than a half and one century have passed since the initial discoveries of ABA and GA, respectively, the precise mechanisms underlying ABA-GA antagonism still need further investigation. Emerging evidence indicates that two APETALA 2 (AP2)-domain-containing transcription factors (ATFs), ABI4 in Arabidopsis and OsAP2-39 in rice, play key roles in ABA and GA antagonism. These two transcription factors precisely regulate the transcription pattern of ABA and GA biosynthesis or inactivation genes, mediating ABA and GA levels. In this Viewpoint article, we try to shed light on the effects of ATFs on ABA-GA antagonism, and summarize the overlapping but distinct biological functions of these ATFs in the antagonism between ABA and GA. Finally, we strongly propose that further research is needed into the detailed roles of additional numerous ATFs in ABA and GA crosstalk, which will improve our understanding of the antagonism between these two phytohormones. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  1. Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit

    Directory of Open Access Journals (Sweden)

    MIKI TSUJITA

    2007-01-01

    Full Text Available Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C0(2. In the other experiment, apneic threshold PaC0(2 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit

  2. First line shape analysis and spectroscopic parameters for the ν11 band of 12C2H4

    KAUST Repository

    Es-sebbar, Et-touhami

    2016-08-11

    An accurate knowledge of line intensities, collisional broadening coefficients and narrowing parameters is necessary for the interpretation of high-resolution infrared spectra of the Earth and other planetary atmospheres. One of the most promising spectral domains for (C2H4)-C-12 monitoring in such environments is located near the 336 gm window, through its v(11) C-H stretching mode. In this paper, we report an extensive study in which we precisely determine spectroscopic parameters of (C2H4)-C-12 v(11) band at 297 +/- 1 K, using a narrow Difference-Frequency-Generation (DFG) laser with 10(-4) cm(-1) resolution. Absorption measurements were performed in the 2975-2980 cm(-1) spectral window to investigate 32 lines corresponding to where, J\\'ka\\',kc\\'<- Jka,kc, 5 <= J <= 7; 0.5 <= K-a <= 6 and 1 <= K-c <= 14. Spectroscopic parameters are retrieved using either Voigt or appropriate Galatry profile to simulate the measured (C2H4)-C-12 line shape. Line intensities along with self-broadening coefficients are reported for all lines. Narrowing coefficients for each isolated line are also derived. To our knowledge, the current study reports the first extensive spectroscopic parameter measurements of the (C2H4)-C-12 v(11) band in the 2975-2980 cm(-1) range. (C) 2016 Elsevier Ltd. All rights reserved.

  3. Equilibrium structure and Ti-catalyzed H-2 desorption in NaAlH4 nanoparticles from density functional theory

    DEFF Research Database (Denmark)

    Vegge, T.

    2006-01-01

    the kinetics significantly, the physical understanding remains elusive. Density functional theory is used to calculate the energy of the potential low energy surfaces of NaAlH4 to establish the equilibrium particle shape, and furthermore to determine the deposition energy of Ti/TiH2 and the substitutional...

  4. Complexation and biodistribution study of 111In complexes of bifunctional phosphinic acid analogues of H4DOTA

    Czech Academy of Sciences Publication Activity Database

    Forsterová, Michaela; Zimová, Jana; Petrík, M.; Lázníček, M.; Lázníčková, A.; Hermann, P.; Melichar, František

    2007-01-01

    Roč. 2, č. 337 (2007), s. 34-34 ISSN 1619-7070 R&D Projects: GA AV ČR 1QS100480501 Institutional research plan: CEZ:AV0Z10480505 Keywords : bifunctional H4DOTA ligands * phosphinic acid analogues, * complexation of 111In Subject RIV: FR - Pharmacology ; Medidal Chemistry

  5. Active Ti Species in TiCl3-Doped NaAlH4. Mechanism for Catalyst Deactivation

    NARCIS (Netherlands)

    Balde, C.P.; Stil, H.A.; van der Eerden, A.M.J.; de Jong, K.P.; Bitter, J.H.

    2007-01-01

    The nature of the active Ti species in TiCl3-doped NaAlH4, a promising hydrogen storage material, was studied as a function of the desorption temperature with Ti K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy, Ti K-edge X-ray absorption near-edge structure (XANES) spectroscopy,

  6. A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks

    DEFF Research Database (Denmark)

    Huang, Hongda; Strømme, Caroline B; Saredi, Giulia

    2015-01-01

    During DNA replication, chromatin is reassembled by recycling of modified old histones and deposition of new ones. How histone dynamics integrates with DNA replication to maintain genome and epigenome information remains unclear. Here, we reveal how human MCM2, part of the replicative helicase......, chaperones histones H3-H4. Our first structure shows an H3-H4 tetramer bound by two MCM2 histone-binding domains (HBDs), which hijack interaction sites used by nucleosomal DNA. Our second structure reveals MCM2 and ASF1 cochaperoning an H3-H4 dimer. Mutational analyses show that the MCM2 HBD is required...... for MCM2-7 histone-chaperone function and normal cell proliferation. Further, we show that MCM2 can chaperone both new and old canonical histones H3-H4 as well as H3.3 and CENPA variants. The unique histone-binding mode of MCM2 thus endows the replicative helicase with ideal properties for recycling...

  7. First line shape analysis and spectroscopic parameters for the ν11 band of 12C2H4

    KAUST Repository

    Es-sebbar, Et-touhami; Mantzaras, John; Benilan, Yves; Farooq, Aamir

    2016-01-01

    An accurate knowledge of line intensities, collisional broadening coefficients and narrowing parameters is necessary for the interpretation of high-resolution infrared spectra of the Earth and other planetary atmospheres. One of the most promising spectral domains for (C2H4)-C-12 monitoring in such environments is located near the 336 gm window, through its v(11) C-H stretching mode. In this paper, we report an extensive study in which we precisely determine spectroscopic parameters of (C2H4)-C-12 v(11) band at 297 +/- 1 K, using a narrow Difference-Frequency-Generation (DFG) laser with 10(-4) cm(-1) resolution. Absorption measurements were performed in the 2975-2980 cm(-1) spectral window to investigate 32 lines corresponding to where, J'ka',kc'<- Jka,kc, 5 <= J <= 7; 0.5 <= K-a <= 6 and 1 <= K-c <= 14. Spectroscopic parameters are retrieved using either Voigt or appropriate Galatry profile to simulate the measured (C2H4)-C-12 line shape. Line intensities along with self-broadening coefficients are reported for all lines. Narrowing coefficients for each isolated line are also derived. To our knowledge, the current study reports the first extensive spectroscopic parameter measurements of the (C2H4)-C-12 v(11) band in the 2975-2980 cm(-1) range. (C) 2016 Elsevier Ltd. All rights reserved.

  8. A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks.

    Science.gov (United States)

    Huang, Hongda; Strømme, Caroline B; Saredi, Giulia; Hödl, Martina; Strandsby, Anne; González-Aguilera, Cristina; Chen, Shoudeng; Groth, Anja; Patel, Dinshaw J

    2015-08-01

    During DNA replication, chromatin is reassembled by recycling of modified old histones and deposition of new ones. How histone dynamics integrates with DNA replication to maintain genome and epigenome information remains unclear. Here, we reveal how human MCM2, part of the replicative helicase, chaperones histones H3-H4. Our first structure shows an H3-H4 tetramer bound by two MCM2 histone-binding domains (HBDs), which hijack interaction sites used by nucleosomal DNA. Our second structure reveals MCM2 and ASF1 cochaperoning an H3-H4 dimer. Mutational analyses show that the MCM2 HBD is required for MCM2-7 histone-chaperone function and normal cell proliferation. Further, we show that MCM2 can chaperone both new and old canonical histones H3-H4 as well as H3.3 and CENPA variants. The unique histone-binding mode of MCM2 thus endows the replicative helicase with ideal properties for recycling histones genome wide during DNA replication.

  9. Reversible hydrogen storage in Ti-Zr-codoped NaAlH4 under realistic operation conditions: Part 2

    International Nuclear Information System (INIS)

    Schmidt, Thomas; Roentzsch, Lars; Weissgaerber, Thomas; Kieback, Bernd

    2011-01-01

    Research highlights: → The dehydrogenation kinetics of NaAlH 4 , codoped with TiCl 4 and Zrcl 3 are studied with respect to hydrogen back-pressure and catalyst concentration. → A strong pressure dependency is found in the second dehydrogenation step, whereas the first step shows little influence by hydrogen pressure. → The influence of the catalyst concentration is strong for both dehydrogenation steps. → Rate constants and activation energies are calculated from isothermal measurements. - Abstract: Recently, we have demonstrated that the dehydrogenation of NaAlH 4 can be carried out with sufficient kinetics even at a hydrogen back pressure of 4 bar, which is needed for a proton exchange membrane (PEM) fuel cell . In this contribution the influence of hydrogen back pressure in the range of 0.2 up to 5 bar and catalyst concentration in the range between 1 and 5 wt.% overall catalyst concentration on the dehydrogenation of Zr-Ti codoped NaAlH 4 is investigated in detail. The influence of the hydrogen back-pressure is significant in the 2nd dehydrogenation step. The catalyst concentration influences both kinetics and storage capacity. Rate constants as a function of the temperature and hydrogen back-pressure and activation energies of the dehydrogenation of NaAlH 4 to Na 3 AlH 6 at 1 bar and 4 bar hydrogen pressure are calculated from isothermal dehydrogenation experiments.

  10. Interleukin-1 antagonism in type 1 diabetes of recent onset

    DEFF Research Database (Denmark)

    Moran, Antoinette; Bundy, Brian; Becker, Dorothy J

    2013-01-01

    Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1...... antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes....

  11. Experimental studies of collisions of excited Li(4p) atoms with C2H4, C2H6, C3H8 and theoretical interpretation of the Li-C2H4 system

    International Nuclear Information System (INIS)

    Semmineh, Natenael; Bililign, Solomon; Hagebaum-Reignier, Denis; Jeung, Gwang-Hi

    2009-01-01

    Collisions of excited Li(4p) states with C 2 H 4 , C 2 H 6 and C 3 H 8 are studied experimentally using far-wing scattering state spectroscopy techniques. High-level ab initio quantum mechanical studies of the Li-C 2 H 4 system are conducted to explain the results of the experiment for this system. The recent and present works indicate that knowledge of the internal structure of the perturber (C 2 H 4 , C 2 H 6 and C 3 H 8 ) is essential to fully understand the interaction between the metal and the hydrocarbon molecules. The ab initio calculation shows that the Li(4d) (with little probability under the experimental conditions) and the Li(4p) can be formed directly through the laser pumping. It also shows that the Li(4s) and Li(3d) states can be formed through an electronic diabatic coupling involving a radiationless process. However, the Li(3p), Li(3s) and Li(2p) states can only be formed through a secondary diabatic coupling which is a much less probable process than the primary one. The calculation limited to two C 2v sections of the potential energy surfaces (PESs) shows peculiar multi-state crossings that we have never seen in other lithium complexes we studied

  12. Hydrogen sulfide alleviates postharvest ripening and senescence of banana by antagonizing the effect of ethylene.

    Directory of Open Access Journals (Sweden)

    Yun Ge

    Full Text Available Accumulating evidence shows that hydrogen sulfide (H2S acts as a multifunctional signaling molecule in plants, whereas the interaction between H2S and ethylene is still unclear. In the present study we investigated the role of H2S in ethylene-promoted banana ripening and senescence by the application of ethylene released from 1.0 g·L-1 ethephon solution or H2S with 1 mM sodium hydrosulfide (NaHS as the donor or in combination. Fumigation with ethylene was found to accelerate banana ripening and H2S treatment effectively alleviated ethylene-induced banana peel yellowing and fruit softening in parallel with decreased activity of polygalacturonase (PG. Ethylene+H2S treatment also delayed the decreases in chlorophyll and total phenolics, and increased the accumulation of flavonoid, whereas decreased the contents of carotenoid, soluble protein in banana peel and reducing sugar in pulp compared with ethylene treatment alone. Besides, ethylene+H2S treatment suppressed the accumulation of superoxide radicals (·O2-, hydrogen peroxide (H2O2 and malondialdehyde (MDA which accumulated highly in ethylene-treated banana peels. Furthermore H2S enhanced total antioxidant capacity in ethylene-treated banana peels with the 2,2'-azobis(3-ethylbenz-thiazoline-6-sulfonic acid (ABTS assay. The result of quantitative real-time PCR showed that the combined treatment of ethylene with H2S down-regulated the expression of ethylene synthesis genes MaACS1, MaACS2 and MaACO1 and pectate lyase MaPL compared with ethylene treatment, while the expression of ethylene receptor genes MaETR, MaERS1 and MaERS2 was enhanced in combination treatment compared with ethylene alone. In all, it can be concluded that H2S alleviates banana fruit ripening and senescence by antagonizing the effect of ethylene through reduction of oxidative stress and inhibition of ethylene signaling pathway.

  13. Hydrogen sulfide alleviates postharvest ripening and senescence of banana by antagonizing the effect of ethylene.

    Science.gov (United States)

    Ge, Yun; Hu, Kang-Di; Wang, Sha-Sha; Hu, Lan-Ying; Chen, Xiao-Yan; Li, Yan-Hong; Yang, Ying; Yang, Feng; Zhang, Hua

    2017-01-01

    Accumulating evidence shows that hydrogen sulfide (H2S) acts as a multifunctional signaling molecule in plants, whereas the interaction between H2S and ethylene is still unclear. In the present study we investigated the role of H2S in ethylene-promoted banana ripening and senescence by the application of ethylene released from 1.0 g·L-1 ethephon solution or H2S with 1 mM sodium hydrosulfide (NaHS) as the donor or in combination. Fumigation with ethylene was found to accelerate banana ripening and H2S treatment effectively alleviated ethylene-induced banana peel yellowing and fruit softening in parallel with decreased activity of polygalacturonase (PG). Ethylene+H2S treatment also delayed the decreases in chlorophyll and total phenolics, and increased the accumulation of flavonoid, whereas decreased the contents of carotenoid, soluble protein in banana peel and reducing sugar in pulp compared with ethylene treatment alone. Besides, ethylene+H2S treatment suppressed the accumulation of superoxide radicals (·O2-), hydrogen peroxide (H2O2) and malondialdehyde (MDA) which accumulated highly in ethylene-treated banana peels. Furthermore H2S enhanced total antioxidant capacity in ethylene-treated banana peels with the 2,2'-azobis(3-ethylbenz-thiazoline-6-sulfonic acid (ABTS) assay. The result of quantitative real-time PCR showed that the combined treatment of ethylene with H2S down-regulated the expression of ethylene synthesis genes MaACS1, MaACS2 and MaACO1 and pectate lyase MaPL compared with ethylene treatment, while the expression of ethylene receptor genes MaETR, MaERS1 and MaERS2 was enhanced in combination treatment compared with ethylene alone. In all, it can be concluded that H2S alleviates banana fruit ripening and senescence by antagonizing the effect of ethylene through reduction of oxidative stress and inhibition of ethylene signaling pathway.

  14. Crystal structure of Lymnaea stagnalis AChBP complexed with the potent nAChR antagonist DHβE suggests a unique mode of antagonism.

    Directory of Open Access Journals (Sweden)

    Azadeh Shahsavar

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are pentameric ligand-gated ion channels that belong to the Cys-loop receptor superfamily. These receptors are allosteric proteins that exist in different conformational states, including resting (closed, activated (open, and desensitized (closed states. The acetylcholine binding protein (AChBP is a structural homologue of the extracellular ligand-binding domain of nAChRs. In previous studies, the degree of the C-loop radial extension of AChBP has been assigned to different conformational states of nAChRs. It has been suggested that a closed C-loop is preferred for the active conformation of nAChRs in complex with agonists whereas an open C-loop reflects an antagonist-bound (closed state. In this work, we have determined the crystal structure of AChBP from the water snail Lymnaea stagnalis (Ls in complex with dihydro-β-erythroidine (DHβE, which is a potent competitive antagonist of nAChRs. The structure reveals that binding of DHβE to AChBP imposes closure of the C-loop as agonists, but also a shift perpendicular to previously observed C-loop movements. These observations suggest that DHβE may antagonize the receptor via a different mechanism compared to prototypical antagonists and toxins.

  15. An in vitro study of peptide-loaded alginate nanospheres for antagonizing the inhibitory effect of Nogo-A protein on axonal growth

    International Nuclear Information System (INIS)

    Zhai, Peng; Chen, X B; Schreyer, David J

    2015-01-01

    The adult mammalian central nervous system has limited ability to regenerate after injury. This is due, in part, to the presence of myelin-associated axon growth inhibitory proteins such as Nogo-A that bind and activate the Nogo receptor, leading to profound inhibition of actin-based motility within the growing axon tip. This paper presents an in vitro study of the use of a Nogo receptor-blocking peptide to antagonize the inhibitory effect of Nogo-A on axon growth. Alginate nanospheres were fabricated using an emulsion technique and loaded with Nogo receptor-blocking peptide, or with other model proteins. Protein release profiles were studied, and retention of the bioactivity of released proteins was verified. Primary dorsal root ganglion neurons were cultured and their ability to grow neurites was challenged with Nogo-A chimeric protein in the absence or presence of Nogo receptor antagonist peptide-loaded alginate nanospheres. Our results demonstrate that peptide released from alginate nanospheres could overcome the growth inhibitory effect of Nogo-A, suggesting that a similar peptide delivery strategy using alginate nanospheres might be used to improve axon regeneration within the injured central nervous system. (paper)

  16. 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.

  17. 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.

  18. Photon Echoes in the 3P0 ← 3H4 Transition of Pr3+/LaF3

    NARCIS (Netherlands)

    Morsink, Jos B.W.; Wiersma, Douwe A.

    1979-01-01

    Photon-echo quantum beats observed in the two-pulse and three-pulse photon echo of the 3P0 ← 3H4 transition in Pr3+/LaF3 were used to determine the excited-state spin-hamiltonian. In addition we report on the anomalous stimulated photon echo observed in the same transition which in a magnetic field

  19. Methylation analysis of histone H4K12ac-associated promoters in sperm of healthy donors and subfertile patients

    Czech Academy of Sciences Publication Activity Database

    Vieweg, M.; Dvořáková-Hortová, Kateřina; Dudková, B.; Waliszewski, P.; Otte, M.; Oels, B.; Hajimohammad, A.; Schorsch, M.; Schuppe, H.M.; Weidner, W.; Steger, K.; Paradowska-Dogan, A.

    2015-01-01

    Roč. 7, č. 31 (2015) ISSN 1868-7083 R&D Projects: GA ČR(CZ) GA14-05547S; GA MŠk(CZ) CZ1.05/1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : H4K12ac in spermatozoa * μChIP * promoter methylation * pyrosequencing * subfertility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.327, year: 2015

  20. Transmission electron microscopy studies of C3N4H4 treated at high pressure and high temperature

    International Nuclear Information System (INIS)

    Yu, R C; Chen, L C; Zhu, J L; Li, F Y; Liu, Z X; Qin, Z C; Yu, T N; Jin, C Q; Duan, X F; Zhang, Z

    2002-01-01

    C 3 N 4 H 4 was treated at 6.0 GPa and 1500 deg C for 2.5 min. Powder x-ray measurement shows that the sample is decomposed and a hexagonal graphite phase forms. Transmission electron microscopy studies show that small amounts of diamond and amorphous carbon phase coexist with the graphite phase. Parallel electron energy-loss spectroscopy analysis was also carried out for these phases

  1. Expressions of B7-H4 and B7-H3 Proteins and Effect of Sorafenib on ...

    African Journals Online (AJOL)

    21. Pardoll DM. The blockage of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4):. 252-264. 22. Wang L, Liu LH, Shan BE. B7-H3: a promising target for tumor immunotherapy. Immunol J 2012; 28(8): 726-729. 23. Liu CZ, Yang KG, Cheng SS. B7-H4: a new negative regulator of T cell immunity.

  2. Suggestion for search of ethylene oxide (c-C2H4O) in a cosmic object

    Science.gov (United States)

    Sharma, M. K.; Sharma, M.; Chandra, S.

    2018-05-01

    Ethylene oxide (c-C2H4O) and its isomer acetaldehyde (CH3CHO) are important organic molecules because of their potential role in the formation of amino acids. The c-C2H4O molecule is a b-type asymmetric top molecule and owing to half-spin of each of the four hydrogen atoms, it has two distinct ortho (nuclear spin one) and para (nuclear spin zero and two) species. It has been detected in the Sgr B2N. Using the rotational and centrifugal distortion constants along with the electric dipole moment, we have calculated energies of 100 rotational levels of each of the ortho and para species of c-C2H4O molecule and the Einstein A-coefficients for radiative transitions between the levels. The values of Einstein A-coefficients along with the scaled values for the collisional rate coefficients are used for solving a set of statistical equilibrium equations coupled with the equations of radiative transfer. Brightness-temperatures of five rotational transitions of each of the ortho and para species of c-C2H4O molecule are investigated. Out of these ten transitions, three transitions are found to show the anomalous absorption and rest seven are found to show the emission feature. We have also investigated seven transitions observed unblended in the Sgr B2(N). We have found that the transitions 3_{3 0} - 3_{2 1} (23.134 GHz), 2_{2 0} - 2_{1 1} (15.603 GHz), 3_{3 1} - 3_{2 2} (39.680 GHz) and 1_{1 1} - 0_{0 0} (39.582 GHz) may play important role for the identification of ethylene oxide in a cosmic object.

  3. Geohydrologic and drill-hole data for test well USW H-4, Yucca Mountain, Nye County, Nevada

    Science.gov (United States)

    Whitfield, M.S.; Thordarson, William; Eshom, E.P.

    1984-01-01

    Data are presented on drilling operations, lithology, geophysical well logs, sidewall-core samples, water-level monitoring, pumping tests, injection tests, radioactive-tracer borehole flow survey, and water chemistry for test well USW H-4. The well is one of a series of test wells drilled in the southwestern part of the Nevada Test Site, Nye County, Nevada, in cooperation with the U.S. Department of Energy. These test wells are part of the Nevada Nuclear Waste Storage Investigations to identify sites for storage of high-level radioactive wastes. Test well USW H-4 was drilled in ash-flow tuff to a total depth of 1,219 meters. Depth to water below land surface was 519 meters or at an altitude of 730 meters above sea level. After test pumping at a rate of 17.4 liters per second for approximately 9 days, the drawdown was 4.85 meters. A radioactive borehole-flow survey indicated that the Bullfrog Member was the most productive geologic unit, producing 36.5 percent of the water in the well. The second most productive geologic unit was the Tram Member, which produced 32 percent of the water. The water in test well USW H-4 is predominantly a soft, sodium bicarbonate type of water typical of water produced in tuffaceous rocks in southern Nevada. (USGS)

  4. Enteroaggregative Shiga toxin-producing Escherichia coli of serotype O104:H4 in Belgium and Luxembourg

    Directory of Open Access Journals (Sweden)

    K. De Rauw

    2014-09-01

    Full Text Available In 2011, a large outbreak of infections caused by Shiga toxin-producing Escherichia coli (STEC O104:H4 occurred in Germany. This exceptionally virulent strain combined virulence factors of enteroaggregative E. coli (EAggEC and STEC. After the outbreak only a few sporadic cases of infection with this rare serotype were reported, most of which were related to travel to the Middle East or North Africa. Here we describe two cases of enteroaggregative STEC (Agg-STEC O104:H4 infection that occurred in Belgium in 2012 and 2013 respectively. In both cases travel in a Mediterranean country preceded the infection. The first strain was isolated from the stool of a 42-year-old woman presenting bloody diarrhoea, who had travelled to Tunisia the week before. The second case involves a 14-year-old girl who, upon her return from Turkey to Belgium, suffered from an episode of bloody diarrhoea and haemolytic uraemic syndrome. Extended typing of the isolates with pulsed field gel electrophoresis revealed that the strains were closely related, though not exactly the same as the 2011 outbreak strain. This report supports the previously made hypothesis that Agg-STEC has a human reservoir and might be imported by travellers coming from an area where the pathogen is endemic. Furthermore, it emphasizes the concern that these bacteria may cause future outbreaks as evenly virulent O104:H4 isolates seem to be widespread.

  5. DAXX-dependent supply of soluble (H3.3-H4) dimers to PML bodies pending deposition into chromatin.

    Science.gov (United States)

    Delbarre, Erwan; Ivanauskiene, Kristina; Küntziger, Thomas; Collas, Philippe

    2013-03-01

    Replication-independent chromatin deposition of histone variant H3.3 is mediated by several chaperones. We report a multistep targeting of newly synthesized epitope-tagged H3.3 to chromatin via PML bodies. H3.3 is recruited to PML bodies in a DAXX-dependent manner, a process facilitated by ASF1A. DAXX is required for enrichment of ATRX, but not ASF1A or HIRA, with PML. Nonetheless, the chaperones colocalize with H3.3 at PML bodies and are found in one or more complexes with PML. Both DAXX and PML are necessary to prevent accumulation of a soluble, nonincorporated pool of H3.3. H3.3 targeting to PML is enhanced with an (H3.3-H4)2 tetramerization mutant of H3.3, suggesting H3.3 recruitment to PML as an (H3.3-H4) dimer rather than as a tetramer. Our data support a model of DAXX-mediated recruitment of (H3.3-H4) dimers to PML bodies, which may function as triage centers for H3.3 deposition into chromatin by distinct chaperones.

  6. DAXX envelops a histone H3.3-H4 dimer for H3.3-specific recognition

    Energy Technology Data Exchange (ETDEWEB)

    Elsässer, Simon J; Huang, Hongda; Lewis, Peter W; Chin, Jason W; Allis, C David; Patel, Dinshaw J [MSKCC; (Rockefeller); (MRC)

    2013-01-24

    Histone chaperones represent a structurally and functionally diverse family of histone-binding proteins that prevent promiscuous interactions of histones before their assembly into chromatin. DAXX is a metazoan histone chaperone specific to the evolutionarily conserved histone variant H3.3. Here we report the crystal structures of the DAXX histone-binding domain with a histone H3.3–H4 dimer, including mutants within DAXX and H3.3, together with in vitro and in vivo functional studies that elucidate the principles underlying H3.3 recognition specificity. Occupying 40% of the histone surface-accessible area, DAXX wraps around the H3.3–H4 dimer, with complex formation accompanied by structural transitions in the H3.3–H4 histone fold. DAXX uses an extended α-helical conformation to compete with major inter-histone, DNA and ASF1 interaction sites. Our structural studies identify recognition elements that read out H3.3-specific residues, and functional studies address the contributions of Gly90 in H3.3 and Glu225 in DAXX to chaperone-mediated H3.3 variant recognition specificity.

  7. ChIP on SNP-chip for genome-wide analysis of human histone H4 hyperacetylation

    Directory of Open Access Journals (Sweden)

    Porter Christopher J

    2007-09-01

    Full Text Available Abstract Background SNP microarrays are designed to genotype Single Nucleotide Polymorphisms (SNPs. These microarrays report hybridization of DNA fragments and therefore can be used for the purpose of detecting genomic fragments. Results Here, we demonstrate that a SNP microarray can be effectively used in this way to perform chromatin immunoprecipitation (ChIP on chip as an alternative to tiling microarrays. We illustrate this novel application by mapping whole genome histone H4 hyperacetylation in human myoblasts and myotubes. We detect clusters of hyperacetylated histone H4, often spanning across up to 300 kilobases of genomic sequence. Using complementary genome-wide analyses of gene expression by DNA microarray we demonstrate that these clusters of hyperacetylated histone H4 tend to be associated with expressed genes. Conclusion The use of a SNP array for a ChIP-on-chip application (ChIP on SNP-chip will be of great value to laboratories whose interest is the determination of general rules regarding the relationship of specific chromatin modifications to transcriptional status throughout the genome and to examine the asymmetric modification of chromatin at heterozygous loci.

  8. Combinatorial modification of human histone H4 quantitated by two-dimensional liquid chromatography coupled with top down mass spectrometry.

    Science.gov (United States)

    Pesavento, James J; Bullock, Courtney R; LeDuc, Richard D; Mizzen, Craig A; Kelleher, Neil L

    2008-05-30

    Quantitative proteomics has focused heavily on correlating protein abundances, ratios, and dynamics by developing methods that are protein expression-centric (e.g. isotope coded affinity tag, isobaric tag for relative and absolute quantification, etc.). These methods effectively detect changes in protein abundance but fail to provide a comprehensive perspective of the diversity of proteins such as histones, which are regulated by post-translational modifications. Here, we report the characterization of modified forms of HeLa cell histone H4 with a dynamic range >10(4) using a strictly Top Down mass spectrometric approach coupled with two dimensions of liquid chromatography. This enhanced dynamic range enabled the precise characterization and quantitation of 42 forms uniquely modified by combinations of methylation and acetylation, including those with trimethylated Lys-20, monomethylated Arg-3, and the novel dimethylated Arg-3 (each <1% of all H4 forms). Quantitative analyses revealed distinct trends in acetylation site occupancy depending on Lys-20 methylation state. Because both modifications are dynamically regulated through the cell cycle, we simultaneously investigated acetylation and methylation kinetics through three cell cycle phases and used these data to statistically assess the robustness of our quantitative analysis. This work represents the most comprehensive analysis of histone H4 forms present in human cells reported to date.

  9. Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome.

    Science.gov (United States)

    Luthra, Priya; Ramanan, Parameshwaran; Mire, Chad E; Weisend, Carla; Tsuda, Yoshimi; Yen, Benjamin; Liu, Gai; Leung, Daisy W; Geisbert, Thomas W; Ebihara, Hideki; Amarasinghe, Gaya K; Basler, Christopher F

    2013-07-17

    The cytoplasmic pattern recognition receptor RIG-I is activated by viral RNA and induces type I IFN responses to control viral replication. The cellular dsRNA binding protein PACT can also activate RIG-I. To counteract innate antiviral responses, some viruses, including Ebola virus (EBOV), encode proteins that antagonize RIG-I signaling. Here, we show that EBOV VP35 inhibits PACT-induced RIG-I ATPase activity in a dose-dependent manner. The interaction of PACT with RIG-I is disrupted by wild-type VP35, but not by VP35 mutants that are unable to bind PACT. In addition, PACT-VP35 interaction impairs the association between VP35 and the viral polymerase, thereby diminishing viral RNA synthesis and modulating EBOV replication. PACT-deficient cells are defective in IFN induction and are insensitive to VP35 function. These data support a model in which the VP35-PACT interaction is mutually antagonistic and plays a fundamental role in determining the outcome of EBOV infection. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. The elongin complex antagonizes the chromatin factor Corto for vein versus intervein cell identity in Drosophila wings.

    Science.gov (United States)

    Rougeot, Julien; Renard, Myrtille; Randsholt, Neel B; Peronnet, Frédérique; Mouchel-Vielh, Emmanuèle

    2013-01-01

    Drosophila wings mainly consist of two cell types, vein and intervein cells. Acquisition of either fate depends on specific expression of genes that are controlled by several signaling pathways. The nuclear mechanisms that translate signaling into regulation of gene expression are not completely understood, but they involve chromatin factors from the Trithorax (TrxG) and Enhancers of Trithorax and Polycomb (ETP) families. One of these is the ETP Corto that participates in intervein fate through interaction with the Drosophila EGF Receptor--MAP kinase ERK pathway. Precise mechanisms and molecular targets of Corto in this process are not known. We show here that Corto interacts with the Elongin transcription elongation complex. This complex, that consists of three subunits (Elongin A, B, C), increases RNA polymerase II elongation rate in vitro by suppressing transient pausing. Analysis of phenotypes induced by EloA, B, or C deregulation as well as genetic interactions suggest that the Elongin complex might participate in vein vs intervein specification, and antagonizes corto as well as several TrxG genes in this process. Chromatin immunoprecipitation experiments indicate that Elongin C and Corto bind the vein-promoting gene rhomboid in wing imaginal discs. We propose that Corto and the Elongin complex participate together in vein vs intervein fate, possibly through tissue-specific transcriptional regulation of rhomboid.

  11. The elongin complex antagonizes the chromatin factor Corto for vein versus intervein cell identity in Drosophila wings.

    Directory of Open Access Journals (Sweden)

    Julien Rougeot

    Full Text Available Drosophila wings mainly consist of two cell types, vein and intervein cells. Acquisition of either fate depends on specific expression of genes that are controlled by several signaling pathways. The nuclear mechanisms that translate signaling into regulation of gene expression are not completely understood, but they involve chromatin factors from the Trithorax (TrxG and Enhancers of Trithorax and Polycomb (ETP families. One of these is the ETP Corto that participates in intervein fate through interaction with the Drosophila EGF Receptor--MAP kinase ERK pathway. Precise mechanisms and molecular targets of Corto in this process are not known. We show here that Corto interacts with the Elongin transcription elongation complex. This complex, that consists of three subunits (Elongin A, B, C, increases RNA polymerase II elongation rate in vitro by suppressing transient pausing. Analysis of phenotypes induced by EloA, B, or C deregulation as well as genetic interactions suggest that the Elongin complex might participate in vein vs intervein specification, and antagonizes corto as well as several TrxG genes in this process. Chromatin immunoprecipitation experiments indicate that Elongin C and Corto bind the vein-promoting gene rhomboid in wing imaginal discs. We propose that Corto and the Elongin complex participate together in vein vs intervein fate, possibly through tissue-specific transcriptional regulation of rhomboid.

  12. 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

  13. Endogenous opioid antagonism in physiological experimental pain models

    DEFF Research Database (Denmark)

    Werner, Mads U; Pereira, Manuel P; Andersen, Lars Peter H

    2015-01-01

    hyperalgesia models (6 studies), 'pain' models (25 studies), summation models (2 studies), nociceptive reflex models (3 studies) and miscellaneous models (2 studies). A consistent reversal of analgesia by a MOR-antagonist was demonstrated in 10 of the 25 ITP-studies, including stress-induced analgesia and r...... ratings, threshold assessments and somatosensory evoked potentials (SSEP), did not appear consistent in 28 out of 32 'pain' model studies. In conclusion, only in 2 experimental human pain models, i.e., stress-induced analgesia and rTMS, administration of MOR-antagonist demonstrated a consistent effect......Opioid antagonists are pharmacological tools applied as an indirect measure to detect activation of the endogenous opioid system (EOS) in experimental pain models. The objective of this systematic review was to examine the effect of mu-opioid-receptor (MOR) antagonists in placebo-controlled, double...

  14. B7-H4 gene polymorphisms are associated with sporadic breast cancer in a Chinese Han population

    Directory of Open Access Journals (Sweden)

    Fu Zhenkun

    2009-11-01

    Full Text Available Abstract Background B7-H4, a co-inhibitory molecule of the B7 family, can restrain T cell proliferation, cytokine secretion and the development of cytotoxicity. B7-H4 is expressed in tumor tissues at a higher level than in normal tissues, and has a potential effect to protect tumors from anti-tumor immune responses. This case-control study was carried out to determine the potential influences of B7-H4 gene polymorphisms on the susceptibility and progression of breast cancer in Han women of Northeast China. Methods We genotyped three B7-H4 variants (rs10754339, rs10801935 and rs3738414 and tagged all common haplotypes (frequency greater than or equal to 1% in a Chinese population consisting of 500 breast cancer cases and 504 control individuals matched for age. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP technique was used to determine the genotypes. Results Our data indicated that, compared with the common genotype and allele of each SNP, the rs10754339 AG genotype and G allele showed a significantly increased risk of breast cancer (OR = 1.455, 95% CI 1.119-1.892; OR = 1.325, 95% CI 1.073-1.637, respectively. The rs10801935 CC genotype, the rs3738414 AA genotype and the rs3738414 A allele were associated with a significantly decreased risk of breast cancer (OR = 0.328, 95% CI 0.145-0.739; OR = 0.412, 95% CI 0.203-0.835; OR = 0.698, 95% CI 0.564-0.864, respectively. Additionally, the rs10754339 GG genotype was significantly associated with lymph node metastasis and PR status, and the G allele and the AG genotype were respectively associated with lymph node metastasis and ER status. In haplotype analysis, we observed that compared with the AAG haplotype, the AAA haplotype showed a significantly decreased risk of breast cancer (OR = 0.689, 95% CI 0.539-0.881, but the GAG haplotype was associated with a significantly increased risk of breast cancer (OR = 1.511, 95% CI 1.125-2.031. And the AAA and the GCG haplotypes

  15. B7-H4 gene polymorphisms are associated with sporadic breast cancer in a Chinese Han population

    International Nuclear Information System (INIS)

    Zhang, Jie; Zhang, Mingyan; Jiang, Wei; Wang, Lihong; Fu, Zhenkun; Li, Dalin; Pang, Da; Li, Dianjun

    2009-01-01

    B7-H4, a co-inhibitory molecule of the B7 family, can restrain T cell proliferation, cytokine secretion and the development of cytotoxicity. B7-H4 is expressed in tumor tissues at a higher level than in normal tissues, and has a potential effect to protect tumors from anti-tumor immune responses. This case-control study was carried out to determine the potential influences of B7-H4 gene polymorphisms on the susceptibility and progression of breast cancer in Han women of Northeast China. We genotyped three B7-H4 variants (rs10754339, rs10801935 and rs3738414) and tagged all common haplotypes (frequency greater than or equal to 1%) in a Chinese population consisting of 500 breast cancer cases and 504 control individuals matched for age. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to determine the genotypes. Our data indicated that, compared with the common genotype and allele of each SNP, the rs10754339 AG genotype and G allele showed a significantly increased risk of breast cancer (OR = 1.455, 95% CI 1.119-1.892; OR = 1.325, 95% CI 1.073-1.637, respectively). The rs10801935 CC genotype, the rs3738414 AA genotype and the rs3738414 A allele were associated with a significantly decreased risk of breast cancer (OR = 0.328, 95% CI 0.145-0.739; OR = 0.412, 95% CI 0.203-0.835; OR = 0.698, 95% CI 0.564-0.864, respectively). Additionally, the rs10754339 GG genotype was significantly associated with lymph node metastasis and PR status, and the G allele and the AG genotype were respectively associated with lymph node metastasis and ER status. In haplotype analysis, we observed that compared with the AAG haplotype, the AAA haplotype showed a significantly decreased risk of breast cancer (OR = 0.689, 95% CI 0.539-0.881), but the GAG haplotype was associated with a significantly increased risk of breast cancer (OR = 1.511, 95% CI 1.125-2.031). And the AAA and the GCG haplotypes also respectively have significant influences on

  16. Antagonism between penicillin and erythromycin against Streptococcus pneumoniae in vitro and in vivo

    DEFF Research Database (Denmark)

    Johansen, H K; Jensen, T G; Dessau, R B

    2000-01-01

    The combination of beta-lactam antibiotics and macrolides is often recommended for the initial empirical treatment of acute pneumonia in order to obtain activity against the most important pathogens. Theoretically, this combination may be inexpedient, as the bacteriostatic agent may antagonize th...

  17. [Antagonism of Trichoderma spp. to fungi caused root rot of Sophora tonkinensis].

    Science.gov (United States)

    Qin, Liu-yan; Jiang, Ni; Tang, Mei-qiong; Miao, Jian-hua; Li, Lin-xuan

    2011-04-01

    To study the antagonism of Trichoderma spp. to fungi S9(Fusarium solani)which caused root rot of Sophora tonkinensis and discuss the further develop prospects of microbial biological control in soil-borne diseases on Chinese herbal medicines. Antagonism of H2 (Trichoderma harsianum), M6 (Trichoderma viride) and K1 (Trichoderma koningii) to Fusarium solani were researched by growth rate and confront culture. And their mechanisms were discussed. H2 and M6 had obvious competitive advantage, the growth rate of which were 1.43-2.72 times and 1.43-1.95 times as S9 respectively. The space competitive advantage of K1 was relatively weak; the growth rate was slower than S9. The antagonism of three species of Trichoderma spp. to S9 was in varying degrees. The antagonism to S9 of M6 and H2 was better,the inhibition rate were 100% and 82.35% respectively, even cultivated S9 for three days in advance. And their inhibition indexes were both reached class I. The inhibition index and inhibition rate of K1 was respectively 46.36% and class IV. The Trichoderma spp. could cause S9 mycelium to appear some phenomenon just like fracture, constriction reduced, digestion, etc. which were observed under the microscope. Trichoderma harsianum and Trichoderma viride showed the further develop prospects in the fight against soil-borne disease on Chinese herbal medicines.

  18. Mutualism and Antagonism: Ecological Interactions Among Bark Beetles, Mite and Fungi

    Science.gov (United States)

    K.D. Klepzig; J.C. Moser; M.J. Lombardero; M.P. Ayres; R.W. Hofstetter; C.J. Walkinshaw

    2001-01-01

    Insect-fungal complexes provide challenging and fascinating systems for the study of biotic interactions between plants. plant pathogens, insect vectors and other associated organisms. The types of interactions among these organisms (mutualism. antagonism. parasitism. phoresy. etc.) are as variable as the range of organisms involved (plants, fungi, insects. mites. etc...

  19. FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function

    OpenAIRE

    Jensen, Kim Steen; Binderup, Tina; Jensen, Klaus Thorleif; Therkelsen, Ib; Borup, Rehannah; Nilsson, Elise; Multhaupt, Hinke; Bouchard, Caroline; Quistorff, Bjørn; Kjær, Andreas; Landberg, Göran; Staller, Peter

    2011-01-01

    This paper characterizes FoxO3A as required for hypoxic suppression of mitochondrial mass, oxygen consumption, and ROS production. Mechanistically, FoxO3A is shown to promote hypoxic cell survival by directly antagonizing c-Myc at nuclear encoded mitochondrial genes.

  20. Isolation, Characterization and Identification of Environmental Bacterial Isolates with Screening for Antagonism Against Three Bacterial Targets

    Science.gov (United States)

    2017-04-01

    ISOLATES WITH SCREENING FOR ANTAGONISM AGAINST THREE BACTERIAL TARGETS 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...Identification of environmental isolates followed the flowchart from “Bergey’s Manual of Determinative Bacteriology” (Holt et al. 1994), which

  1. Development of Peptide Antagonists of Chemokine Receptors Involved in Breast Cancer Metastasis

    National Research Council Canada - National Science Library

    Blondelle, Sylvie E

    2004-01-01

    .... This was accomplished by screening in a competitive assay synthetic combinatorial libraries (SCLs) made up of D-amino acid peptides for their ability to antagonize CXCR4 receptor function using HeLa cells and PBMC cells (used as standard...

  2. Development of Peptide Antagonists of Chemokine Receptors Involved in Breast Cancer Metastasis

    National Research Council Canada - National Science Library

    Blondelle, Sylvie E

    2005-01-01

    .... This was accomplished by screening in a competitive assay synthetic combinatorial libraries (SCLs) made up of D-amino acid peptides for their ability to antagonize CXCR4 receptor function using HeLa cells and PBMC cells (used as standard...

  3. Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

    NARCIS (Netherlands)

    Zalachoras, I.; Houtman, R.; Atucha, E.; Devos, R.; Tijssen, A.M.I.; Hu, P.; Lockey, P.M.; Datson, N.A.; Belanoff, J.K.; Lucassen, P.J.; Joëls, M.; de Kloet, E.R.; Roozendaal, B.; Hunt, H.; Meijer, O.C.

    2013-01-01

    Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels.

  4. Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor.

    Science.gov (United States)

    Armour, S L; Foord, S; Kenakin, T; Chen, W J

    1999-12-01

    Receptor-activity-modifying proteins (RAMPs) are a family of single transmembrane domain proteins shown to be important for the transport and ligand specificity of the calcitonin gene-related peptide (CGRP) receptor. In this report, we describe the analysis of pharmacological properties of the human calcitonin receptor (hCTR) coexpressed with different RAMPs with the use of the Xenopus laevis melanophore expression system. We show that coexpression of RAMP3 with human calcitonin receptor changed the relative potency of hCTR to human calcitonin (hCAL) and rat amylin. RAMP1 and RAMP2, in contrast, had little effect on the change of hCTR potency to hCAL or rat amylin. When coexpressed with RAMP3, hCTR reversed the relative potency by a 3.5-fold loss in sensitivity to hCAL and a 19-fold increase in sensitivity to rat amylin. AC66, an inverse agonist, produced apparent simple competitive antagonism of hCAL and rat amylin, as indicated by linear Schild regressions. The potency of AC66 was changed in the blockade of rat amylin but not hCAL responses with RAMP3 coexpression. The mean pK(B) for AC66 to hCAL was 9.4 +/- 0.3 without RAMP3 and 9.45 +/- 0.07 with RAMP3. For the antagonism of AC66 to rat amylin, the pK(B) was 9.25 +/- 0.15 without RAMP3 and 8.2 +/- 0.35 with RAMP3. The finding suggests that RAMP3 might modify the active states of calcitonin receptor in such a way as to create a new receptor phenotype that is "amylin-like." Irrespective of the physiological association of the new receptor species, the finding that a coexpressed membrane protein can completely change agonist and antagonist affinities for a receptor raises implications for screening in recombinant receptor systems.

  5. Interactions of CB1 and mGlu5 receptor antagonists in food intake, anxiety and memory models in rats.

    Science.gov (United States)

    Varga, Balázs; Kassai, Ferenc; Gyertyán, István

    2012-12-01

    CB(1) receptor antagonists proved to be effective anti-obesity drugs, however, their depressive and anxiogenic effects became also evident. Finding solution to overcome these psychiatric side effects is still in focus of research. Based on the available clinical and preclinical results we hypothesized that the combination of CB(1) and mGlu(5) receptor antagonisms may result in a pharmacological intervention, where the anxiolytic mGlu(5) receptor inhibition may counteract the anxiogenic psychiatric side effects of CB(1) antagonism, while CB(1) antagonism may ameliorate the memory impairing effect of mGlu(5) receptor antagonism. Further, the two components will synergistically interact in blocking food-intake and reducing obesity. For testing the interaction of mGlu(5) and CB(1) receptor antagonism MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pridine; SIB-1757, 6-methyl-2-(phenylazo)-3-pyridinol)] (mGlu(5) antagonist) and rimonabant [(5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)hydrochloride] (CB(1) antagonist) were used. All experiments were carried out in rats. Effects of the compounds on anxiety were tested in two foot shock induced ultrasonic vocalization paradigms, appetite suppression was assessed in the food intake test, while memory effects were tested in a context conditioned ultrasonic vocalization setup. MTEP abolished the anxiogenic effect of rimonabant, while there was an additive cooperation in suppressing appetite. However, rimonabant did not ameliorate the memory impairing effect of MTEP. By combination of CB(1) and mGluR5 antagonism, anxiety related side effects might be attenuated, appetite suppression maintained, nevertheless, the possible emergence of unwanted memory impairments can overshadow its therapeutic success. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation

    Science.gov (United States)

    The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 depositi...

  7. Preparation of deuteriated adipic [2H2]-, [2H4]-, [2H6]-, and [2H8]-acids by use of Kolbe electrolysis as a key reaction

    International Nuclear Information System (INIS)

    Tashiro, Masahi; Tsuzuki, Hirohisa; Mataka, Shuntaro; Goto, Hideyuki; Ogasahara, Shoji

    1990-01-01

    Using Kolbe electrolysis of methyl hydrogen [ 2 H 0 ]-, [ 2 H 2 ]-, and [ 2 H 4 ]-succinates as a key reaction, adipic [2,2- 2 H 2 ]-, [2,3- 2 H 2 ]-, [2,2,3,3- 2 H 4 ]-, [2,3,4,5- 2 H 4 ]-, [2,3,5,5- 2 H 4 ]-, [2,2,3,3,5,5- 2 H 6 ]-, and [2,2,3,3,4,4,5,5- 2 H 8 ]-acids were prepared in high deuterium contents. (author)

  8. Fast Homoepitaxial Growth of 4H-SiC Films on 4° off-Axis Substrates in a SiH4-C2H4-H2 System

    International Nuclear Information System (INIS)

    Liu Bin; Sun Guo-Sheng; Liu Xing-Fang; Zhang Feng; Dong Lin; Zheng Liu; Yan Guo-Guo; Liu Sheng-Bei; Zhao Wan-Shun; Wang Lei; Zeng Yi-Ping; Wang Zhan-Guo; Li Xi-Guang; Yang Fei

    2013-01-01

    Homoepitaxial growth of 4H-SiC epilayers is conducted in a SiH 4 -C 2 H 4 -H 2 system by low pressure hot-wall vertical chemical vapor deposition (CVD). Thick epilayers of 45 μm are achieved at a high growth rate up to 26 μm/h under an optimized growth condition, and are characterized by using a Normaski optical microscope, a scanning electronic microscope (SEM), an atomic force microscope (AFM) and an x-ray diffractometer (XRD), indicating good crystalline quality with mirror-like smooth surfaces and an rms roughness of 0.9 nm in a 5 μm × 5μm area. The dependence of the 4H-SiC growth rate on growth conditions on 4° off-axis 4H-SiC substrates and its mechanism are investigated. It is found that the H 2 flow rate could influence the surface roughness, while good surface morphologies without Si droplets and epitaxial defects such as triangular defects could be obtained by increasing temperature

  9. Understanding Am3+/Cm3+ separation with H4TPAEN and its hydrophilic derivatives: a quantum chemical study.

    Science.gov (United States)

    Huang, Pin-Wen; Wang, Cong-Zhi; Wu, Qun-Yan; Lan, Jian-Hui; Song, Gang; Chai, Zhi-Fang; Shi, Wei-Qun

    2018-05-10

    Am3+/Cm3+ separation is an extremely hard but important task in nuclear waste treatment. In this study, Am and Cm complexes formed with a back-extraction agent N,N,N',N'-tetrakis[(6-carboxypyridin-2-yl)methyl]ethylene-diamine (H4TPAEN) and its two derivatives with hydrophilic substituents (methoxy and morpholine groups) were investigated using the density functional theory (DFT). The optimized geometrical structures indicated that the Am3+ cation matched better with the cavities of the three studied ligands than Cm3+, and the Am3+ cations were located deeper in the cavities of the ligands. The bond order and quantum theory of atoms in molecules (QTAIM) analyses suggested that ionic interactions dominated An-N and An-O (An = Cm and Am) bonds. However, weak and different extents of partial covalency could also be found in the Am-N and Cm-N bonds. The O donor atoms in the carboxylate groups preferably coordinated with Cm3+ rather than Am3+, whereas the N atoms preferred Am3+. Therefore, the Am3+/Cm3+ selectivity of H4TPAEN and its two hydrophilic derivatives may be ascribed to the competition between the An-N and An-O interactions and the few dissimilarities in their geometrical structures. Based on our calculations, the methoxy and morpholine groups in the two derivatives can serve as electron-donating groups and enhance the strength of the An-NPY bonds (NPY denotes the nitrogen atom of pyridine ring). When compared with the Am-complex, the Cm-complex exhibited significant strength effect, resulting in the relatively lower Am3+/Cm3+ separation ability of the H4TPAEN's hydrophilic derivatives.

  10. Analysis of Histones H3 and H4 Reveals Novel and Conserved Post-Translational Modifications in Sugarcane.

    Science.gov (United States)

    Moraes, Izabel; Yuan, Zuo-Fei; Liu, Shichong; Souza, Glaucia Mendes; Garcia, Benjamin A; Casas-Mollano, J Armando

    2015-01-01

    Histones are the main structural components of the nucleosome, hence targets of many regulatory proteins that mediate processes involving changes in chromatin. The functional outcome of many pathways is "written" in the histones in the form of post-translational modifications that determine the final gene expression readout. As a result, modifications, alone or in combination, are important determinants of chromatin states. Histone modifications are accomplished by the addition of different chemical groups such as methyl, acetyl and phosphate. Thus, identifying and characterizing these modifications and the proteins related to them is the initial step to understanding the mechanisms of gene regulation and in the future may even provide tools for breeding programs. Several studies over the past years have contributed to increase our knowledge of epigenetic gene regulation in model organisms like Arabidopsis, yet this field remains relatively unexplored in crops. In this study we identified and initially characterized histones H3 and H4 in the monocot crop sugarcane. We discovered a number of histone genes by searching the sugarcane ESTs database. The proteins encoded correspond to canonical histones, and their variants. We also purified bulk histones and used them to map post-translational modifications in the histones H3 and H4 using mass spectrometry. Several modifications conserved in other plants, and also novel modified residues, were identified. In particular, we report O-acetylation of serine, threonine and tyrosine, a recently identified modification conserved in several eukaryotes. Additionally, the sub-nuclear localization of some well-studied modifications (i.e., H3K4me3, H3K9me2, H3K27me3, H3K9ac, H3T3ph) is described and compared to other plant species. To our knowledge, this is the first report of histones H3 and H4 as well as their post-translational modifications in sugarcane, and will provide a starting point for the study of chromatin regulation in

  11. Investigation of histone H4 hyperacetylation dynamics in the 5S rRNA genes family by chromatin immunoprecipitation assay.

    Science.gov (United States)

    Burlibașa, Liliana; Suciu, Ilinca

    2015-12-01

    Oogenesis is a critical event in the formation of female gamete, whose role in development is to transfer genomic information to the next generation. During this process, the gene expression pattern changes dramatically concomitant with genome remodelling, while genomic information is stably maintained. The aim of the present study was to investigate the presence of H4 acetylation of the oocyte and somatic 5S rRNA genes in Triturus cristatus, using chromatin immunoprecipitation assay (ChIP). Our findings suggest that some epigenetic mechanisms such as histone acetylation could be involved in the transcriptional regulation of 5S rRNA gene families.

  12. A novel fluffy nanostructured 3D network of Ni(C7H4O5) for supercapacitors

    International Nuclear Information System (INIS)

    Chen, Qiulin; Lei, Shuijin; Chen, Lianfu; Deng, Peiqin; Xiao, Yanhe; Cheng, Baochang

    2017-01-01

    Highlights: • The fluffy 3D network of Ni(C 7 H 4 O 5 ) complex is firstly prepared on Ni foam. • The fluffy 3D network shows high areal capacitance and excellent cycle stability. • The fluffy network has large superior pseudocapacitive performance than the powder. • An asymmetric supercapacitor with high capacitance and energy density is assembled. - Abstract: Supercapacitors have raised considerable research interest in recent years due to their extensive potential application in next-generation energy storage. It is always of great importance to develop new electrode materials for supercapacitors so far. In this research, nickel gallate complex (Ni(C 7 H 4 O 5 )) nanostructures are successfully grown on nickel foam by a facile hydrothermal route, which can be directly used as the electrodes for supercapacitors. X-ray diffraction patterns show that the sample is amorphous. The scanning electron microscopy images reveal that the products consist of novel fluffy 3D network with a mass of fibers. The electrochemical measurements demonstrate that the prepared Ni(C 7 H 4 O 5 ) electrode possesses the specific capacitance of 3.688 F cm −2 (1229.3 F g −1 ) at a current density of 9 mA cm −2 (3 A g −1 ). It presents an excellent cycling stability with a capacitance retention of 87.9% after 5000 cycles even at a very high current density of 40 mA cm −2 . An asymmetric supercapacitor device is assembled using the Ni(C 7 H 4 O 5 ) sample as positive electrode and activated carbon as negative one. A high gravimetric capacitance of 71.4 F g −1 at a current density of 0.5 A g −1 can be achieved. The fabricated device delivers the highest energy density of 23.8 W h kg −1 at a power density of 388.2 W kg −1 with a voltage window of 1.55 V. This strategy should be extended to other organometallic compounds for supercapacitors.

  13. No Effect of Nutritional Adenosine Receptor Antagonists on Exercise Performance in the Heat

    Science.gov (United States)

    2008-11-01

    358–363, 1996. 11. Cook NC, Samman S. Flavonoids —chemistry, metabolism, cardiopro- tective effects, and dietary sources. Nutr Biochem 7: 66–76, 1996...metabolism and health effects of dietary flavonoids in man. Biomed Pharmacother 51: 305–310, 1997. R400 ADENOSINE RECEPTOR ANTAGONISM AND EXERCISE IN THE HEAT...Interactions of flavonoids with adenosine receptors. J Med Chem 39: 781–788, 1996. 35. MacRae HS, Mefferd KM. Dietary antioxidant supplementation com

  14. Cancer cell-associated cytoplasmic B7–H4 is induced by hypoxia through hypoxia-inducible factor-1α and promotes cancer cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Jeon, You-Kyoung [Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735 (Korea, Republic of); Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735 (Korea, Republic of); Park, Sae-Gwang; Choi, Il-Whan [Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735 (Korea, Republic of); Lee, Soo-Woong [Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735 (Korea, Republic of); Lee, Sang Min [Department of Internal Medicine, Division of Hematology/Oncology, Busan Paik Hospital, Inje University, Busan 614-735 (Korea, Republic of); Choi, Inhak, E-mail: miccih@inje.ac.kr [Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735 (Korea, Republic of); Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735 (Korea, Republic of)

    2015-04-03

    Aberrant B7–H4 expression in cancer tissues serves as a novel prognostic biomarker for poor survival in patients with cancer. However, the factor(s) that induce cancer cell-associated B7–H4 remain to be fully elucidated. We herein demonstrate that hypoxia upregulates B7–H4 transcription in primary CD138{sup +} multiple myeloma cells and cancer cell lines. In support of this finding, analysis of the Multiple Myeloma Genomics Portal (MMGP) data set revealed a positive correlation between the mRNA expression levels of B7–H4 and the endogenous hypoxia marker carbonic anhydrogenase 9. Hypoxia-induced B7–H4 expression was detected in the cytoplasm, but not in cancer cell membranes. Chromatin immunoprecipitation analysis demonstrated binding of hypoxia-inducible factor-1α (HIF-1α) to proximal hypoxia-response element (HRE) sites within the B7–H4 promoter. Knockdown of HIF-1α and pharmacological inhibition of HIF-1α diminished B7–H4 expression. Furthermore, knockdown of cytoplasmic B7–H4 in MCF-7 decreased the S-phase cell population under hypoxia. Finally, MMGP analysis revealed a positive correlation between the transcript levels of B7–H4 and proliferation-related genes including MKI67, CCNA1, and Myc in several patients with multiple myeloma. Our results provide insight into the mechanisms underlying B7–H4 upregulation and its role in cancer cell proliferation in a hypoxic tumor microenvironment. - Highlights: • Hypoxia upregulates B7–H4 transcription and protein expression. • Hypoxia-induced B7–H4 is detected in the cytoplasm, but not on membrane. • ChIP assay reveals a binding of HIF-1α to B7–H4 promoter at HRE site. • Knockdown and pharmacological inhibition of HIF-1α reduce B7–H4 expression. • B7–H4 knockdown decrease the number of cells in S-phase of cell cycle.

  15. Pharmacological significance of the interplay between angiotensin receptors: MAS receptors as putative final mediators of the effects elicited by angiotensin AT1 receptors antagonists.

    Science.gov (United States)

    Pernomian, Larissa; Pernomian, Laena; Gomes, Mayara S; da Silva, Carlos H T P

    2015-12-15

    The interplay between angiotensin AT1 receptors and MAS receptors relies on several inward regulatory mechanisms from renin-angiotensin system (RAS) including the functional crosstalk between angiotensin II and angiotensin-(1-7), the competitive AT1 antagonism exhibited by angiotensin-(1-7), the antagonist feature assigned to AT1/MAS heterodimerization on AT1 signaling and the AT1-mediated downregulation of angiotensin-converting enzyme 2 (ACE2). Recently, such interplay has acquired an important significance to RAS Pharmacology since a few studies have supporting strong evidences that MAS receptors mediate the effects elicited by AT1 antagonists. The present Perspective provides an overview of the regulatory mechanisms involving AT1 and MAS receptors, their significance to RAS Pharmacology and the future directions on the interplay between angiotensin receptors. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. In-situ investigation of the hydrogen release mechanism in bulk Mg2NiH4

    Science.gov (United States)

    Tran, Xuan Quy; McDonald, Stuart D.; Gu, Qinfen; Yamamoto, Tomokazu; Shigematsu, Koji; Aso, Kohei; Tanaka, Eishi; Matsumura, Syo; Nogita, Kazuhiro

    2017-02-01

    Hydrogen storage is an important aspect to enable the so-called hydrogen economy. Mg-Ni alloys are among the most promising candidates for solid-state hydrogen storage systems yet many questions remain unanswered regarding the hydriding/dehydriding mechanism of the alloys. Mg2NiH4 particularly has received much attention both for its potential as a hydrogen storage medium and also exhibits interesting properties relating to its different polymorphs. Here, the dehydriding mechanism in bulk Mg2NiH4 is investigated using in-situ ultra-high voltage transmission electron microscopy (TEM) combined with Synchrotron powder X-ray diffraction (XRPD) and differential scanning calorimetry (DSC). We find that the hydrogen release is based on a mechanism of nucleation and growth of Mg2NiHx (x∼0-0.3) solid solution grains and is greatly enhanced in the presence of crystal defects occurring as a result of the polymorphic phase transformation. Also importantly, with atomic resolution TEM imaging a high density of stacking faults is identified in the dehydrided Mg2NiHx (x∼0-0.3) lattices.

  17. Histone H4 acetylation by immunohistochemistry and prognosis in newly diagnosed adult acute lymphoblastic leukemia (ALL) patients

    International Nuclear Information System (INIS)

    Advani, Anjali S; Sungren, Shawnda; Hsi, Eric D; Gibson, Sarah E; Douglas, Elizabeth; Jin, Tao; Zhao, Xiaoxian; Kalaycio, Matt; Copelan, Ed; Sobecks, Ronald; Sekeres, Mikkael

    2010-01-01

    Histone deacetylase (HDAC) inhibitors are a novel anti-tumor therapy. To determine whether HDAC inhibitors may be useful in the treatment of adult acute lymphoblastic leukemia (ALL), we examined the acetylation of histone H4 by immunohistochemistry in newly diagnosed ALL patients and evaluated the impact of acetylation on complete remission (CR) rate, relapse-free survival (RFS), and overall survival (OS). Patients ≥18 years of age and an available diagnostic bone marrow biopsy were evaluated. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, RFS, and OS. The variables histone H4 acetylation (positive or negative), white blood count, cytogenetic (CG) risk group (CALGB criteria), and age were used in multivariate analysis. On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09). In patients without poor risk CG, there was an impressive association between the presence of histone acetylation and an improved CR rate (OR 3.43, p = 0.035), RFS (HR 0.07, p = 0.005), and OS (HR 0.24, p = 0.007). This association remained statistically significant in multivariate analysis. These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL

  18. Serological evidence of asymptomatic infections during Escherichia coli O104:H4 outbreak in Germany in 2011.

    Directory of Open Access Journals (Sweden)

    Yanina Balabanova

    Full Text Available INTRODUCTION: The largest known outbreak caused by a rare hybrid strain of Shiga toxin-producing E.coli (STEC and enteroaggregative E. coli (EAEC (E.coli O104:H4 of serotype O104:H4 occurred in Germany in 2011. Fenugreek sprouts acted as a transmission vehicle and were widely consumed in the outbreak area at the time of the epidemic. In total 3,842 people developed a clinical illness caused by this strain; however the rates of asymptomatic infections remain unclear. We aimed to develop a serological assay for detection of E.coli O104 LPS specific antibodies and to establish the post-outbreak levels of seropositivity among people with documented exposure to contaminated sprouts. RESULTS AND DISCUSSION: Developed serological assays (ELISA with 84% sensitivity, 63% specificity and Western Blot with 100% sensitivity, 82.5% specificity identified 33% (16/49 level of asymptomatic infection. Relatively small sample size and a significant time- lapse between the onset of symptoms and serum samples collection (appr. 8 weeks might explain the assay variability. No association was found between clinical or demographic characteristics and assay positivity. Larger studies are needed to understand the complexity of human immune response and factors influencing development of clinical symptoms. Development of intra-outbreak research plans will substantially aid the conduct of more thorough scientific investigation during an outbreak period.

  19. Synthesis and spectral studies of Pd(II) complexes with 2, 3-disubstituted quinazolin-(3H)-4-ones

    International Nuclear Information System (INIS)

    Prabhakar, B.; Lingaiah, P.; Laxima Reddy, K.

    1991-01-01

    A number of palladium(II) complexes of bidentate O-O and O-N donors, 2,3-disubstituted quinazoline-(3H)-4-ones, have been synthesized and characterized based on analytical, conductivity, magnetic, thermal, IR, electronic and PMR spectral data. The complexes of Pd(II) with ligands such as 2-(R)-3-(X)-substituted quinazoline-(3H)-4-ones, where R=methyl/phenyl and X=2'-hydroxybenzalimino (MHBQ/PHBQ), carboxymethyl (MCMQ/PCMQ), furfuralimino (MFQ/PFQ), acetamino (MAQ/PAQ), uramino (MUQ/PUQ) and thiouramino (MTUQ/PTUQ), yielded the complexes of the type [Pd(O-N) 2 ]Cl 2 and [Pd(O-O) 2 ]. The IR and PMR spectral data of the metal complexes indicate that MHQB, PHQB, MCMQ, and PCMQ act as uninegative bidentate ligands whereas MFQ, PFQ, MAQ, PAQ, MUQ, PUQ, MTUQ and PTUQ act as neutral bidentate ligands. The electronic spectral studies of these complexes indicate that they were square-planar geometry. (author). 23 refs., 2 tabs

  20. The influence of ball-milling time on the dehydrogenation properties of the NaAlH4-MgH2 composite

    NARCIS (Netherlands)

    Bendyna, J.K.; Dyjak, S.M.; Notten, P.H.L.

    2015-01-01

    The recently developed NaAlH4eMgH2 composite shows improved hydrogen-storage properties compared to MgH2 and NaAlH4. However, the dehydrogenation reaction rates are still too limited, hampering practical applications. Mechanical ball milling is broadly used to improve the dehydrogenation reaction

  1. 24 CFR 257.203 - Calculation of up-front and annual mortgage insurance premiums for H4H program mortgages.

    Science.gov (United States)

    2010-04-01

    ... mortgage insurance premiums for H4H program mortgages. 257.203 Section 257.203 Housing and Urban... mortgage insurance premiums for H4H program mortgages. (a) Applicable premiums. Any mortgage presented for... LOAN INSURANCE PROGRAMS UNDER NATIONAL HOUSING ACT AND OTHER AUTHORITIES HOPE FOR HOMEOWNERS PROGRAM...

  2. Evidence for two distinct defects contributing to the H4 deep-level transient spectroscopy peak in electron-irradiated InP

    International Nuclear Information System (INIS)

    Darwich, R.; Massarani, B.; Kaaka, M.; Awad, F.

    2000-01-01

    Deep-level transient spectroscopy (DLTS) has been used to study the dominant deep-level H4 produced in InP by electron irradiation. The characteristics of the H4 peak in Zn-doped Inp has been studied as a function of pulse duration (t p ) before and after annealing. The results show that at least two traps contribute to the H4 peak: one is a fast trap (labeled H4 f ) and the other is a show trap (labeled H4 s ). This is show through several results concerning the activation energy, the capture cross section, the full width at half-maximum, and the peak temperature shift. It is shown that both traps are irradiation defects created in P sublattice. (authors)

  3. Does gestrinone antagonize the effects of estrogen on endometrial implants upon the peritoneum of rats?

    Directory of Open Access Journals (Sweden)

    Vera Lúcia Rodrigues Lobo

    2008-01-01

    Full Text Available OBJECTIVE: To evaluate the effects of estrogen treatment in combination with gestrinone on an experimental rat model of endometriosis. METHODS: Uterine transplants were attached to the peritoneum of female Wistar rats via a surgical autotransplantation technique. The implanted area was measured during the proestrus phase and after hormonal treatment. We performed morphometric analysis and examined the macroscopic and morphometric alterations of endometrial implants after hormonal treatment in ovariectomized rats. RESULTS: The high dose of estrogen caused macroscopic increases in the endometrial implant group compared with other groups, which were similar to increases in the proestrus phase. The low dose showed morphometric development of implants, such as an increase in number of endometrial glands, leukocyte infiltration and mitosis. Gestrinone antagonized both doses of estrogen. CONCLUSION: Our findings suggest that gestrinone antagonizes estrogen's effects on rat peritoneal endometrial implants.

  4. Antipsychotic-like effect of the muscarinic acetylcholine receptor agonist BuTAC in non-human primates

    DEFF Research Database (Denmark)

    Andersen, Maibritt B; Croy, Carrie Hughes; Dencker, Ditte

    2015-01-01

    Cholinergic, muscarinic receptor agonists exhibit functional dopamine antagonism and muscarinic receptors have been suggested as possible future targets for the treatment of schizophrenia and drug abuse. The muscarinic ligand (5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane...... (BuTAC) exhibits high affinity for muscarinic receptors with no or substantially less affinity for a large number of other receptors and binding sites, including the dopamine receptors and the dopamine transporter. In the present study, we wanted to examine the possible antipsychotic-like effects...

  5. [Antagonism in vitro among phytopathogenic and saprobic fungi from horticultural soils].

    Science.gov (United States)

    Alippi, H E; Monaco, C

    1990-01-01

    Two methods were tested in order to determine the existence of in vitro antagonism among saprobic and pathogenic fungi. These microorganisms were the most common isolates from horticultural soils of La Plata (Buenos Aires). Trichoderma harzianum; T. koningii and Penicillium sp. were antagonistic to all the pathogenic fungi tested, Fusarium solani; F. oxysporum; Alternaria solani; Colletotrichum sp. and Sclerotium rolfsii Spicaria sp., Paecilomyces sp. and Chaetomiun sp. were antagonistic only to Colletotrichum sp. and Fusarium solani.

  6. In vitro antagonism of Trichoderma harzianum Rifai against Mycosphaerella fijiensis Morelet

    Directory of Open Access Journals (Sweden)

    Mayra Acosta-Suárez

    2013-10-01

    Full Text Available The in vitro antagonism of Trichoderma harzianum against Mycosphaerella fijiensis, foliar pathogen of banana and plantain, was evaluated. The assays were performed using the dual culture method. Competition for space and nutrients, the antagonistic capacity and forms and intensity of antagonism were determined considering the invasion of the surface of the colony, colonization and sporulation of T. harzianum on M. fijiensis after seven days of inoculation. Finally, the effect of volatile metabolites of T. harzianum was evaluated. The results showed in vitro antagonism of T. harzianum against M. fijiensis by competition for space and nutrients of the culture medium. Trichoderma grew over the pathogen colony with hyperparasitism and high intensity. Also, it completely covered the surface of the culture medium. T. harzianum not inhibited the growth of M. fijiensis by volatile metabolites. Damage was observed in the integrity of the cell wall of M. fijiensis hyphae and the cell content exit. The use of antagonistic fungi, could contribute to the design of strategies for integrated management of this disease. Key words: banana and plantain, biocontrol, mechanisms of action

  7. Antagonism of Sorafenib and Regorafenib actions by platelet factors in hepatocellular carcinoma cell lines

    International Nuclear Information System (INIS)

    D’Alessandro, Rosalba; Refolo, Maria G; Lippolis, Catia; Giannuzzi, Grazia; Carella, Nicola; Messa, Caterina; Cavallini, Aldo; Carr, Brian I

    2014-01-01

    Platelets are frequently altered in hepatocellular carcinoma (HCC) patients. Platelet lysates (hPL) can enhance HCC cell growth and decrease apoptosis. The aims were to evaluate whether hPL can modulate the actions of Sorafenib or Regorafenib, two clinical HCC multikinase antagonists. Several human HCC cell lines were grown in the presence and absence of Sorafenib or Regorafenib, with or without hPL. Growth was measured by MTT assay, apoptosis was assessed by Annexin V and by western blot, and autophagy and MAPK growth signaling were also measured by western blot, and migration and invasion were measured by standard in vitro assays. Both Sorafenib and Regorafenib-mediated inhibition of cell growth, migration and invasion were all antagonized by hPL. Drug-mediated apoptosis and decrease in phospho-ERK levels were both blocked by hPL, which also increased anti-apoptotic phospho-STAT, Bax and Bcl-xL levels. Preliminary data, obtained with epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I), included in hPL, revealed that these factors were able to antagonized Sorafenib in a proliferation assay, in particular when used in combination. Platelet factors can antagonize Sorafenib or Regorafenib-mediated growth inhibition and apoptosis in HCC cells. The modulation of platelet activity or numbers has the potential to enhance multikinase drug actions

  8. [Antagonism against Beauveria bassiana by lipopeptide metabolites produced by entophyte Bacillus amyloliquefaciens strain SWB16].

    Science.gov (United States)

    Wang, Jingjie; Zhao, Dongyang; Liu, Yonggui; Ao, Xiang; Fan, Rui; Duan, Zhengqiao; Liu, Yanping; Chen, Qianqian; Jin, Zhixiong; Wan, Yongji

    2014-07-04

    We screened bacterial strains that have strong antagonism against Beauveria bassiana, an important pathogen of silkworm industry, and detected the antagonistic activity of lipopeptide metabolites. We identified bacterium SWB16 by morphological observation, physiological and biochemical experiments, 16SrRNA, and gyrA gene sequence analysis, tested antagonistic activity of strain SWB16 against Beauveria bassiana by measuring the inhibition zone diameter using filter paper diffusion method (Kirby-Bauer method), obtained lipopeptide metabolites of the strain using methanol extraction and observed the antagonism of strain SWB16 lipopeptide extracts against the conidia and hyphae of Beauveria bassiana, detected main ingredients and genes of lipopeptide metabolites by high-performance liquid chromatography-mass spectrometry and PCR amplification. SWB16 isolated from tissue of plant Dioscorea zingiberensis C. H. Wright belongs to Bacillus amyloliquefaciens and showed high antagonistic activity to Beauveria bassiana, and the lipopeptide extracts of isolate SWB16 exhibited significant inhibition to conidial germination and mycelial growth of Beauveria bassiana. The result of mass spectrometric detection indicated main component of the lipopeptide metabolites were fengcin and iturin, and genes fenB, ituA involved in the synthesis of them were amplified in the genome. Bacillus amyloliquefaciens strain SWB16 could produce lipopeptide antibiotics with strong antagonism to the entomopathogenic fungus Beauveria bassiana, and the results suggested that strain SWB16 has potential application value for controlling white muscardine of economic insects including silkworm.

  9. Growth of crystallized Ge films from VHF inductively-coupled plasma of H2-diluted GeH4

    International Nuclear Information System (INIS)

    Sakata, T.; Makihara, K.; Murakami, H.; Higashi, S.; Miyazaki, S.

    2007-01-01

    We have studied the Ge crystalline nucleation and film growth on quartz substrate at 250 deg. C from inductively-coupled plasma (ICP) of GeH 4 diluted with H 2 . The ICP was generated by supplying 60 MHz power to an external single-turn antenna which was placed on a quartz plate window of a stainless steel reactor and parallel to the substrate. We have found that the growth rate is significantly increased when the preferential growth of the (110) plane becomes pronounced after the formation of randomly-oriented crystalline network. The (110) oriented Ge films, of which average crystallinity is as high as 70%. The integrated intensity ratio of TO phonons in crystalline phase to those in disordered phase, were grown at a rate of ∼ 4.0 nm/s after the formation of amorphous incubation layer with a thickness of ∼ 0.1 μm on quartz

  10. Mechanisms controlling temperature dependent mechanical and electrical behavior of SiH4 reduced chemically vapor deposited W

    International Nuclear Information System (INIS)

    Joshi, R.V.; Prasad, V.; Krusin-Elbaum, L.; Yu, M.; Norcott, M.

    1990-01-01

    The effects of deposition temperature on growth, composition, structure, adhesion properties, stress, and resistivity of chemically vapor deposited W deposited purely by SiH 4 reduction of WF 6 are discussed. At lower deposition temperatures, due to incomplete Si reduction reaction, a small amount of Si is incorporated in the film. This elemental Si in W is responsible for the observed high stresses and high resistivities over a wide temperature range. With the increase in the deposition temperature, the conversion of incorporated Si as well as the initial Si reduction are taking place, stimulating increased grain growth and thereby relieving stress and reducing resistivity. The optimum values for stress and resistivity are achieved around 500 degree C, as Si content is at its minimum. At higher temperatures the reaction between residual Si and W, is the prime cause of resistivity increase

  11. Histone deacetylase 1, 2, 6 and acetylated histone H4 in B- and T-cell lymphomas

    DEFF Research Database (Denmark)

    Marquard, L.; Poulsen, C.B.; Gjerdrum, L.M.

    2009-01-01

    AIMS: Histone deacetylase (HDAC) inhibitors are novel therapeutics in the treatment of peripheral T-cell lymphoma, unspecified (PTCL) and diffuse large B-cell lymphoma (DLBCL), where, for unknown reasons, T-cell malignancies appear to be more sensitive than B-cell malignancies. The aim was to det......AIMS: Histone deacetylase (HDAC) inhibitors are novel therapeutics in the treatment of peripheral T-cell lymphoma, unspecified (PTCL) and diffuse large B-cell lymphoma (DLBCL), where, for unknown reasons, T-cell malignancies appear to be more sensitive than B-cell malignancies. The aim...... was to determine HDAC expression in DLBCL and PTCL which has not previously been investigated. METHODS AND RESULTS: The expression of HDAC1, HDAC2, HDAC6 and acetylated histone H4 was examined immunohistochemically in 31 DLBCL and 45 PTCL. All four markers showed high expression in both DLBCL and PTCL compared...

  12. Quantitative analysis of modified proteins and their positional isomers by tandem mass spectrometry: human histone H4.

    Science.gov (United States)

    Pesavento, James J; Mizzen, Craig A; Kelleher, Neil L

    2006-07-01

    Here we show that fragment ion abundances from dissociation of ions created from mixtures of multiply modified histone H4 (11 kDa) or of N-terminal synthetic peptides (2 kDa) correspond to their respective intact ion abundances measured by Fourier transform mass spectrometry. Isomeric mixtures of modified forms of the same protein are resolved and quantitated with a precision of

  13. Shedding light on avian influenza H4N6 infection in mallards: modes of transmission and implications for surveillance.

    Directory of Open Access Journals (Sweden)

    Kaci K VanDalen

    Full Text Available BACKGROUND: Wild mallards (Anas platyrhychos are considered one of the primary reservoir species for avian influenza viruses (AIV. Because AIV circulating in wild birds pose an indirect threat to agriculture and human health, understanding the ecology of AIV and developing risk assessments and surveillance systems for prevention of disease is critical. METHODOLOGY/PRINCIPAL FINDINGS: In this study, mallards were experimentally infected with an H4N6 subtype of AIV by oral inoculation or contact with an H4N6 contaminated water source. Cloacal swabs, oropharyngeal swabs, fecal samples, and water samples were collected daily and tested by real-time RT-PCR (RRT-PCR for estimation of viral shedding. Fecal samples had significantly higher virus concentrations than oropharyngeal or cloacal swabs and 6 month old ducks shed significantly more viral RNA than 3 month old ducks regardless of sample type. Use of a water source contaminated by AIV infected mallards, was sufficient to transmit virus to naïve mallards, which shed AIV at higher or similar levels as orally-inoculated ducks. CONCLUSIONS: Bodies of water could serve as a transmission pathway for AIV in waterfowl. For AIV surveillance purposes, water samples and fecal samples appear to be excellent alternatives or additions to cloacal and oropharyngeal swabbing. Furthermore, duck age (even within hatch-year birds may be important when interpreting viral shedding results from experimental infections or surveillance. Differential shedding among hatch-year mallards could affect prevalence estimates, modeling of AIV spread, and subsequent risk assessments.

  14. The Effects of Alpha Interferon on the Development of Autoimmune Thyroiditis in the NOD H2h4 Mouse

    Directory of Open Access Journals (Sweden)

    Yael Oppenheim

    2003-01-01

    Full Text Available Alpha interferon (αIFN therapy is known to induce thyroid autoimmunity in up to 40% of patients. The mechanism is unknown, but Th1 switching has been hypothesized. The aim of our study was to examine whether αIFN accelerated the development of thyroiditis in genetically susceptible mice. We took advantage of NOD-H2h4, a genetically susceptible animal model, which develops thyroiditis when fed a high iodine diet. Six to eight week old male NOD H2h4 mice were injected with mouse αIFN (200 units or with saline three times a week for 8 weeks. All mice drank iodinated water (0.15%. Mice were sacrificed after 8 weeks of injection. Their thyroids were examined for histology and blood was tested for antithyroglobulin antibody levels. T4 and glucose levels were also assessed. In the IFN-injected group, 6/13 (46.2% developed thyroiditis and/or thyroid antibodies while in the saline-injected group, only 4/13 (30.8% developed thyroiditis and/or thyroid antibodies (p=0.4. The grade of thyroiditis was not different amongst the two groups. None of the mice developed clinical thyroiditis or diabetes mellitus. Our results showed that αIFN treatment did not accelerate thyroiditis in this mouse model. This may imply that αIFN induces thyroiditis in a non-genetically dependent manner, and this would not be detected in a genetically susceptible mouse model if the effect were small. Alternatively, it is possible that αIFN did not induce thyroiditis in mice because, unlike in humans, in mice αIFN does not induce Th1 switching.

  15. Protective and detrimental effects of kaempferol in rat H4IIE cells: Implication of oxidative stress and apoptosis

    International Nuclear Information System (INIS)

    Niering, Petra; Michels, Gudrun; Waetjen, Wim; Ohler, Sandra; Steffan, Baerbel; Chovolou, Yvonni; Kampkoetter, Andreas; Proksch, Peter; Kahl, Regine

    2005-01-01

    Flavonoids are ubiquitous substances in fruits and vegetables. Among them, the flavonol kaempferol contributes up to 30% of total dietary flavonoid intake. Flavonoids are assumed to exert beneficial effects on human health, e.g., anticancer properties. For this reason, they are used in food supplements at high doses. The aim of this project was to determine the effects of kaempferol on oxidative stress and apoptosis in H4IIE rat hepatoma cells over a broad concentration range. Kaempferol is rapidly taken up and glucuronidated by H4IIE cells. The results demonstrate that kaempferol protects against H 2 O 2 -induced cellular damage at concentrations which lead to cell death and DNA strand breaks in the absence of H 2 O 2 -mediated oxidative stress. Preincubation with 50 μM kaempferol exerts protection against the loss of cell viability induced by 500 μM H 2 O 2 (2 h) while the same concentration of kaempferol reduces cell viability by 50% in the absence of H 2 O 2 (24 h). Preincubation with 50 μM kaempferol ameliorates the strong DNA damage induced by 500 μM H 2 O 2 while 50 μM kaempferol leads to a significant increase of DNA breakage in the absence of H 2 O 2 . Preincubation with 50 μM kaempferol reduces H 2 O 2 -mediated caspase-3 activity by 40% (4 h) while the same concentration of kaempferol leads to the formation of a DNA ladder in the absence of H 2 O 2 (24 h). It is concluded that the intake of high dose kaempferol in food supplements may not be advisable because in our cellular model protective kaempferol concentrations can also induce DNA damage and apoptosis by themselves

  16. Ihh enhances differentiation of CFK-2 chondrocytic cells and antagonizes PTHrP-mediated activation of PKA.

    Science.gov (United States)

    Deckelbaum, Ron A; Chan, George; Miao, Dengshun; Goltzman, David; Karaplis, Andrew C

    2002-07-15

    Indian Hedgehog (Ihh), a member of the hedgehog (HH) family of secreted morphogens, and parathyroid hormone-related peptide (PTHrP) are key regulators of cartilage cell (chondrocyte) differentiation. We have investigated, in vitro, the actions of HH signalling and its possible interplay with PTHrP using rat CFK-2 chondrocytic cells. Markers of chondrocyte differentiation [alkaline phosphatase (ALP) activity, and type II (Col2a1) and type X collagen (Col10a1) expression] were enhanced by overexpression of Ihh or its N-terminal domain (N-Ihh), effects mimicked by exogenous administration of recombinant N-terminal HH peptide. Moreover, a missense mutation mapping to the N-terminal domain of Ihh (W160G) reduces the capacity of N-Ihh to induce differentiation. Prolonged exposure of CFK-2 cells to exogenous N-Shh (5x10(-9) M) in the presence of PTHrP (10(-8) M) or forskolin (10(-7) M) resulted in perturbation of HH-mediated differentiation. In addition, overexpression of a constitutively active form of the PTHrP receptor (PTHR1 H223R) inhibited Ihh-mediated differentiation, implicating activation of protein kinase A (PKA) by PTHR1 as a probable mediator of the antagonistic effects of PTHrP. Conversely, overexpression of Ihh/N-Ihh or exogenous treatment with N-Shh led to dampening of PTHrP-mediated activation of PKA. Taken together, our data suggest that Ihh harbors the capacity to induce rather than inhibit chondrogenic differentiation, that PTHrP antagonizes HH-mediated differentiation through a PKA-dependent mechanism and that HH signalling, in turn, modulates PTHrP action through functional inhibition of signalling by PTHR1 to PKA.

  17. The histone H4 lysine 20 monomethyl mark, set by PR-Set7 and stabilized by L(3mbt, is necessary for proper interphase chromatin organization.

    Directory of Open Access Journals (Sweden)

    Ayako Sakaguchi

    Full Text Available Drosophila PR-Set7 or SET8 is a histone methyltransferase that specifically monomethylates histone H4 lysine 20 (H4K20. L(3MBT has been identified as a reader of methylated H4K20. It contains several conserved domains including three MBT repeats binding mono- and dimethylated H4K20 peptides. We find that the depletion of PR-Set7 blocks de novo H4K20me1 resulting in the immediate activation of the DNA damage checkpoint, an increase in the size of interphase nuclei, and drastic reduction of cell viability. L(3mbt on the other hand stabilizes the monomethyl mark, as L(3mbt-depleted S2 cells show a reduction of more than 60% of bulk monomethylated H4K20 (H4K20me1 while viability is barely affected. Ploidy and basic chromatin structure show only small changes in PR-Set7-depleted cells, but higher order interphase chromatin organization is significantly affected presumably resulting in the activation of the DNA damage checkpoint. In the absence of any other known functions of PR-Set7, the setting of the de novo monomethyl mark appears essential for cell viability in the presence or absence of the DNA damage checkpoint, but once newly assembled chromatin is established the monomethyl mark, protected by L(3mbt, is dispensable.

  18. PR-Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription

    Science.gov (United States)

    Beck, David B.; Oda, Hisanobu; Shen, Steven S.; Reinberg, Danny

    2012-01-01

    Histone post-translational modifications impact many aspects of chromatin and nuclear function. Histone H4 Lys 20 methylation (H4K20me) has been implicated in regulating diverse processes ranging from the DNA damage response, mitotic condensation, and DNA replication to gene regulation. PR-Set7/Set8/KMT5a is the sole enzyme that catalyzes monomethylation of H4K20 (H4K20me1). It is required for maintenance of all levels of H4K20me, and, importantly, loss of PR-Set7 is catastrophic for the earliest stages of mouse embryonic development. These findings have placed PR-Set7, H4K20me, and proteins that recognize this modification as central nodes of many important pathways. In this review, we discuss the mechanisms required for regulation of PR-Set7 and H4K20me1 levels and attempt to unravel the many functions attributed to these proteins. PMID:22345514

  19. Pathophysiological Consequences of a Break in S1P1-Dependent Homeostasis of Vascular Permeability Revealed by S1P1 Competitive Antagonism.

    Science.gov (United States)

    Bigaud, Marc; Dincer, Zuhal; Bollbuck, Birgit; Dawson, Janet; Beckmann, Nicolau; Beerli, Christian; Fishli-Cavelti, Gina; Nahler, Michaela; Angst, Daniela; Janser, Philipp; Otto, Heike; Rosner, Elisabeth; Hersperger, Rene; Bruns, Christian; Quancard, Jean

    2016-01-01

    Homeostasis of vascular barriers depends upon sphingosine 1-phosphate (S1P) signaling via the S1P1 receptor. Accordingly, S1P1 competitive antagonism is known to reduce vascular barrier integrity with still unclear pathophysiological consequences. This was explored in the present study using NIBR-0213, a potent and selective S1P1 competitive antagonist. NIBR-0213 was tolerated at the efficacious oral dose of 30 mg/kg BID in the rat adjuvant-induced arthritis (AiA) model, with no sign of labored breathing. However, it induced dose-dependent acute vascular pulmonary leakage and pleural effusion that fully resolved within 3-4 days, as evidenced by MRI monitoring. At the supra-maximal oral dose of 300 mg/kg QD, NIBR-0213 impaired lung function (with increased breathing rate and reduced tidal volume) within the first 24 hrs. Two weeks of NIBR-0213 oral dosing at 30, 100 and 300 mg/kg QD induced moderate pulmonary changes, characterized by alveolar wall thickening, macrophage accumulation, fibrosis, micro-hemorrhage, edema and necrosis. In addition to this picture of chronic inflammation, perivascular edema and myofiber degeneration observed in the heart were also indicative of vascular leakage and its consequences. Overall, these observations suggest that, in the rat, the lung is the main target organ for the S1P1 competitive antagonism-induced acute vascular leakage, which appears first as transient and asymptomatic but could lead, upon chronic dosing, to lung remodeling with functional impairments. Hence, this not only raises the question of organ specificity in the homeostasis of vascular barriers, but also provides insight into the pre-clinical evaluation of a potential safety window for S1P1 competitive antagonists as drug candidates.

  20. Stacking reactions of the borole complex Cp*Rh(η5-C4H4BPh) with the dicationic fragments [Cp*M]2+ (M = Rh or Ir)

    International Nuclear Information System (INIS)

    Loginov, D.A.; Muratov, D.V.; Starikova, Z.A.; Petrovskij, P.V.; Kudinov, A.R.

    2006-01-01

    The reaction of the (borole)rhodium iodide complex [(η-C 4 H 4 BPh)RhI] 4 with Cp*Li afforded the sandwich compound Cp*Rh(η-C 4 H 4 BPh) (1). The reactions of compound 1 with the solvated complexes [Cp*M(MeNO 2 ) 3 ] 2+ (BF 4 - ) 2 gave triple-decker cationic complexes with the central borole ligand [Cp*Rh(μ-η 5 :η 5 -C 4 H 4 BPh)MCp*] 2+ (BF 4 - ) 2 (M = Rh or Ir). The structure of complex 1 was established by X-ray diffraction [ru

  1. Low cost silicon solar array project. Task 1: Establishment of the feasibility of a process capable of low cost, high volume production of silane, SiH4

    Science.gov (United States)

    Breneman, W. C.; Mui, J. Y. P.

    1976-01-01

    The kinetics of the redistribution of dichlorosilane and trichlorosilane vapor over a tertiary amine ion exchange resin catalyst were investigated. The hydrogenation of SiCl4 to form HSiCl3 and the direct synthesis of H2SiCl2 from HCl gas and metallurgical silicon metal were also studied. The purification of SiH4 using activated carbon adsorbent was studied along with a process for storing SiH4 absorbed on carbon. The latter makes possible a higher volumetric efficiency than compressed gas storage. A mini-plant designed to produce ten pounds per day of SiH4 is described.

  2. 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...

  3. Arginine vasopressin antagonizes the effects of prostaglandin E2 on the spontaneous activity of warm-sensitive and temperature-insensitive neurons in the medial preoptic area in rats.

    Science.gov (United States)

    Xu, Jian-Hui; Hou, Xiao-Yu; Tang, Yu; Luo, Rong; Zhang, Jie; Liu, Chang; Yang, Yong-Lu

    2018-01-01

    Arginine vasopressin (AVP) plays an important role in thermoregulation and antipyresis. We have demonstrated that AVP could change the spontaneous activity of thermosensitive and temperature insensitive neurons in the preoptic area. However, whether AVP influences the effects of prostaglandin E 2 (PGE 2 ) on the spontaneous activity of neurons in the medial preoptic area (MPO) remains unclear. Our experiment showed that PGE 2 decreased the spontaneous activity of warm-sensitive neurons, and increased that of low-slope temperature-insensitive neurons in the MPO. AVP attenuated the inhibitory effect of PGE 2 on warm-sensitive neurons, and reversed the excitatory effect of PGE 2 on low-slope temperature-insensitive neurons, demonstrating that AVP antagonized the effects of PGE 2 on the spontaneous activity of these neurons. The effect of AVP was suppressed by an AVP V 1a receptor antagonist, suggesting that V 1a receptor mediated the action of AVP. We also demonstrated that AVP attenuated the PGE 2 -induced decrease in the prepotential's rate of rise in warm-sensitive neurons and the PGE 2 -induced increase in that in low-slope temperature-insensitive neurons through the V 1a receptor. Together, these data indicated that AVP antagonized the PGE 2 -induced change in the spontaneous activity of warm-sensitive and low-slope temperature-insensitive neurons in the MPO partly by reducing the PGE 2 -induced change in the prepotential of these neurons in a V 1a receptor-dependent manner. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Quantum-Chemical ab initio Calculations on the Three Isomers of Diborabenzene (C4H4B2)

    Science.gov (United States)

    Singh, Jaswinder; Wang, Yuekui; Raabe, Gerhard

    2010-01-01

    Quantum-chemical ab initio calculations up to the ZPE+CCSD(T)/aug-cc-pVTZ//MP2/6- 311++G** level were performed on three possible structural isomers of diborabenzene (C4H4B2). All three molecules were found to be local minima on the C4H4B2 energy surface and to have closed shell singlet ground states. While the ground states of the 1,3- and 1,4-isomer are planar and of C2v and D2h symmetry, respectively, 1,2-diborabenzene is non-planar with a C2 axis passing through the center of the BB bond and the middle of the opposite carbon-carbon bond as the only symmetry element. The energetically most favourable 1,3-diborabenzene was found to be about 19 and 36 kcal/mol lower in energy than the 1,2- and the 1,4-isomer. Planar 1,3- and 1,4-diborabenzene have three doubly occupied π orbitals while non-planar 1,2-diborabenzene has also three doubly occupied orbitals which can be derived from the π orbitals of its 3.7 kcal/mol energetically less favourable planar form ("π-like" orbitals). The lowest unoccupied orbitals of all three isomers have σ symmetry with large coefficients at the two boron atoms. These orbitals are lower in energy than the lowest unoccupied molecular orbitals (LUMOs) of e. g. benzene and pyridine and might cause pronounced acceptor properties which could be one of the reasons for the elusiveness of the title compounds. The results of bond separation reactions show that cyclic conjugation stabilizes all three diborabenzenes relative to their isolated fragments. The most effective stabilization energy of about 24 kcal/mol was found for the energetically lowest 1,3-isomer. This value amounts to approximately one third of the experimental value for the bond separation energy of pyridine. In all cases the energetically lowest triplet states are significantly (16 - 24 kcal/mol) higher in energy than the singlet ground states. Also among the triplets the 1,3-isomer is the energetically most fabourable species.

  5. Dual interaction of agmatine with the rat α2D-adrenoceptor: competitive antagonism and allosteric activation

    Science.gov (United States)

    Molderings, G J; Menzel, S; Kathmann, M; Schlicker, E; Göthert, M

    2000-01-01

    In segments of rat vena cava preincubated with [3H]-noradrenaline and superfused with physiological salt solution, the influence of agmatine on the electrically evoked [3H]-noradrenaline release, the EP3 prostaglandin receptor-mediated and the α2D-adrenoceptor-mediated inhibition of evoked [3H]-noradrenaline release was investigated. Agmatine (0.1–10 μM) by itself was without effect on evoked [3H]-noradrenaline release. In the presence of 10 μM agmatine, the prostaglandin E2(PGE2)-induced EP3-receptor-mediated inhibition of [3H]-noradrenaline release was not modified, whereas the α2D-adrenoceptor-mediated inhibition of [3H]-noradrenaline release induced by noradrenaline, moxonidine or clonidine was more pronounced than in the absence of agmatine. However, 1 mM agmatine antagonized the moxonidine-induced inhibition of [3H]-noradrenaline release. Agmatine concentration-dependently inhibited the binding of [3H]-clonidine and [3H]-rauwolscine to rat brain cortex membranes (Ki values 6 μM and 12 μM, respectively). In addition, 30 and 100 μM agmatine increased the rate of association and decreased the rate of dissociation of [3H]-clonidine resulting in an increased affinity of the radioligand for the α2D-adrenoceptors. [14C]-agmatine labelled specific binding sites on rat brain cortex membranes. In competition experiments. [14C]-agmatine was inhibited from binding to its specific recognition sites by unlabelled agmatine, but not by rauwolscine and moxonidine. In conclusion, the present data indicate that agmatine both acts as an antagonist at the ligand recognition site of the α2D-adrenoceptor and enhances the effects of α2-adrenoceptor agonists probably by binding to an allosteric binding site of the α2D-adrenoceptor which seems to be labelled by [14C]-agmatine. PMID:10928978

  6. BCL-x{sub L}/MCL-1 inhibition and RARγ antagonism work cooperatively in human HL60 leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Perri, Mariarita; Yap, Jeremy L.; Yu, Jianshi [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201 (United States); Cione, Erika [Department of Pharmacy, Health and Nutritional Sciences, Ed. Polifunzionale, University of Calabria, 87036 Rende, CS (Italy); Fletcher, Steven [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201 (United States); Kane, Maureen A., E-mail: mkane@rx.umaryland.edu [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201 (United States)

    2014-10-01

    The acute promyelocytic leukemia (APL) subtype of acute myeloid leukemia (AML) is characterized by chromosomal translocations that result in fusion proteins, including the promyelocytic leukemia–retinoic acid receptor, alpha fusion protein (PML–RARα). All-trans retinoic acid (atRA) treatment is the standard drug treatment for APL yielding cure rates >80% by activating transcription and proteasomal degradation of retinoic acid receptor, alpha (RARα). Whereas combination therapy with As{sub 2}O{sub 3} has increased survival further, patients that experience relapse and are refractory to atRA and/or As{sub 2}O{sub 3} is a clinically significant problem. BCL-2 family proteins regulate apoptosis and over-expression of anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) family proteins has been associated with chemotherapeutic resistance in APL including impairment of the ability of atRA to induce growth arrest and differentiation. Here we investigated the novel BH3 domain mimetic, JY-1-106, which antagonizes the anti-apoptotic BCL-2 family members B-cell lymphoma-extra large (BCL-x{sub L}) and myeloid cell leukemia-1 (MCL-1) alone and in combination with retinoids including atRA, AM580 (RARα agonist), and SR11253 (RARγ antagonist). JY-1-106 reduced cell viability in HL-60 cells alone and in combination with retinoids. The combination of JY-1-106 and SR11253 had the greatest impact on cell viability by stimulating apoptosis. These studies indicate that dual BCL-x{sub L}/MCL-1 inhibitors and retinoids could work cooperatively in leukemia treatment. - Highlights: • Novel Bcl-x{sub L}/Mcl-1 inhibitor JY-1-106 reduces HL60 cell viability. • JY-1-106 is investigated in combination with retinoic acid, AM580, and SR11253. • AM580 is an RARα agonist; SR11253 is an RARγ antagonist. • Combined use of JY-1-106/SR11253 exhibited the greatest cell viability reduction. • JY-1-106 alone or in combination with retinoids induces apoptosis.

  7. Allosteric and orthosteric sites in CC chemokine receptor (CCR5), a chimeric receptor approach

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Steen, Anne; Jensen, Pia C

    2011-01-01

    -allosteric molecules. A chimera was successfully constructed between CCR5 and the closely related CCR2 by transferring all extracellular regions of CCR2 to CCR5, i.e. a Trojan horse that resembles CCR2 extracellularly but signals through a CCR5 transmembrane unit. The chimera bound CCR2 (CCL2 and CCL7), but not CCR5...... preserved, the allosteric enhancement of chemokine binding was disrupted. In summary, the Trojan horse chimera revealed that orthosteric and allosteric sites could be structurally separated and still act together with transmission of agonism and antagonism across the different receptor units....

  8. Compaction of LiBH4-LiAlH4 nanoconfined in activated carbon nanofibers: Dehydrogenation kinetics, reversibility, and mechanical stability during cycling

    DEFF Research Database (Denmark)

    Plerdsranoy, Praohatsorn; Javadian-Deylami, Seyd Payam; Jensen, Nicholai Daugaard

    2017-01-01

    To enhance volumetric hydrogen capacity for on-board fuel cells, compaction of LiAlH4-LiBH4 nanoconfined in activated carbon nanofibers (ACNF) is for the first time proposed. Loose powders of milled and nanoconfined LiAlH4-LiBH4 samples are compacted under 976 MPa to obtain the pellet samples...... with thickness and diameter of ∼1.20–1.30 and 8.0 mm, respectively. Dehydrogenation temperature of milled LiAlH4-LiBH4 increases from 415 to 434 °C due to compaction, while those of both compacted and loose powder samples of nanoconfined LiAlH4-LiBH4 are lower at comparable temperature of 330–335 °C. Hydrogen...

  9. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer.

    Science.gov (United States)

    Fraga, Mario F; Ballestar, Esteban; Villar-Garea, Ana; Boix-Chornet, Manuel; Espada, Jesus; Schotta, Gunnar; Bonaldi, Tiziana; Haydon, Claire; Ropero, Santiago; Petrie, Kevin; Iyer, N Gopalakrishna; Pérez-Rosado, Alberto; Calvo, Enrique; Lopez, Juan A; Cano, Amparo; Calasanz, Maria J; Colomer, Dolors; Piris, Miguel Angel; Ahn, Natalie; Imhof, Axel; Caldas, Carlos; Jenuwein, Thomas; Esteller, Manel

    2005-04-01

    CpG island hypermethylation and global genomic hypomethylation are common epigenetic features of cancer cells. Less attention has been focused on histone modifications in cancer cells. We characterized post-translational modifications to histone H4 in a comprehensive panel of normal tissues, cancer cell lines and primary tumors. Using immunodetection, high-performance capillary electrophoresis and mass spectrometry, we found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4. These changes appeared early and accumulated during the tumorigenic process, as we showed in a mouse model of multistage skin carcinogenesis. The losses occurred predominantly at the acetylated Lys16 and trimethylated Lys20 residues of histone H4 and were associated with the hypomethylation of DNA repetitive sequences, a well-known characteristic of cancer cells. Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells.

  10. High resolution study of MSiH4 (M=28, 29, 30) in the Dyad Region: Analysis of line positions, intensities and half-widths

    Science.gov (United States)

    Ulenikov, O. N.; Gromova, O. V.; Bekhtereva, E. S.; Raspopova, N. I.; Kashirina, N. V.; Fomchenko, A. L.; Sydow, C.; Bauerecker, S.

    2017-12-01

    The infrared spectra of SiH4 in natural abundance (92.23% of 28SiH4, 4.68% of 29SiH4, and 3.09% of 30SiH4) were measured in the region of 600-1200 cm-1 with a Bruker IFS 120HR Fourier transform spectrometer, analyzed and compared with the results available in the literature. More than 3500 transitions with Jmax. = 27 were assigned to the dyad bands ν4 and ν2 of 28SiH4 (the band ν2 is allowed in Raman, but forbidden in absorption spectra for symmetry reasons, and its transitions appear in absorption spectra only because of strong Coriolis interaction with the ν4 band). Rotational, centrifugal distortion, tetrahedral splitting, and interaction parameters for the ground, (0100) and (0001) vibrational states were determined from the fit of experimental line positions. The obtained set of parameters reproduces the initial experimental data with accuracy close to experimental uncertainties. The results of the analogous analyses of the 29SiH4 and 30SiH4 isotopologues are also presented (the numbers of the assigned transitions are here more than 1360 and 1120). An further analysis of about 790 experimental ro-vibrational lines in the dyad region of 28SiH4 was performed using the Voigt profile to simulate the measured line shape and to determine experimental line intensities. A set of 4 effective dipole moment parameters for the dyad of 28SiH4 was obtained on that basis from the weighted fit, which reproduce the initial experimental intensities of about 790 lines with the drms = 5.6 % . Analogous analyses were made for the two other isotopic species, 29SiH4, and 30SiH4. A detailed line list of transitions in the region of 750-1150 cm-1 is generated. The half-widths of 40 ro-vibrational lines (Jup.max. = 16) are studied from the multi-spectrum analysis, and self-pressure broadening coefficients are determined.

  11. The adenosine A2A receptor agonist CGS 21680 exhibits antipsychotic-like activity in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Andersen, M B; Fuxe, K; Werge, T

    2002-01-01

    The adenosine A2A receptor agonist CGS 21680 has shown effects similar to dopamine antagonists in behavioural assays in rats predictive for antipsychotic activity, without induction of extrapyramidal side-effects (EPS). In the present study, we examined whether this functional dopamine antagonism...... showed a functional anti-dopaminergic effect in Cebus apella monkeys without production of EPS. This further substantiates that adenosine A2A receptor agonists may have potential as antipsychotics with atypical profiles....

  12. Insights into chondrule formation process and shock-thermal history of the Dergaon chondrite (H4-5

    Directory of Open Access Journals (Sweden)

    D. Ray

    2017-05-01

    Full Text Available The Dergaon fall represents a shock-melted H4-5 (S5 ordinary chondrite which includes at least ten textural varieties of chondrules and belongs to the high chondrule-matrix ratio type. Our study reveals that the chondrules are of diverse mineralogy with variable olivine-pyroxene ratios (Type II, igneous melt textures developed under variable cooling rates and formed through melt fractionations from two different melt reservoirs. Based on the experimental analogues, mineralogical associations and phase compositions, it is suggested that the Dergaon chondrules reflect two contrasting environments: a hot, dust-enriched and highly oxidized nebular environment through melting, without significant evaporation, and an arrested reducing environment concomitant with major evaporation loss of alkali and highly volatile trace elements. Coexistence of chlorapatite and merrillite suggests formation of the Dergaon matrix in an acidic accretionary environment. Textural integration and chemical homogenization occurred at ∼1 atmospheric pressure and a mean temperature of 765 °C mark the radiogenic thermal event. Equilibrated shock features (olivine mosaicism, diaplectic plagioclase, polycrystalline troilite due to an impact-induced thermal event reflect a shock pressure >45 GPa and temperature of 600 °C. By contrast, the local disequilibrium shock features (silicate melt veins comprising of olivine crystallites, troilite melt veins and metal droplets correspond to a shock pressure up to 75 GPa and temperature >950 °C.

  13. Genetic characterization of natural reassortant H4 subtype avian influenza viruses isolated from domestic ducks in Zhejiang province in China from 2013 to 2014.

    Science.gov (United States)

    Wu, Haibo; Peng, Xiuming; Peng, Xiaorong; Cheng, Linfang; Lu, Xiangyun; Jin, Changzhong; Xie, Tiansheng; Yao, Hangping; Wu, Nanping

    2015-12-01

    The H4 subtype of the influenza virus was first isolated in 1999 from pigs with pneumonia in Canada. H4 avian influenza viruses (AIVs) are able to cross the species barrier to infect humans. In order to better understand the genetic relationships between H4 AIV strains circulating in Eastern China and other AIV strains from Asia, a survey of domestic ducks in live poultry markets was undertaken in Zhejiang province from 2013 to 2014. In this study, 23 H4N2 (n = 14) and H4N6 (n = 9) strains were isolated from domestic ducks, and all eight gene segments of these strains were sequenced and compared to reference AIV strains available in GenBank. The isolated strains clustered primarily within the Eurasian lineage. No mutations associated with adaption to mammalian hosts or drug resistance was observed. The H4 reassortant strains were found to be of low pathogenicity in mice and able to replicate in the lung of the mice without prior adaptation. Continued surveillance is required, given the important role of domestic ducks in reassortment events leading to new AIVs.

  14. Both H4K20 mono-methylation and H3K56 acetylation mark transcription-dependent histone turnover in fission yeast

    International Nuclear Information System (INIS)

    Yang, Hanna; Kwon, Chang Seob; Choi, Yoonjung; Lee, Daeyoup

    2016-01-01

    Nucleosome dynamics facilitated by histone turnover is required for transcription as well as DNA replication and repair. Histone turnover is often associated with various histone modifications such as H3K56 acetylation (H3K56Ac), H3K36 methylation (H3K36me), and H4K20 methylation (H4K20me). In order to correlate histone modifications and transcription-dependent histone turnover, we performed genome wide analyses for euchromatic regions in G2/M-arrested fission yeast. The results show that transcription-dependent histone turnover at 5′ promoter and 3′ termination regions is directly correlated with the occurrence of H3K56Ac and H4K20 mono-methylation (H4K20me1) in actively transcribed genes. Furthermore, the increase of H3K56Ac and H4K20me1 and antisense RNA production was observed in the absence of the histone H3K36 methyltransferase Set2 and histone deacetylase complex (HDAC) that are involved in the suppression of histone turnover within the coding regions. These results together indicate that H4K20me1 as well as H3K56Ac are bona fide marks for transcription-dependent histone turnover in fission yeast.

  15. H3 and H4 Lysine Acetylation Correlates with Developmental and Experimentally Induced Adult Experience-Dependent Plasticity in the Mouse Visual Cortex

    Directory of Open Access Journals (Sweden)

    Gabriela Vierci

    2016-01-01

    Full Text Available Histone posttranslational modifications play a fundamental role in orchestrating gene expression. In this work, we analyzed the acetylation of H3 and H4 histones (AcH3-AcH4 and its modulation by visual experience in the mouse visual cortex (VC during normal development and in two experimental conditions that restore juvenile-like plasticity levels in adults (fluoxetine treatment and enriched environment. We found that AcH3-AcH4 declines with age and is upregulated by treatments restoring plasticity in the adult. We also found that visual experience modulates AcH3-AcH4 in young and adult plasticity-restored mice but not in untreated ones. Finally, we showed that the transporter vGAT is downregulated in adult plasticity-restored models. In summary, we identified a dynamic regulation of AcH3-AcH4, which is associated with high plasticity levels and enhanced by visual experience. These data, along with recent ones, indicate H3-H4 acetylation as a central hub in the control of experience-dependent plasticity in the VC.

  16. Both H4K20 mono-methylation and H3K56 acetylation mark transcription-dependent histone turnover in fission yeast

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Hanna [Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 34141 (Korea, Republic of); Kwon, Chang Seob [Department of Chemistry and Biology, Korea Science Academy of KAIST, Busan, 614-822 (Korea, Republic of); Choi, Yoonjung, E-mail: jjungii@kaist.ac.kr [Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 34141 (Korea, Republic of); Lee, Daeyoup, E-mail: daeyoup@kaist.ac.kr [Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 34141 (Korea, Republic of)

    2016-08-05

    Nucleosome dynamics facilitated by histone turnover is required for transcription as well as DNA replication and repair. Histone turnover is often associated with various histone modifications such as H3K56 acetylation (H3K56Ac), H3K36 methylation (H3K36me), and H4K20 methylation (H4K20me). In order to correlate histone modifications and transcription-dependent histone turnover, we performed genome wide analyses for euchromatic regions in G2/M-arrested fission yeast. The results show that transcription-dependent histone turnover at 5′ promoter and 3′ termination regions is directly correlated with the occurrence of H3K56Ac and H4K20 mono-methylation (H4K20me1) in actively transcribed genes. Furthermore, the increase of H3K56Ac and H4K20me1 and antisense RNA production was observed in the absence of the histone H3K36 methyltransferase Set2 and histone deacetylase complex (HDAC) that are involved in the suppression of histone turnover within the coding regions. These results together indicate that H4K20me1 as well as H3K56Ac are bona fide marks for transcription-dependent histone turnover in fission yeast.

  17. Alcohol-Induced Impairment of Balance is Antagonized by Energy Drinks.

    Science.gov (United States)

    Marczinski, Cecile A; Fillmore, Mark T; Stamates, Amy L; Maloney, Sarah F

    2018-01-01

    The acute administration of alcohol reliably impairs balance and motor coordination. While it is common for consumers to ingest alcohol with other stimulant drugs (e.g., caffeine, nicotine), little is known whether prototypical alcohol-induced balance impairments are altered by stimulant drugs. The purpose of this study was to examine whether the coadministration of a high-caffeine energy drink with alcohol can antagonize expected alcohol-induced increases in body sway. Sixteen social drinkers (of equal gender) participated in 4 separate double-blind dose administration sessions that involved consumption of alcohol and energy drinks, alone and in combination. Following dose administration, participants completed automated assessments of balance stability (both eyes open and eyes closed) measured using the Biosway Portable Balance System. Participants completed several subjective measures including self-reported ratings of sedation, stimulation, fatigue, and impairment. Blood pressure and pulse rate were recorded repeatedly. The acute administration of alcohol increased body sway, and the coadministration of energy drinks antagonized this impairment. When participants closed their eyes, alcohol-induced body sway was similar whether or not energy drinks were ingested. While alcohol administration increased ratings of sedation and fatigue, energy drink administration increased ratings of stimulation and reduced ratings of fatigue. Modest increases in systolic and diastolic blood pressure following energy drink administration were also observed. Visual assessment of balance impairment is frequently used to indicate that an individual has consumed too much alcohol (e.g., as part of police-standardized field sobriety testing or by a bartender assessing when someone should no longer be served more alcohol). The current findings suggest that energy drinks can antagonize alcohol-induced increases in body sway, indicating that future work is needed to determine whether this

  18. Bacterial Seed Endophytes of Domesticated Cucurbits Antagonize Fungal and Oomycete Pathogens Including Powdery Mildew

    Science.gov (United States)

    Khalaf, Eman M.; Raizada, Manish N.

    2018-01-01

    The cucurbit vegetables, including cucumbers, melons and pumpkins, have been cultivated for thousands of years without fungicides. However, their seed germination stage is prone to be infected by soil-borne fungal and oomycete pathogens. Endophytes are symbionts that reside inside plant tissues including seeds. Seed endophytes are founders of the juvenile plant microbiome and can promote host defense at seed germination and later stages. We previously isolated 169 bacterial endophytes associated with seeds of diverse cultivated cucurbits. We hypothesized that these endophytes can antagonize major fungal and oomycete pathogens. Here we tested the endophytes for in vitro antagonism (dual culture assays) against important soil-borne pathogens (Rhizoctonia solani, Fusarium graminearum, Phytophthora capsici, Pythium aphanideratum). The endophytes were also assayed in planta (leaf disk and detached leaf bioassays) for antagonism against a foliar pathogen of global importance, Podosphaera fuliginea, the causative agent of cucurbit powdery mildew. The endophytes were further tested in vitro for secretion of volatile organic compounds (VOCs) known to induce plant defense. Extracellular ribonuclease activity was also tested, as a subset of pathogenesis-related (PR) proteins of plant hosts implicated in suppression of fungal pathogens, displays ribonuclease activity. An unexpected majority of the endophytes (70%, 118/169) exhibited antagonism to the five phytopathogens, of which 68% (50/73) of in vitro antagonists belong to the genera Bacillus and Paenibacillus. All Lactococcus and Pantoea endophytes exhibited anti-oomycete activity. However, amongst the most effective inoculants against Podosphaera fuliginea were Pediococcus and Pantoea endophytes. Interestingly, 67% (113/169) of endophytes emitted host defense inducing VOCs (acetoin/diacetyl) and 62% (104/169) secreted extracellular ribonucleases in vitro, respectively. These results show that seeds of cultivated cucurbits

  19. Bacterial Seed Endophytes of Domesticated Cucurbits Antagonize Fungal and Oomycete Pathogens Including Powdery Mildew

    Directory of Open Access Journals (Sweden)

    Eman M. Khalaf

    2018-02-01

    Full Text Available The cucurbit vegetables, including cucumbers, melons and pumpkins, have been cultivated for thousands of years without fungicides. However, their seed germination stage is prone to be infected by soil-borne fungal and oomycete pathogens. Endophytes are symbionts that reside inside plant tissues including seeds. Seed endophytes are founders of the juvenile plant microbiome and can promote host defense at seed germination and later stages. We previously isolated 169 bacterial endophytes associated with seeds of diverse cultivated cucurbits. We hypothesized that these endophytes can antagonize major fungal and oomycete pathogens. Here we tested the endophytes for in vitro antagonism (dual culture assays against important soil-borne pathogens (Rhizoctonia solani, Fusarium graminearum, Phytophthora capsici, Pythium aphanideratum. The endophytes were also assayed in planta (leaf disk and detached leaf bioassays for antagonism against a foliar pathogen of global importance, Podosphaera fuliginea, the causative agent of cucurbit powdery mildew. The endophytes were further tested in vitro for secretion of volatile organic compounds (VOCs known to induce plant defense. Extracellular ribonuclease activity was also tested, as a subset of pathogenesis-related (PR proteins of plant hosts implicated in suppression of fungal pathogens, displays ribonuclease activity. An unexpected majority of the endophytes (70%, 118/169 exhibited antagonism to the five phytopathogens, of which 68% (50/73 of in vitro antagonists belong to the genera Bacillus and Paenibacillus. All Lactococcus and Pantoea endophytes exhibited anti-oomycete activity. However, amongst the most effective inoculants against Podosphaera fuliginea were Pediococcus and Pantoea endophytes. Interestingly, 67% (113/169 of endophytes emitted host defense inducing VOCs (acetoin/diacetyl and 62% (104/169 secreted extracellular ribonucleases in vitro, respectively. These results show that seeds of cultivated

  20. SPOC1-mediated antiviral host cell response is antagonized early in human adenovirus type 5 infection

    DEFF Research Database (Denmark)

    Schreiner, Sabrina; Kinkley, Sarah; Bürck, Carolin

    2013-01-01

    , and playing a role in DNA damage response. SPOC1 co-localized with viral replication centers in the host cell nucleus, interacted with Ad DNA, and repressed viral gene expression at the transcriptional level. We discovered that this SPOC1-mediated restriction imposed upon Ad growth is relieved by its...... viruses (HSV-1, HSV-2, HIV-1, and HCV) also depleted SPOC1 in infected cells. Our findings provide a general model for how pathogenic human viruses antagonize intrinsic SPOC1-mediated antiviral responses in their host cells. A better understanding of viral entry and early restrictive functions in host...

  1. Bacterial Seed Endophytes of Domesticated Cucurbits Antagonize Fungal and Oomycete Pathogens Including Powdery Mildew

    Directory of Open Access Journals (Sweden)

    Eman M. Khalaf

    2018-02-01

    Full Text Available The cucurbit vegetables, including cucumbers, melons and pumpkins, have been cultivated for thousands of years without fungicides. However, their seed germination stage is prone to be infected by soil-borne fungal and oomycete pathogens. Endophytes are symbionts that reside inside plant tissues including seeds. Seed endophytes are founders of the juvenile plant microbiome and can promote host defense at seed germination and later stages. We previously isolated 169 bacterial endophytes associated with seeds of diverse cultivated cucurbits. We hypothesized that these endophytes can antagonize major fungal and oomycete pathogens. Here we tested the endophytes for in vitro antagonism (dual culture assays against important soil-borne pathogens (Rhizoctonia solani, Fusarium graminearum, Phytophthora capsici, Pythium aphanidermatum. The endophytes were also assayed in planta (leaf disk and detached leaf bioassays for antagonism against a foliar pathogen of global importance, Podosphaera fuliginea, the causative agent of cucurbit powdery mildew. The endophytes were further tested in vitro for secretion of volatile organic compounds (VOCs known to induce plant defense. Extracellular ribonuclease activity was also tested, as a subset of pathogenesis-related (PR proteins of plant hosts implicated in suppression of fungal pathogens, displays ribonuclease activity. An unexpected majority of the endophytes (70%, 118/169 exhibited antagonism to the five phytopathogens, of which 68% (50/73 of in vitro antagonists belong to the genera Bacillus and Paenibacillus. All Lactococcus and Pantoea endophytes exhibited anti-oomycete activity. However, amongst the most effective inoculants against Podosphaera fuliginea were Pediococcus and Pantoea endophytes. Interestingly, 67% (113/169 of endophytes emitted host defense inducing VOCs (acetoin/diacetyl and 62% (104/169 secreted extracellular ribonucleases in vitro, respectively. These results show that seeds of cultivated

  2. Silencing of B7-H4 suppresses the tumorigenicity of the MGC-803 human gastric cancer cell line and promotes cell apoptosis via the mitochondrial signaling pathway.

    Science.gov (United States)

    Zhou, Donghui; Zhou, Yong; Li, Chao; Yang, Lina

    2018-04-01

    B7-H4 is a transmembrane protein which is a member of the B7 superfamily. It is overexpressed in various types of cancer, including gastric cancer. However, the effects of B7-H4 on the tumorigenicity of gastric cancer and the underlying mechanisms have not yet been fully explored. Thus, the aim of this study was to examine the effects of B7-H4 on the tumorigenicity of gastric cancer cells and to elucidate the underlying mechanisms. For this purpose, B7-H4 expression in gastric cancer tissues was detected by immunohistochemical staining. The effects of B7-H4 on the biological behavior of the MGC-803 human gastric cancer cell line were examined by Cell Counting kit-8 (CCK-8) assay, cell cycle analysis, wound healing assay, Annexin V/propidium iodide staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Moreover, the expression levels of apoptotic markers, such as cleaved caspase‑3, cleaved caspase‑9, Bcl-2 and Bax were examined by western blot analysis. Immunohistochemical staining revealed that a high expression of B7-H4 was found in about 41.8% of tissues obtained from patients with gastric cancer. Comparative analysis revealed that B7-H4 expression significantly correlated with lymph node metastasis and the TNM stage. The results of CCK-8 assay, cell cycle analysis, wound healing assay, Annexin V/propidium iodide staining assay and TUNEL assay all demonstrated that the silencing of B7-H4 by small interfering RNA decreased cell proliferation, suppressed cell motility, and induced cell cycle arrest and the apoptosis of MGC-803 human gastric cancer cells. Furthermore, the results of western blot analysis indicated that the downregulation of B7-H4 induced the apoptosis of the MGC-803 cells via the mitochondrial signaling pathway through the activation of caspase‑3 and caspase‑9, and by altering the Bax/Bcl-2 ratio in a manner that favored apoptosis. Based on the findings on human gastric cancer cell line MGC-803, the

  3. Experimental testing of Mackay's model for functional antagonism in the isolated costo-uterus of the rat.

    Science.gov (United States)

    Henry, P. J.; Lulich, K. M.; Paterson, J. W.

    1985-01-01

    Several key predictions of a recently developed model for functional antagonism (Mackay, 1981) were experimentally tested using the rat isolated costo-uterine preparation. In the presence of the functional antagonist fenoterol (Fen), the functional constants (KAF) for carbachol and oxotremorine (Oxo) were respectively 9.9 and 3.4 fold greater than their corresponding affinity constants (KA). According to Mackay's model for functional antagonism, the higher KAF/KA ratio for carbachol indicates that this cholinoceptor agonist has a greater efficacy than Oxo. This was confirmed by using conventional pharmacological methods. As predicted from the model of functional antagonism, the plot of KAF/KA-1 against the fraction of cholinoceptors not irreversibly blocked by phenoxybenzamine (Pbz) was linear for both carbachol and Oxo and the lines of best fit crossed the axes at a point not significantly different from the origin. The value of 4.6 for the relative efficacy of carbachol to Oxo estimated from functional antagonism studies was comparable to the value of 5.6 calculated using the method of irreversible antagonism proposed by Furchgott (1966). PMID:3840396

  4. Sexual antagonism and meiotic drive cause stable linkage disequilibrium and favour reduced recombination on the X chromosome.

    Science.gov (United States)

    Rydzewski, W T; Carioscia, S A; Liévano, G; Lynch, V D; Patten, M M

    2016-06-01

    Sexual antagonism and meiotic drive are sex-specific evolutionary forces with the potential to shape genomic architecture. Previous theory has found that pairing two sexually antagonistic loci or combining sexual antagonism with meiotic drive at linked autosomal loci augments genetic variation, produces stable linkage disequilibrium (LD) and favours reduced recombination. However, the influence of these two forces has not been examined on the X chromosome, which is thought to be enriched for sexual antagonism and meiotic drive. We investigate the evolution of the X chromosome under both sexual antagonism and meiotic drive with two models: in one, both loci experience sexual antagonism; in the other, we pair a meiotic drive locus with a sexually antagonistic locus. We find that LD arises between the two loci in both models, even when the two loci freely recombine in females and that driving haplotypes will be enriched for male-beneficial alleles, further skewing sex ratios in these populations. We introduce a new measure of LD, Dz', which accounts for population allele frequencies and is appropriate for instances where these are sex specific. Both models demonstrate that natural selection favours modifiers that reduce the recombination rate. These results inform observed patterns of congealment found on driving X chromosomes and have implications for patterns of natural variation and the evolution of recombination rates on the X chromosome. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.

  5. Probe-Dependent Negative Allosteric Modulators of the Long-Chain Free Fatty Acid Receptor FFA4

    DEFF Research Database (Denmark)

    Watterson, Kenneth R; Hansen, Steffen V F; Hudson, Brian D

    2017-01-01

    High-affinity and selective antagonists that are able to block the actions of both endogenous and synthetic agonists of G protein-coupled receptors are integral to analysis of receptor function and to support suggestions of therapeutic potential. Although there is great interest in the potential...... of endogenous and synthetic agonists, clear agonist probe dependence in the nature of allosteric modulation was apparent. Although AH-7614 did not antagonize the second long-chain free fatty acid receptor, free fatty acid receptor 1, the simple chemical structure of AH-7614 containing features found in many...

  6. Intersystem crossing and dynamics in O(3P) + C2H4 multichannel reaction: Experiment validates theory

    Science.gov (United States)

    Fu, Bina; Han, Yong-Chang; Bowman, Joel M.; Angelucci, Luca; Balucani, Nadia; Leonori, Francesca; Casavecchia, Piergiorgio

    2012-01-01

    The O(3P) + C2H4 reaction, of importance in combustion and atmospheric chemistry, stands out as a paradigm reaction involving triplet- and singlet-state potential energy surfaces (PESs) interconnected by intersystem crossing (ISC). This reaction poses challenges for theory and experiments owing to the ruggedness and high dimensionality of these potentials, as well as the long lifetimes of the collision complexes. Primary products from five competing channels (H + CH2CHO, H + CH3CO, H2 + CH2CO, CH3 + HCO, CH2 + CH2O) and branching ratios (BRs) are determined in crossed molecular beam experiments with soft electron-ionization mass-spectrometric detection at a collision energy of 8.4 kcal/mol. As some of the observed products can only be formed via ISC from triplet to singlet PESs, from the product BRs the extent of ISC is inferred. A new full-dimensional PES for the triplet state as well as spin-orbit coupling to the singlet PES are reported, and roughly half a million surface hopping trajectories are run on the coupled singlet-triplet PESs to compare with the experimental BRs and differential cross-sections. Both theory and experiment find almost equal contributions from the two PESs to the reaction, posing the question of how important is it to consider the ISC as one of the nonadiabatic effects for this and similar systems involved in combustion chemistry. Detailed comparisons at the level of angular and translational energy distributions between theory and experiment are presented for the two primary channel products, CH3 + HCO and H + CH2CHO. The agreement between experimental and theoretical functions is excellent, implying that theory has reached the capability of describing complex multichannel nonadiabatic reactions. PMID:22665777

  7. Mutation in ESBL Plasmid from Escherichia coli O104:H4 Leads Autoagglutination and Enhanced Plasmid Dissemination

    Directory of Open Access Journals (Sweden)

    Mickaël Poidevin

    2018-02-01

    Full Text Available Conjugative plasmids are one of the main driving force of wide-spreading of multidrug resistance (MDR bacteria. They are self-transmittable via conjugation as carrying the required set of genes and cis-acting DNA locus for direct cell-to-cell transfer. IncI incompatibility plasmids are nowadays often associated with extended-spectrum beta-lactamases producing Enterobacteria in clinic and environment. pESBL-EA11 was isolated from Escherichia coli O104:H4 outbreak strain in Germany in 2011. During the previous study identifying transfer genes of pESBL-EA11, it was shown that transposon insertion at certain DNA region of the plasmid, referred to as Hft, resulted in great enhancement of transfer ability. This suggested that genetic modifications can enhance dissemination of MDR plasmids. Such ‘superspreader’ mutations have attracted little attention so far despite their high potential to worsen MDR spreading. Present study aimed to gain our understanding on regulatory elements that involved pESBL transfer. While previous studies of IncI plasmids indicated that immediate downstream gene of Hft, traA, is not essential for conjugative transfer, here we showed that overexpression of TraA in host cell elevated transfer rate of pESBL-EA11. Transposon insertion or certain nucleotide substitutions in Hft led strong TraA overexpression which resulted in activation of essential regulator TraB and likely overexpression of conjugative pili. Atmospheric Scanning Electron Microscopy observation suggested that IncI pili are distinct from other types of conjugative pili (such as long filamentous F-type pili and rather expressed throughout the cell surface. High transfer efficiency in the mutant pESBL-EA11 was involved with hyperpiliation which facilitates cell-to-cell adhesion, including autoagglutination. The capability of plasmids to evolve to highly transmissible mutant is alarming, particularly it might also have adverse effect on host pathogenicity.

  8. Risk factors for development of hemolytic uremic syndrome in a cohort of adult patients with STEC 0104:H4 infection.

    Directory of Open Access Journals (Sweden)

    Alexander Zoufaly

    Full Text Available The outbreak of Shiga toxin producing E.coli O104:H4 in northern Germany in 2011 was one of the largest worldwide and involved mainly adults. Post-diarrheal hemolytic uremic syndrome (HUS occurred in 22% of STEC positive patients. This study's aim was to assess risk factors for HUS in STEC-infected patients and to develop a score from routine hospital parameters to estimate patient risks for developing HUS. In a cohort analysis, adult patients with STEC infection were included in five participating hospitals in northern Germany between May and July 2011. Clinical data were obtained from questionnaires and medical records, laboratory data were extracted from hospitals' electronic data systems. HUS was defined as thrombocytopenia, hemolytic anemia and acute renal dysfunction. Random forests and multivariate logistic regression were used to identify risk factors for HUS and develop a score using the estimated coefficients as weights. Among 259 adults with STEC infection, vomiting (OR 3.48,95%CI 1.88-6.53, visible blood in stools (OR 3.91,95%CI1.20-16.01, age above 75 years (OR 3.27, 95%CI 1.12-9.70 and elevated leukocyte counts (OR 1.20, 95%CI 1.10-1.31, per 1000 cells/mm(3 were identified as independent risk factors for HUS. A score using these variables has an area under the ROC curve of 0.74 (95%CI 0.68-0.80. Vomiting, visible blood in stools, higher leukocyte counts, and higher age indicate increased risk for developing HUS. A score using these variables might help to identify high risk patients who potentially benefit from aggressive pre-emptive treatment to prevent or mitigate the devastating consequences of HUS.

  9. Endogenous activation of adenosine A(1) receptors accelerates ischemic suppression of spontaneous electrocortical activity

    DEFF Research Database (Denmark)

    Ilie, Andrei; Ciocan, Dragos; Zagrean, Ana-Maria

    2006-01-01

    Cerebral ischemia induces a rapid suppression of spontaneous brain rhythms prior to major alterations in ionic homeostasis. It was found in vitro during ischemia that the rapidly formed adenosine, resulting from the intracellular breakdown of ATP, may inhibit synaptic transmission via the A(1......) receptor subtype. The link between endogenous A(1) receptor activation during ischemia and the suppression of spontaneous electrocortical activity has not yet been established in the intact brain. The aim of this study was to investigate in vivo the effects of A(1) receptor antagonism by 8-cyclopentyl-1...

  10. Hexavalent Chromium (Cr(VI Down-Regulates Acetylation of Histone H4 at Lysine 16 through Induction of Stressor Protein Nupr1.

    Directory of Open Access Journals (Sweden)

    Danqi Chen

    Full Text Available The environmental and occupational carcinogen Hexavalent Chromium (Cr(VI has been shown to cause lung cancer in humans when inhaled. In spite of a considerable research effort, the mechanisms of Cr(VI-induced carcinogenesis remain largely unknown. Nupr1 (nuclear protein 1 is a small, highly basic, and unfolded protein with molecular weight of 8,800 daltons and is induced by a variety of stressors. Studies in animal models have suggested that Nupr1 is a key factor in the development of lung and pancreatic cancers, with little known about the underlying molecular mechanisms. Here we report that the level of Nupr1 is significantly increased in human bronchial epithelial BEAS2B cells following exposure to Cr(VI through epigenetic mechanisms. Interestingly, Cr(VI exposure also results in the loss of acetylation at histone H4K16, which is considered a 'hallmark' of human cancer. Cr(VI-induced reduction of H4K16 acetylation appears to be caused by the induction of Nupr1, since (a overexpression of Nupr1 decreased the levels of both H4K16 acetylation and the histone acetyltransferase MOF (male absent on the first; also known as Kat8, Myst 1, which specifically acetylates H4K16; (b the loss of acetylation of H4K16 upon Cr(VI exposure is greatly compromised by knockdown of Nupr1. Moreover, Nupr1-induced reduction of H4K16 acetylation correlates with the transcriptional down-regulation at several genomic loci. Notably, overexpression of Nupr1 induces anchorage-independent cell growth and knockdown of Nupr1 expression prevents Cr(VI-induced cell transformation. We propose that Cr(VI induces Nupr1 and rapidly perturbs gene expression by downregulating H4K16 acetylation, thereby contributing to Cr(VI-induced carcinogenesis.

  11. Cloning and Functional Analysis of Histones H3 and H4 in Nuclear Shaping during Spermatogenesis of the Chinese Mitten Crab, Eriocheir sinensis.

    Directory of Open Access Journals (Sweden)

    Jiang-Li Wu

    Full Text Available During spermatogenesis in most animals, the basic proteins associated with DNA are continuously changing and somatic-typed histones are partly replaced by sperm-specific histones, which are then successively replaced by transition proteins and protamines. With the replacement of sperm nuclear basic proteins, nuclei progressively undergo chromatin condensation. The Chinese Mitten Crab (Eriocheir sinensis is also known as the hairy crab or river crab (phylum Arthropoda, subphylum Crustacea, order Decapoda, and family Grapsidae. The spermatozoa of this species are aflagellate, and each has a spherical acrosome surrounded by a cup-shaped nucleus, peculiar to brachyurans. An interesting characteristic of the E. sinensis sperm nucleus is its lack of electron-dense chromatin. However, its formation is not clear. In this study, sequences encoding histones H3 and H4 were cloned by polymerase chain reaction amplification. Western blotting indicated that H3 and H4 existed in the sperm nuclei. Immunofluorescence and ultrastructural immunocytochemistry demonstrated that histones H3 and H4 were both present in the nuclei of spermatogonia, spermatocytes, spermatids and mature spermatozoa. The nuclear labeling density of histone H4 decreased in sperm nuclei, while histone H3 labeling was not changed significantly. Quantitative real-time PCR showed that the mRNA expression levels of histones H3 and H4 were higher at mitotic and meiotic stages than in later spermiogenesis. Our study demonstrates that the mature sperm nuclei of E. sinensis contain histones H3 and H4. This is the first report that the mature sperm nucleus of E. sinensis contains histones H3 and H4. This finding extends the study of sperm histones of E. sinensis and provides some basic data for exploring how decapod crustaceans form uncondensed sperm chromatin.

  12. Cloning and Functional Analysis of Histones H3 and H4 in Nuclear Shaping during Spermatogenesis of the Chinese Mitten Crab, Eriocheir sinensis.

    Science.gov (United States)

    Wu, Jiang-Li; Kang, Xian-Jiang; Guo, Ming-Shen; Mu, Shu-Mei; Zhang, Zhao-Hui

    2015-01-01

    During spermatogenesis in most animals, the basic proteins associated with DNA are continuously changing and somatic-typed histones are partly replaced by sperm-specific histones, which are then successively replaced by transition proteins and protamines. With the replacement of sperm nuclear basic proteins, nuclei progressively undergo chromatin condensation. The Chinese Mitten Crab (Eriocheir sinensis) is also known as the hairy crab or river crab (phylum Arthropoda, subphylum Crustacea, order Decapoda, and family Grapsidae). The spermatozoa of this species are aflagellate, and each has a spherical acrosome surrounded by a cup-shaped nucleus, peculiar to brachyurans. An interesting characteristic of the E. sinensis sperm nucleus is its lack of electron-dense chromatin. However, its formation is not clear. In this study, sequences encoding histones H3 and H4 were cloned by polymerase chain reaction amplification. Western blotting indicated that H3 and H4 existed in the sperm nuclei. Immunofluorescence and ultrastructural immunocytochemistry demonstrated that histones H3 and H4 were both present in the nuclei of spermatogonia, spermatocytes, spermatids and mature spermatozoa. The nuclear labeling density of histone H4 decreased in sperm nuclei, while histone H3 labeling was not changed significantly. Quantitative real-time PCR showed that the mRNA expression levels of histones H3 and H4 were higher at mitotic and meiotic stages than in later spermiogenesis. Our study demonstrates that the mature sperm nuclei of E. sinensis contain histones H3 and H4. This is the first report that the mature sperm nucleus of E. sinensis contains histones H3 and H4. This finding extends the study of sperm histones of E. sinensis and provides some basic data for exploring how decapod crustaceans form uncondensed sperm chromatin.

  13. Role of adenosine receptors in caffeine tolerance

    Energy Technology Data Exchange (ETDEWEB)

    Holtzman, S.G.; Mante, S.; Minneman, K.P. (Emory Univ. School of Medicine, Atlanta, GA (USA))

    1991-01-01

    Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity.

  14. Role of adenosine receptors in caffeine tolerance

    International Nuclear Information System (INIS)

    Holtzman, S.G.; Mante, S.; Minneman, K.P.

    1991-01-01

    Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity

  15. Neurokinin NK1 and NK3 receptors as targets for drugs to treat gastrointestinal motility disorders and pain.

    Science.gov (United States)

    Sanger, Gareth J

    2004-04-01

    NK1 and NK3 receptors do not appear to play significant roles in normal GI functions, but both may be involved in defensive or pathological processes. NK1 receptor antagonists are antiemetic, operating via vagal sensory and motor systems, so there is a need to study their effects on other gastro-vagal functions thought to play roles in functional bowel disorders. Interactions between NK1 receptors and enteric nonadrenergic, noncholinergic motorneurones suggest a need to explore the role of this receptor in disrupted colonic motility. NK1 receptor antagonism does not exert consistent analgesic activity in humans, but similar studies have not been carried out against pain of GI origin, where NK1 receptors may have additional influences on mucosal inflammatory or "irritant" processes. NK3 receptors mediate certain disruptions of intestinal motility. The activity may be driven by tachykinins released from intrinsic primary afferent neurones (IPANs), which induce slow EPSP activity in connecting IPANs and hence, a degree of hypersensitivity within the enteric nervous system. The same process is also proposed to increase C-fibre sensitivity, either indirectly or directly. Thus, NK3 receptor antagonists inhibit intestinal nociception via a "peripheral" mechanism that may be intestine-specific. Studies with talnetant and other selective NK3 receptor antagonists are, therefore, revealing an exciting and novel pathway by which pathological changes in intestinal motility and nociception can be induced, suggesting a role for NK3 receptor antagonism in irritable bowel syndrome.

  16. A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes.

    Science.gov (United States)

    Cervetto, Chiara; Venturini, Arianna; Passalacqua, Mario; Guidolin, Diego; Genedani, Susanna; Fuxe, Kjell; Borroto-Esquela, Dasiel O; Cortelli, Pietro; Woods, Amina; Maura, Guido; Marcoli, Manuela; Agnati, Luigi F

    2017-01-01

    Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes' participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were co-expressed on the same astrocyte processes. Evidence for A2A-D2 receptor-receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A-D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor-mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A-D2 receptors that via allosteric receptor-receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders. © 2016 International Society for Neurochemistry.

  17. Antagonism by hemoglobin of effects induced by L-arginine in neuromuscular preparations from rats

    Directory of Open Access Journals (Sweden)

    C.R. Ambiel

    2001-04-01

    Full Text Available Nitric oxide (NO-synthase is present in diaphragm, phrenic nerve and vascular smooth muscle. It has been shown that the NO precursor L-arginine (L-Arg at the presynaptic level increases the amplitude of muscular contraction (AMC and induces tetanic fade when the muscle is indirectly stimulated at low and high frequencies, respectively. However, the precursor in muscle reduces AMC and maximal tetanic fade when the preparations are stimulated directly. In the present study the importance of NO synthesized in different tissues for the L-Arg-induced neuromuscular effects was investigated. Hemoglobin (50 nM did not produce any neuromuscular effect, but antagonized the increase in AMC and tetanic fade induced by L-Arg (9.4 mM in rat phrenic nerve-diaphragm preparations. D-Arg (9.4 mM did not produce any effect when preparations were stimulated indirectly at low or high frequency. Hemoglobin did not inhibit the decrease of AMC or the reduction in maximal tetanic tension induced by L-Arg in preparations previously paralyzed with d-tubocurarine and directly stimulated. Since only the presynaptic effects induced by L-Arg were antagonized by hemoglobin, the present results suggest that NO synthesized in muscle acts on nerve and skeletal muscle. Nevertheless, NO produced in nerve and vascular smooth muscle does not seem to act on skeletal muscle.

  18. IFITM Proteins Restrict HIV-1 Infection by Antagonizing the Envelope Glycoprotein

    Directory of Open Access Journals (Sweden)

    Jingyou Yu

    2015-10-01

    Full Text Available The interferon-induced transmembrane (IFITM proteins have been recently shown to restrict HIV-1 and other viruses. Here, we provide evidence that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env, thereby inhibiting viral infection. IFITM proteins interact with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions does not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes leads to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appears to be virus-strain dependent. Overall, our study uncovers a mechanism by which IFITM proteins specifically antagonize HIV-1 Env to restrict HIV-1 infection and provides insight into the specialized role of IFITMs in HIV infection.

  19. Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria

    International Nuclear Information System (INIS)

    Molenaar, P.; Malta, E.

    1986-01-01

    In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-[ 125 I]iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants

  20. Antagonism of Trichoderma harzianum ETS 323 on Botrytis cinerea mycelium in culture conditions.

    Science.gov (United States)

    Cheng, Chi-Hua; Yang, Chia-Ann; Peng, Kou-Cheng

    2012-11-01

    ABSTRACT Previous studies have shown that the extracellular proteins of Trichoderma harzianum ETS 323 grown in the presence of deactivated Botrytis cinerea in culture include a putative l-amino acid oxidase and have suggested the involvement of this enzyme in the antagonistic mechanism. Here, we hypothesized that the mycoparasitic process of Trichoderma spp. against B. cinerea involves two steps; that is, an initial hyphal coiling stage and a subsequent hyphal coiling stage, with different coiling rates. The two-step antagonism of T. harzianum ETS 323 against B. cinerea during the mycoparasitic process in culture was evaluated using a biexponential equation. In addition, an l-amino acid oxidase (Th-l-AAO) was identified from T. harzianum ETS 323. The secretion of Th-l-AAO was increased when T. harzianum ETS 323 was grown with deactivated hyphae of B. cinerea. Moreover, in vitro assays indicated that Th-l-AAO effectively inhibited B. cinerea hyphal growth, caused cytosolic vacuolization in the hyphae, and led to hyphal lysis. Th-l-AAO also showed disease control against the development of B. cinerea on postharvest apple fruit and tobacco leaves. Furthermore, an apoptosis-like response, including the generation of reactive oxygen species, was observed in B. cinerea after treatment with Th-l-AAO, suggesting that Th-l-AAO triggers programmed cell death in B. cinerea. This may be associated with the two-step antagonism of T. harzianum ETS 323 against B. cinerea.

  1. Dynamical transitions in a pollination-herbivory interaction: a conflict between mutualism and antagonism.

    Directory of Open Access Journals (Sweden)

    Tomás A Revilla

    Full Text Available Plant-pollinator associations are often seen as purely mutualistic, while in reality they can be more complex. Indeed they may also display a diverse array of antagonistic interactions, such as competition and victim-exploiter interactions. In some cases mutualistic and antagonistic interactions are carried-out by the same species but at different life-stages. As a consequence, population structure affects the balance of inter-specific associations, a topic that is receiving increased attention. In this paper, we developed a model that captures the basic features of the interaction between a flowering plant and an insect with a larval stage that feeds on the plant's vegetative tissues (e.g. leaves and an adult pollinator stage. Our model is able to display a rich set of dynamics, the most remarkable of which involves victim-exploiter oscillations that allow plants to attain abundances above their carrying capacities and the periodic alternation between states dominated by mutualism or antagonism. Our study indicates that changes in the insect's life cycle can modify the balance between mutualism and antagonism, causing important qualitative changes in the interaction dynamics. These changes in the life cycle could be caused by a variety of external drivers, such as temperature, plant nutrients, pesticides and changes in the diet of adult pollinators.

  2. FCJ-156 Hacking the Social: Internet Memes, Identity Antagonism, and the Logic of Lulz.

    Directory of Open Access Journals (Sweden)

    Ryan M. Milner

    2013-12-01

    Full Text Available 4chan and reddit are participatory media collectives undergirded by a “logic of lulz” that favours distanced irony and critique. It often works at the expense of core identity categories like race and gender. However, the logic need not be entirely counterproductive to public discourse. Provided that diverse identities find voice instead of exclusion, these sites may facilitate vibrant, agonistic discussion instead of disenfranchising antagonism. In order to assess this potential for productive agonism, I undertook a critical discourse analysis of these collectives. Emphasising the image memes they produce, I evaluated discourses on race and gender. Both race and gender representations were dominated by familiar stereotypes and partial representations. However, while dissenting perspectives on race were repressed or excluded, dissenting perspectives on gender were vocalised and contested. The ‘logic of lulz’ facilitated both dominance and counter, each articulated with heavy reliance on irony and critique. This logic ambiguously balanced agonism and antagonism, but contestation provided sharper engagement than repression.

  3. Antagonism between abscisic acid and gibberellins is partially mediated by ascorbic acid during seed germination in rice.

    Science.gov (United States)

    Ye, Nenghui; Zhang, Jianhua

    2012-05-01

    The antagonism between abscisic acid (ABA) and gibberellin (GA) plays a key role in controlling seed germination, but the mechanism of antagonism during this process is not known. In the associated study, we investigated the relationship among ABA, reactive oxygen species (ROS), ascorbic acid (ASC) and GA during rice seed germination. ROS production is reduced by ABA, which hence results in decreasing ASC accumulation during imbibition. GA accumulation was also suppressed by a reduced ROS and ASC level, whereas application of exogenous ASC can partially rescue seed germination from ABA treatment. Further results show that production of ASC, which acts as a substrate in GA biosynthesis, was significantly inhibited by lycorine which thus suppressed the accumulation of GA. Consequently, expression of GA biosynthesis genes was suppressed by the low levels of ROS and ASC in ABA-treated seeds. These studies reveal a new role for ASC in mediating the antagonism between ABA and GA during seed germination in rice.

  4. Aggression, Sibling Antagonism, and Theory-of-Mind During the First Year of Siblinghood: A Developmental Cascade Model

    Science.gov (United States)

    Song, Ju-Hyun; Volling, Brenda L.; Lane, Jonathan D.; Wellman, Henry M.

    2016-01-01

    A developmental cascade model was tested to examine longitudinal associations among firstborn children’s aggression, Theory-of-Mind, and antagonism toward their younger sibling during the first year of siblinghood. Aggression and Theory-of-Mind were assessed before the birth of a sibling, and 4 and 12 months after the birth, and antagonism was examined at 4 and 12 months in a sample of 208 firstborn children (initial M age = 30 months, 56% girls) from primarily European American, middle- class families. Firstborns’ aggression consistently predicted high sibling antagonism both directly and through poorer Theory-of-Mind. Results highlight the importance of examining longitudinal influences across behavioral, social-cognitive, and relational factors that are closely intertwined even from the early years of life. PMID:27096923

  5. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Kuo, Alex J; Song, Jikui; Cheung, Peggie; Ishibe-Murakami, Satoko; Yamazoe, Sayumi; Chen, James K; Patel, Dinshaw J; Gozani, Or [Stanford; (MSKCC); (Stanford-MED)

    2012-07-11

    The recognition of distinctly modified histones by specialized 'effector' proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1 - a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing - contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier-Gorlin syndrome (MGS), a form of primordial dwarfism, and ORC1 depletion in zebrafish results in an MGS-like phenotype. We find that wild-type human ORC1, but not ORC1-H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.

  6. Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat

    DEFF Research Database (Denmark)

    Axel, Anne Marie Dixen; Mikkelsen, Jens D; Hansen, Henrik H

    2010-01-01

    ) and partially antagonized by co-administration of SCH23390 (0.03 mg/kg, DA D(1) receptor antagonist). In contrast, tesofensine-induced hypophagia was not affected by RX821002 (0.3 mg/kg, alpha(2) adrenoceptor antagonist), haloperidol (0.03 mg/kg, D(2) receptor antagonist), NGB2904 (0.1 mg/kg, D(3) receptor...

  7. Novel 2D or 3D alkaline-earth metal sulfonate-phosphonates based on [O 3S-C 2H 4-PO 3H] 2- ligand

    Science.gov (United States)

    Du, Zi-Yi; Wen, He-Rui; Xie, Yong-Rong

    2008-11-01

    Three novel alkaline-earth metal sulfonate-phosphonates based on [O 3S-C 2H 4-PO 3H] 2- ligand, namely, [Ca(O 3SC 2H 4PO 3H)(H 2O) 2] ( 1), [Sr(O 3SC 2H 4PO 3H)] ( 2) and [Ba 2(O 3SC 2H 4PO 3H) 2] ( 3), have been synthesized by hydrothermal reactions. They represent the first structurally characterized alkaline-earth metal complexes of phosphonic acid attached with a sulfonate group. The structure of compound 1 features a 2D layer based on 1D chains of [Ca 2(PO 3) 2] bridged by -CH 2-CH 2-SO 3- groups. Compounds 2 and 3 show pillar-layer architecture based on two different inorganic layers linked by -CH 2-CH 2- groups. The inorganic layer in compound 2 features a 1D chain of edge-sharing SrO 8 polyhedra whereas that in compound 3 features an edge-sharing Ba 2O 14 di-polyhedral unit which is further corner-shared with four neighboring ones. The [O 3S-C 2H 4-PO 3H] 2- ligand shows diverse coordination modes in the three alkaline-earth metal sulfonate-phosphonates.

  8. The expression of B7-H1 and B7-H4 molecules on immature myeloid and lymphoid dendritic cells in cord blood of healthy neonates

    Directory of Open Access Journals (Sweden)

    Kludka-Sternik M

    2010-04-01

    Full Text Available The aim of our study was to estimate both B7-H1 and B7-H4 molecules on immature myeloid and lymphoid dendriticcells in umbilical cord blood of healthy neonates in comparison with peripheral blood of healthy adults. Thirty ninehealthy full-term neonates from physiological single pregnancies and 27 healthy adults were included in the study. Theexpression of B7-H1 and B7-H4 was revealed using the immunofluorescence method. Statistical analysis was performedusing a non-parametric test (Mann-Whitney U-Test. The percentages of BDCA-1+ dendritic cells with B7-H1 and B7-H4expressions were significantly higher in peripheral blood of healthy adults (p<0.00003. It was either observed that the percentageof BDCA-2+ dendritic cells with the expression of B7-H4 molecules was significantly higher in peripheral blood ofhealthy adults in comparison with umbilical cord blood (p<0.02. Decreased percentages of dendritic cells and co-stimulatorymolecules indicate that neonates have immature immune system. Depletion of co-stimulatory B7-H1 and B7-H4 moleculesenable appropriate development of immune response.

  9. The expression of B7-H1 and B7-H4 molecules on immature myeloid and lymphoid dendritic cells in cord blood of healthy neonates.

    Directory of Open Access Journals (Sweden)

    S Radej

    2011-04-01

    Full Text Available The aim of our study was to estimate both B7-H1 and B7-H4 molecules on immature myeloid and lymphoid dendritic cells in umbilical cord blood of healthy neonates in comparison with peripheral blood of healthy adults. Thirty nine healthy full-term neonates from physiological single pregnancies and 27 healthy adults were included in the study. The expression of B7-H1 and B7-H4 was revealed using the immunofluorescence method. Statistical analysis was performed using a non-parametric test (Mann-Whitney U-Test. The percentages of BDCA-1+ dendritic cells with B7-H1 and B7-H4 expressions were significantly higher in peripheral blood of healthy adults (p<0.00003. It was either observed that the percentage of BDCA-2+ dendritic cells with the expression of B7-H4 molecules was significantly higher in peripheral blood of healthy adults in comparison with umbilical cord blood (p<0.02. Decreased percentages of dendritic cells and co-stimulatory molecules indicate that neonates have immature immune system. Depletion of co-stimulatory B7-H1 and B7-H4 molecules enable appropriate development of immune response.

  10. Facile Synthesis and Superior Catalytic Activity of Nano-TiN@N-C for Hydrogen Storage in NaAlH4.

    Science.gov (United States)

    Zhang, Xin; Ren, Zhuanghe; Lu, Yunhao; Yao, Jianhua; Gao, Mingxia; Liu, Yongfeng; Pan, Hongge

    2018-05-09

    Herein, we synthesize successfully ultrafine TiN nanoparticles (hydrogen storage in NaAlH 4 . Adding 7 wt % nano-TiN@N-C induces more than 100 °C reduction in the onset dehydrogenation temperature of NaAlH 4 . Approximately 4.9 wt % H 2 is rapidly released from the 7 wt % nano-TiN@N-C-containing NaAlH 4 at 140 °C within 60 min, and the dehydrogenation product is completely hydrogenated at 100 °C within 15 min under 100 bar of hydrogen, exhibiting significantly improved desorption/absorption kinetics. No capacity loss is observed for the nano-TiN@N-C-containing sample within 25 de-/hydrogenation cycles because nano-TiN functions as an active catalyst instead of a precursor. A severe structural distortion with extended bond lengths and reduced bond strengths for Al-H bonding when the [AlH 4 ] - group adsorbs on the TiN cluster is demonstrated for the first time by density functional theory calculations, which well-explains the reduced de-/hydrogenation temperatures of the nano-TiN@N-C-containing NaAlH 4 . These findings provide new insights into designing and synthesizing high-performance catalysts for hydrogen storage in complex hydrides.

  11. Hyperacetylation and differential deacetylation of histones H4 and H3 define two distinct classes of acetylated SV40 chromosomes early in infection

    International Nuclear Information System (INIS)

    Milavetz, Barry

    2004-01-01

    SV40 chromosomes undergoing encapsidation late in infection and SV40 chromatin in virions are hyperacetylated on histones H4 and H3. However, the fate of the SV40 chromosomes containing hyperacetylated histones in a subsequent round of infection has not been determined. In order to determine if SV40 chromosomes undergo changes in the extent of histone acetylation during early infection, we have analyzed SV40 chromosomes isolated 30 min and 3 h postinfection by quantitative ChIP assays, depletion ChIP assays, competitive ChIP assays, and ChIP assays combined with restriction endonuclease sensitivity using antibodies to hyperacetylated histones H4 and H3. We have shown that at 30 min postinfection, the hyperacetylated histones are associated with two distinct classes of SV40 chromosomes. One form is hyperacetylated specifically on histone H4 while a second form is hyperacetylated on both H4 and H3. Both forms of chromosomes appear to contain a nucleosome-free promoter region. Over the course of the next few hours of infection, the class of SV40 chromosomes hyperacetylated on only H4 is reduced or completely eliminated through deacetylation

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

    International Nuclear Information System (INIS)

    Czech, M.P.

    1985-01-01

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

  13. Symbiont interactions in a tripartite mutualism: exploring the presence and impact of antagonism between two fungus-growing ant mutualists.

    Directory of Open Access Journals (Sweden)

    Michael Poulsen

    Full Text Available Mutualistic associations are shaped by the interplay of cooperation and conflict among the partners involved, and it is becoming increasingly clear that within many mutualisms multiple partners simultaneously engage in beneficial interactions. Consequently, a more complete understanding of the dynamics within multipartite mutualism communities is essential for understanding the origin, specificity, and stability of mutualisms. Fungus-growing ants cultivate fungi for food and maintain antibiotic-producing Pseudonocardia actinobacteria on their cuticle that help defend the cultivar fungus from specialized parasites. Within both ant-fungus and ant-bacterium mutualisms, mixing of genetically distinct strains can lead to antagonistic interactions (i.e., competitive conflict, which may prevent the ants from rearing multiple strains of either of the mutualistic symbionts within individual colonies. The success of different ant-cultivar-bacterium combinations could ultimately be governed by antagonistic interactions between the two mutualists, either as inhibition of the cultivar by Pseudonocardia or vice versa. Here we explore cultivar-Pseudonocardia antagonism by evaluating in vitro interactions between strains of the two mutualists, and find frequent antagonistic interactions both from cultivars towards Pseudonocardia and vice versa. To test whether such in vitro antagonistic interactions affect ant colonies in vivo, we performed sub-colony experiments using species of Acromyrmex leaf-cutting ants. We created novel ant-fungus-bacterium pairings in which there was antagonism from one, both, or neither of the ants' microbial mutualists, and evaluated the effect of directional antagonism on cultivar biomass and Pseudonocardia abundance on the cuticle of workers within sub-colonies. Despite the presence of frequent in vitro growth suppression between cultivars and Pseudonocardia, antagonism from Pseudonocardia towards the cultivar did not reduce sub

  14. Activation of sp3-CH Bonds in a Mono(pentamethylcyclopentadienyl)yttrium Complex. X-ray Crystal Structures and Dynamic Behavior of Cp*Y(o-C6H4CH2NMe2)2 and Cp*Y[o-C6H4CH2NMe(CH2-μ)][μ-o-C6H4CH2NMe(CH2-μ)]YCp*[THF

    NARCIS (Netherlands)

    Booij, Martin; Kiers, Niklaas H.; Meetsma, Auke; Teuben, Jan H.; Smeets, Wilberth J.J.; Spek, Anthony L.

    1989-01-01

    Reaction of Y(o-C6H4CH2NMe2)3 (1) with Cp*H gives Cp*Y(o-C6H4CH2NMe2)2 (2), which crystallizes in the monoclinic space group P21/n (No. 14) with a = 18.607 (4) Å, b = 15.633 (3) Å, c = 8.861 (3) Å, β = 102.73 (3)°, and Z = 4. Least-squares refinement with 3006 independent reflections (F > 4.0σ(F))

  15. Synthesis of a novel tripeptidomimetic scaffold and biological evaluation for CXC chemokine receptor 4 (CXCR4) antagonism

    DEFF Research Database (Denmark)

    Baumann, Markus; Nome, Lina Marie; Zachariassen, Zack G.

    2017-01-01

    We here report the preparation of a new 2,6,8-trisubstituted bicyclic tripeptidomimetic scaffold through TFA-mediated cyclization of a linear precursor containing three side chains. The introduction of a triphenylmethyl-protected thiol into carboxylic acid containing building blocks through sulfa...... the stereochemical outcome of the cyclization differently when the R1 side chain is positioned on C2 in the bicycles (present work) instead of C3 (previous work). Tripeptidomimetic compounds based on the new scaffold were synthesized and evaluated for antagonistic potency toward CXCR4, and one compound (45a...

  16. Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription

    OpenAIRE

    Vidal, Marcos; Ramana, Chilakamarti V.; Dusso, Adriana S.

    2002-01-01

    The cytokine gamma interferon (IFN-γ) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-γ induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-γ-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of ...

  17. Antagonism of corticotrophin-releasing factor receptors in the fourth ventricle modifies responses to mild but not restraint stress

    OpenAIRE

    Miragaya, Joanna R.; Harris, Ruth B. S.

    2008-01-01

    Repeated restraint stress (RRS; 3 h of restraint on 3 consecutive days) in rodents produces temporary hypophagia, but a long-term downregulation of body weight. The mild stress (MS) of an intraperitoneal injection of saline and housing in a novel room for 2 h also inhibits food intake and weight gain, but the effects are smaller than for RRS. Previous exposure to RRS exaggerates hypophagia, glucocorticoid release, and anxiety-type behavior caused by MS. Here we tested the involvement of brain...

  18. Inhibition of protein synthesis does not antagonize induction of UV-induced sister-chromatid exchange in xeroderma pigmentosum cells

    International Nuclear Information System (INIS)

    Sono, Akira; Sakaguchi, Kengo.

    1988-01-01

    Cycloheximide strongly antagonizes the induction of sisterchromatid exchanges by ethyl methanesulfonate or mitomycin C in human skin fibroblast and xeroderma pigmentosum cells (group A). Analogous behavior has been observed in several other species including Chinese hamster and plant cells. This report documents an exception to that pattern: cycloheximide fails to antagonize UV-induced sister chromatid exchange in xeroderma pigmentosum cells, whereas it does in normal human skin fibroblast cells. A genetic defect in these cells is postulated to alter the UV-mediated DNA recombination process. (author)

  19. The Existence of a Designer Al=Al Double Bond in the LiAl2 H4- Cluster Formed by Electronic Transmutation.

    Science.gov (United States)

    Lundell, Katie A; Zhang, Xinxing; Boldyrev, Alexander I; Bowen, Kit H

    2017-12-22

    The Al=Al double bond is elusive in chemistry. Herein we report the results obtained via combined photoelectron spectroscopy and ab initio studies of the LiAl 2 H 4 - cluster that confirm the formation of a conventional Al=Al double bond. Comprehensive searches for the most stable structures of the LiAl 2 H 4 - cluster have shown that the global minimum isomer I possesses a geometric structure which resembles that of Si 2 H 4 , demonstrating a successful example of the transmutation of Al atoms into Si atoms by electron donation. Theoretical simulations of the photoelectron spectrum discovered the coexistence of two isomers in the ion beam, including the one with the Al=Al double bond. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Farnesoid X Receptor Activation Promotes Hepatic Amino Acid Catabolism and Ammonium Clearance in Mice

    NARCIS (Netherlands)

    Massafra, Vittoria; Milona, Alexandra; Vos, Harmjan R; Ramos, Rúben J J; Gerrits, Johan; Willemsen, Ellen C L; Ramos Pittol, José M; Ijssennagger, Noortje; Houweling, Martin; Prinsen, Hubertus C M T; Verhoeven-Duif, Nanda M; Burgering, Boudewijn M T; van Mil, Saskia W C

    2017-01-01

    BACKGROUND & AIMS: The nuclear receptor subfamily 1 group H member 4 (NR1H4 or farnesoid X receptor [FXR]) regulates bile acid synthesis, transport, and catabolism. FXR also regulates postprandial lipid and glucose metabolism. We performed quantitative proteomic analyses of liver tissues from mice

  1. Comparative Genomics of Recent Shiga Toxin-Producing Escherichia coli O104:H4: Short-Term Evolution of an Emerging Pathogen

    Science.gov (United States)

    Grad, Yonatan H.; Godfrey, Paul; Cerquiera, Gustavo C.; Mariani-Kurkdjian, Patricia; Gouali, Malika; Bingen, Edouard; Shea, Terrence P.; Haas, Brian J.; Griggs, Allison; Young, Sarah; Zeng, Qiandong; Lipsitch, Marc; Waldor, Matthew K.; Weill, François-Xavier; Wortman, Jennifer R.; Hanage, William P.

    2013-01-01

    ABSTRACT The large outbreak of diarrhea and hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli O104:H4 in Europe from May to July 2011 highlighted the potential of a rarely identified E. coli serogroup to cause severe disease. Prior to the outbreak, there were very few reports of disease caused by this pathogen and thus little known of its diversity and evolution. The identification of cases of HUS caused by E. coli O104:H4 in France and Turkey after the outbreak and with no clear epidemiological links raises questions about whether these sporadic cases are derived from the outbreak. Here, we report genome sequences of five independent isolates from these cases and results of a comparative analysis with historical and 2011 outbreak isolates. These analyses revealed that the five isolates are not derived from the outbreak strain; however, they are more closely related to the outbreak strain and each other than to isolates identified prior to the 2011 outbreak. Over the short time scale represented by these closely related organisms, the majority of genome variation is found within their mobile genetic elements: none of the nine O104:H4 isolates compared here contain the same set of plasmids, and their prophages and genomic islands also differ. Moreover, the presence of closely related HUS-associated E. coli O104:H4 isolates supports the contention that fully virulent O104:H4 isolates are widespread and emphasizes the possibility of future food-borne E. coli O104:H4 outbreaks. PMID:23341549

  2. Acetylated H4K16 by MYST1 protects UROtsa cells from arsenic toxicity and is decreased following chronic arsenic exposure

    International Nuclear Information System (INIS)

    Jo, William Jaime; Ren, Xuefeng; Chu, Feixia; Aleshin, Maria; Wintz, Henri; Burlingame, Alma; Smith, Martyn Thomas; Vulpe, Chris Dillon; Zhang Luoping

    2009-01-01

    Arsenic, a human carcinogen that is associated with an increased risk of bladder cancer, is commonly found in drinking water. An important mechanism by which arsenic is thought to be carcinogenic is through the induction of epigenetic changes that lead to aberrant gene expression. Previously, we reported that the SAS2 gene is required for optimal growth of yeast in the presence of arsenite (As III ). Yeast Sas2p is orthologous to human MYST1, a histone 4 lysine 16 (H4K16) acetyltransferase. Here, we show that H4K16 acetylation is necessary for the resistance of yeast to As III through the modulation of chromatin state. We further explored the role of MYST1 and H4K16 acetylation in arsenic toxicity and carcinogenesis in human bladder epithelial cells. The expression of MYST1 was knocked down in UROtsa cells, a model of bladder epithelium that has been used to study arsenic-induced carcinogenesis. Silencing of MYST1 reduced acetylation of H4K16 and induced sensitivity to As III and to its more toxic metabolite monomethylarsonous acid (MMA III ) at doses relevant to high environmental human exposures. In addition, both As III and MMA III treatments decreased global H4K16 acetylation levels in a dose- and time-dependent manner. This indicates that acetylated H4K16 is required for resistance to arsenic and that a reduction in its levels as a consequence of arsenic exposure may contribute to toxicity in UROtsa cells. Based on these findings, we propose a novel role for the MYST1 gene in human sensitivity to arsenic.

  3. Tungsten phosphanylarylthiolato complexes [W{PhP(2-SC6H4)2-kappa3S,S',P} 2] and [W{P(2-SC6H4)3-kappa4S,S',S",P}2]: synthesis, structures and redox chemistry.

    Science.gov (United States)

    Hildebrand, Alexandra; Lönnecke, Peter; Silaghi-Dumitrescu, Luminita; Hey-Hawkins, Evamarie

    2008-09-14

    PhP(2-SHC6H4)2 (PS2H2) reacts with WCl6 with reduction of tungsten to give the air-sensitive tungsten(IV) complex [W{PhP(2-SC6H4)2-kappa(3)S,S',P}2] (1). 1 is oxidised in air to [WO{PhPO(2-SC6H4)2-kappa(3)S,S',O}{PhP(2-SC6H4)2-kappa(3)S,S',P}] (2). The attempted synthesis of 2 by reaction of 1 with iodosobenzene as oxidising agent was unsuccessful. [W{P(2-SC6H4)3-kappa(4)S,S',S",P}2] (3) was formed in the reaction of P(2-SHC6H4)3 (PS3H3) with WCl6. The W(VI) complex 3 contains two PS3(3-) ligands, each coordinated in a tetradentate fashion resulting in a tungsten coordination number of eight. The reaction of 3 with AgBF4 yields the dinuclear tungsten complex [W2{P(2-SC6H4)3-kappa(4)S,S',S",P}3]BF4 (4). Complexes 1-4 were characterised by spectral methods and X-ray structure determination.

  4. Control of energy balance by hypothalamic gene circuitry involving two nuclear receptors, neuron-derived orphan receptor 1 and glucocorticoid receptor.

    Science.gov (United States)

    Kim, Sun-Gyun; Lee, Bora; Kim, Dae-Hwan; Kim, Juhee; Lee, Seunghee; Lee, Soo-Kyung; Lee, Jae W

    2013-10-01<