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Sample records for p4 ht ee

  1. 5-HT3 Receptors

    PubMed Central

    Thompson, A. J.; Lummis, S. C. R.

    2009-01-01

    The 5-HT3 receptor is a member of the Cys-loop family of ligand-gated ion channels. These receptors are located in both the peripheral and central nervous systems, where functional receptors are constructed from five subunits. These subunits may be the same (homopentameric 5-HT3A receptors) or different (heteropentameric receptors, usually comprising of 5-HT3A and 5-HT3B receptor subunits), with the latter having a number of distinct properties. The 5-HT3 receptor binding site is comprised of six loops from two adjacent subunits, and critical ligand binding amino acids in these loops have been largely identified. There are a range of selective agonists and antagonists for these receptors and the pharmacophore is reasonably well understood. There are also a wide range of compounds that can modulate receptor activity. Studies have suggested many diverse potential disease targets that might be amenable to alleviation by 5-HT3 receptor selective compounds but to date only two applications have been fully realised in the clinic: the treatment of emesis and irritable-bowel syndrome. PMID:17073663

  2. FCC-ee: Energy Calibration

    SciTech Connect

    Koratzinos, M.; Blondel, A.; Gianfelice-Wendt, E.; Zimmermann, F.

    2015-06-02

    The FCC-ee aims to improve on electroweak precision measurements, with goals of 100 ke V on the Z mass and width, and a fraction of MeV on the W mass. Compared to LEP, this implies a much improved knowledge of the center-of-mass energy when operating at the Z peak and WW threshold. This can be achieved by making systematic use of resonant depolarization. A number of issues have been identified, due in particular to the long polarization times. However the smaller emittance and energy spread of FCC-ee with respect to LEP should help achieve a much improved performance.

  3. EE-3A Logging Report

    SciTech Connect

    Anderson, David W.

    1993-12-15

    Two logs of EE-3A were performed during the last couple of weeks. The first of which, was a Temperature/Casing-Collar Locator (CCL) log, which took place on Friday, December 10th., 1993. The second log was a Caliper log which was done in cooperation with the Dia-Log Company, of Odessa, TX. on Monday, December, 13th., 1993.

  4. Redrilling Plan for EE-3

    SciTech Connect

    Murphy, Hugh D.

    1984-11-14

    Attached is the 3rd draft copy of the EE-3 redrilling plan. We believe that we have taken the document as far as we can and feel that it is ready for distribution as soon as the trajectory question is resolved and necessary changes in wording that result are made. The figures are presently being redrawn by John Paskiewicz and should be ready in about one week.

  5. Safe P4 reagent in a reusable porous coordination network.

    PubMed

    Choi, Wanuk; Ohtsu, Hiroyoshi; Matsushita, Yoshitaka; Kawano, Masaki

    2016-04-12

    P4 generated from red phosphorus via the gas phase was trapped into an interactive pore of a porous coordination network, showing weak interactions which stabilize the reactive P4 in a pore. The network is reusable as a safe container of P4. Furthermore, we found a size dependence of the P4 trapping amount: for 100-50 μm crystal, 27% occupancy of P4; and for <20 μm crystal, ca. 93% occupancy of P4. PMID:27008184

  6. P4P4P: An Agenda for Research on Pay for Performance for Patients

    PubMed Central

    Volpp, Kevin G.; Pauly, Mark V.; Loewenstein, George; Bangsberg, David

    2012-01-01

    Unhealthy behaviors are a major cause of poor health outcomes and high health care costs. In this Commentary, we describe an agenda for research to guide broader use of patient-targeted financial incentives either in conjunction with provider-targeted financial incentives (P4P) or in clinical contexts where provider-targeted approaches are unlikely to be effective. We discuss evidence of proven effectiveness and limitations of the existing evidence, reasons for underutilization of these approaches, and options for operationalizing wider use. Patient-targeted incentives have great potential, and systematic testing will help determine how they can best be used to improve population health. PMID:19124872

  7. Poly(4-hydroxybutyrate) (P4HB) production in recombinant Escherichia coli: P4HB synthesis is uncoupled with cell growth

    PubMed Central

    2013-01-01

    Background Poly(4-hydroxybutyrate) (P4HB), belonging to the family of bacterial polyhydroxyalkanoates (PHAs), is a strong, flexible and absorbable material which has a large variety of medical applications like tissue engineering and drug delivery. For efficient production of P4HB recombinant Escherichia coli has been employed. It was previously found that the P4HB synthesis is co-related with the cell growth. In this study, we aimed to investigate the physiology of P4HB synthesis, and to reduce the total production cost by using cheap and widely available xylose as the growth substrate and sodium 4-hydroxybutyrate (Na-4HB) as the precursor for P4HB synthesis. Results Six different E. coli strains which are able to utilize xylose as carbon source were compared for their ability to accumulate P4HB. E. coli JM109 was found to be the best strain regarding the specific growth rate and the P4HB content. The effect of growth conditions such as temperature and physiological stage of Na-4HB addition on P4HB synthesis was also studied in E. coli JM109 recombinant in batch culture. Under the tested conditions, a cellular P4HB content in the range of 58 to 70% (w w-1) and P4HB concentrations in the range of 2.76 to 4.33 g L-1 were obtained with a conversion yield (YP4HB/Na-4HB) of 92% w w-1 in single stage batch cultures. Interestingly, three phases were identified during P4HB production: the “growth phase”, in which the cells grew exponentially, the “accumulation phase”, in which the exponential cell growth stopped while P4HB was accumulated exponentially, and the “stagnation phase”, in which the P4HB accumulation stopped and the total biomass remained constant. Conclusions P4HB synthesis was found to be separated from the cell growth, i.e. P4HB synthesis mainly took place after the end of the exponential cell growth. High conversion rate and P4HB contents from xylose and precursor were achieved here by simple batch culture, which was only possible previously

  8. Job Prospects for E/E Engineers.

    ERIC Educational Resources Information Center

    Basta, Nicholas

    1987-01-01

    Discusses the trends in employment in the electrical/electronics (E/E) engineering industry. States that although the number of E/E graduates grew at a rate of over 11 percent from 1985 to 1986, the economy continues to be the major determinant in the job outlook in the field. (TW)

  9. EE Certification: Making Best Practice Standard Practice

    ERIC Educational Resources Information Center

    Glenn, Joanne M. Lozar

    2006-01-01

    Pursuing environmental education certification is difficult, so why do it? What does it mean to be certified? Who benefits? How? These are just a few of the compelling questions addressed in "EE Certification: Making Best Practice Standard Practice," a new article exploring advancements and challenges in state and national EE certification. A…

  10. Procedure to Complete EE-2A

    SciTech Connect

    Robinson, Bruce A.; Dash, Zora V.; Brown, Donald W.

    1988-04-07

    This report details the general procedure for testing well EE-2A. Well EE-2A was side-tracked off of a whipstock set at 9,748 ft within section milled in the 9-5/8 in. casing from 9,688 ft. to 9,748 ft. The well was then directionally drilled to 12,360 ft. A number of in-flow zones from well EE-3A have been determined. The shallowest in-flow zones occurs at approximately 10,800 ft.

  11. Theoretical investigation of the electronic and optical properties of pseudocubic Si3P4, Ge3P4 and Sn3P4

    NASA Astrophysics Data System (ADS)

    Xu, Ming; Wang, Songyou; Yin, Gang; Chen, Liangyao; Jia, Yu

    2006-01-01

    Group-IV phosphides are relatively unknown materials as compared to the Group-IV carbide. In this work, we detailed the first principles calculations of the electronic and optical properties of the pseudocubic M3 P4 (M=Si, Ge, Sn) using the density function theory (DFT). Results are in good agreement with those previous works. Furthermore, the optical constants, such as the dielectric function, energy loss function and effective number of valence electrons are calculated and presented in the study.

  12. Endogenous 5-HT outflow from chicken aorta by 5-HT uptake inhibitors and amphetamine derivatives

    PubMed Central

    DELGERMURUN, Dugar; ITO, Shigeo; OHTA, Toshio; YAMAGUCHI, Soichiro; OTSUGURO, Ken-ichi

    2015-01-01

    Chemoreceptor cells aggregating in clusters in the chicken thoracic aorta contain 5-hydroxytryptamine (5-HT) and have voltage-dependent ion channels and nicotinic acetylcholine receptors, which are characteristics typically associated with neurons. The aim of the present study was to investigate the effects of 5-HT uptake inhibitors, fluvoxamine, fluoxetine and clomipramine (CLM), and amphetamine derivatives, p-chloroamphetamine (PCA) and methamphetamine (MET), on endogenous 5-HT outflow from the isolated chick thoracic aorta in vitro. 5-HT was measured by using a HPLC system with electrochemical detection. The amphetamine derivatives and 5-HT uptake inhibitors caused concentration-dependent increases in endogenous 5-HT outflow. PCA was about ten times more effective in eliciting 5-HT outflow than MET. The 5-HT uptake inhibitors examined had similar potency for 5-HT outflow. PCA and CLM increased 5-HT outflow in a temperature-dependent manner. The outflow of 5-HT induced by PCA or 5-HT uptake inhibitors was independent of extracellular Ca2+ concentration. The 5-HT outflow induced by CLM, but not that by PCA, was dependent on the extracellular NaCl concentration. These results suggest that the 5-HT uptake system of 5-HT-containing chemoreceptor cells in the chicken thoracic aorta has characteristics similar to those of 5-HT-containing neurons in the mammalian central nervous system (CNS). PMID:26321443

  13. Endogenous 5-HT outflow from chicken aorta by 5-HT uptake inhibitors and amphetamine derivatives.

    PubMed

    Delgermurun, Dugar; Ito, Shigeo; Ohta, Toshio; Yamaguchi, Soichiro; Otsuguro, Ken-ichi

    2016-01-01

    Chemoreceptor cells aggregating in clusters in the chicken thoracic aorta contain 5-hydroxytryptamine (5-HT) and have voltage-dependent ion channels and nicotinic acetylcholine receptors, which are characteristics typically associated with neurons. The aim of the present study was to investigate the effects of 5-HT uptake inhibitors, fluvoxamine, fluoxetine and clomipramine (CLM), and amphetamine derivatives, p-chloroamphetamine (PCA) and methamphetamine (MET), on endogenous 5-HT outflow from the isolated chick thoracic aorta in vitro. 5-HT was measured by using a HPLC system with electrochemical detection. The amphetamine derivatives and 5-HT uptake inhibitors caused concentration-dependent increases in endogenous 5-HT outflow. PCA was about ten times more effective in eliciting 5-HT outflow than MET. The 5-HT uptake inhibitors examined had similar potency for 5-HT outflow. PCA and CLM increased 5-HT outflow in a temperature-dependent manner. The outflow of 5-HT induced by PCA or 5-HT uptake inhibitors was independent of extracellular Ca(2+) concentration. The 5-HT outflow induced by CLM, but not that by PCA, was dependent on the extracellular NaCl concentration. These results suggest that the 5-HT uptake system of 5-HT-containing chemoreceptor cells in the chicken thoracic aorta has characteristics similar to those of 5-HT-containing neurons in the mammalian central nervous system (CNS). PMID:26321443

  14. Crystallization of recombinant Haemophilus influenzaee (P4) acid phosphatase

    SciTech Connect

    Ou, Zhonghui; Felts, Richard L.; Reilly, Thomas J.; Nix, Jay C.; Tanner, John J.

    2006-05-01

    Lipoprotein e (P4) is a class C acid phosphatase and a potential vaccine candidate for nontypeable H. influenzae infections. This paper reports the crystallization of recombinant e (P4) and the acquisition of a 1.7 Å resolution native X-ray diffraction data set. Haemophilus influenzae infects the upper respiratory tract of humans and can cause infections of the middle ear, sinuses and bronchi. The virulence of the pathogen is thought to involve a group of surface-localized macromolecular components that mediate interactions at the host–pathogen interface. One of these components is lipoprotein e (P4), which is a class C acid phosphatase and a potential vaccine candidate for nontypeable H. influenzae infections. This paper reports the crystallization of recombinant e (P4) and the acquisition of a 1.7 Å resolution native X-ray diffraction data set. The space group is P4{sub 2}2{sub 1}2, with unit-cell parameters a = 65.6, c = 101.4 Å, one protein molecule per asymmetric unit and 37% solvent content. This is the first report of the crystallization of a class C acid phosphatase.

  15. Dielectric strength of parylene HT

    SciTech Connect

    Diaham, S. Bechara, M.; Locatelli, M.-L.; Khazaka, R.; Tenailleau, C.

    2014-02-07

    The dielectric strength of parylene HT (PA-HT) films was studied at room temperature in a wide thickness range from 500 nm to 50 μm and was correlated with nano- and microstructure analyses. X-ray diffraction and polarized optical microscopy have revealed an enhancement of crystallization and spherulites development, respectively, with increasing the material thickness (d). Moreover, a critical thickness d{sub C} (between 5 and 10 μm) is identified corresponding to the beginning of spherulite developments in the films. Two distinct behaviors of the dielectric strength (F{sub B}) appear in the thickness range. For d ≥ d{sub C}, PA-HT films exhibit a decrease in the breakdown field following a negative slope (F{sub B} ∼ d{sup −0.4}), while for d < d{sub C}, it increases with increasing the thickness (F{sub B} ∼ d{sup 0.3}). An optimal thickness d{sub optim} ∼ 5 μm corresponding to a maximum dielectric strength (F{sub B} ∼ 10 MV/cm) is obtained. A model of spherulite development in PA-HT films with increasing the thickness is proposed. The decrease in F{sub B} above d{sub C} is explained by the spherulites development, whereas its increase below d{sub C} is induced by the crystallites growth. An annealing of the material shows both an enhancement of F{sub B} and an increase of the crystallites and spherulites dimensions, whatever the thickness. The breakdown field becomes thickness-independent below d{sub C} showing a strong influence of the nano-scale structural parameters. On the contrary, both nano- and micro-scale structural parameters appear as influent on F{sub B} for d ≥ d{sub C}.

  16. Dielectric strength of parylene HT

    NASA Astrophysics Data System (ADS)

    Diaham, S.; Bechara, M.; Locatelli, M.-L.; Khazaka, R.; Tenailleau, C.; Kumar, R.

    2014-02-01

    The dielectric strength of parylene HT (PA-HT) films was studied at room temperature in a wide thickness range from 500 nm to 50 μm and was correlated with nano- and microstructure analyses. X-ray diffraction and polarized optical microscopy have revealed an enhancement of crystallization and spherulites development, respectively, with increasing the material thickness (d). Moreover, a critical thickness dC (between 5 and 10 μm) is identified corresponding to the beginning of spherulite developments in the films. Two distinct behaviors of the dielectric strength (FB) appear in the thickness range. For d ≥ dC, PA-HT films exhibit a decrease in the breakdown field following a negative slope (FB ˜ d-0.4), while for d < dC, it increases with increasing the thickness (FB ˜ d0.3). An optimal thickness doptim ˜ 5 μm corresponding to a maximum dielectric strength (FB ˜ 10 MV/cm) is obtained. A model of spherulite development in PA-HT films with increasing the thickness is proposed. The decrease in FB above dC is explained by the spherulites development, whereas its increase below dC is induced by the crystallites growth. An annealing of the material shows both an enhancement of FB and an increase of the crystallites and spherulites dimensions, whatever the thickness. The breakdown field becomes thickness-independent below dC showing a strong influence of the nano-scale structural parameters. On the contrary, both nano- and micro-scale structural parameters appear as influent on FB for d ≥ dC.

  17. Production casing for hot dry rock wells EE-2 and EE-3

    SciTech Connect

    Nicholson, D.M.; Pettitt, R.; Sims, J.

    1982-10-01

    The production casing for a pair of hot dry rock (HDR) energy extraction wells had to be designed for unique conditions. Two hot dry rock wells (EE-2 and EE-3) were drilled and production casing installed at Fenton Hill, NM for the Los Alamos National Laboratory HDR program. The design of the production casing and subsequent completion operations in these wells revealed that thermal cycling, anticipated operating pressures, and wear during downhole operations are major considerations for both casing specifications and installation procedures. The first well (Energy Extraction No. 2; EE-2) is intended to be the injection well and EE-3 the production well. The top joint strain in EE-3 was monitored during installation, cementing and tensioning.

  18. Production casing for hot-dry-rock wells EE-2 and EE-3

    SciTech Connect

    Nicholson, R.W.; Pettitt, R.; Sims, J.

    1982-01-01

    The production casing for a pair of hot dry rock (HDR) energy extraction wells had to be designed for unique conditions. Two hot dry rock wells (EE-2 and EE-3) were drilled and production casing installed at Fenton Hill, NM for the Los Alamos National Laboratory HDR program. The design of the production casing and subsequent completion operations in these wells revealed that thermal cycling, anticipated operating pressures, and wear during downhole operations are major considerations for both casing specifications and installation procedures. The first well (Energy Extraction No. 2; EE-2) is intended to be the injection well and EE-3 the production well. The top joint strain in EE-3 was monitored during installation, cementing and tensioning.

  19. Tc with AsqTad and p4rhmc

    SciTech Connect

    Soltz, R; Vranas, P; Gupta, R

    2007-06-20

    We present the ongoing analysis of Lattice Quantum Chromodynamics runs on the LLNL BG/L supercomputer. This installment includes the analysis of 12,000 trajectories from the MILC AsqTad code on a 32{sup 3} x 8 lattice and the time histories from the plaquette and {psi} - bar{psi} trajectories from the p4rhmc code.

  20. Payment for performance (P4P): any future in Italy?

    PubMed Central

    2011-01-01

    Background Pay for Performance (P4P) programs, based on provision of financial incentives for service quality, have been widely adopted to enhance quality of care and to promote a more efficient use of health care resources whilst improving patient outcomes. In Italy, as in other countries, the growing concern over the quality of health services provided and the scarcity of resources would make P4P programs a useful means of improving their performance. The aim of this paper is to evaluate whether it is possible to implement P4P programs in the Lombardy Region, in Italy, based on the existing data set. Methods Thirteen quality measures were identified regarding four clinical conditions (acute myocardial infarction (AMI), heart failure (HF), ischemic stroke and hip and knee replacement) on the basis of an international literature review. Data was collected using the database of three institutions, which included hospital discharge records (Scheda di Dimissione ospedaliera-SDO-) and letters of discharge. The study population was identified using both the Principal ICD-9-CM diagnosis codes and the discharge date. A Statistical Analysis System (SAS) program was used for the text analysis. Results It was possible to calculate almost all the parameters pertaining to the three hospitals as all the data required was available with the exception of inpatient mortality in two hospitals and smoking cessation advice/counseling in one hospital. Conclusions On the ground of this analysis, we believe that it is possible to implement a P4P program in the Lombardy Region. However, for this program to be initiated, all necessary data must be available in electronic format and uniformly collected. Moreover, several other factors must be assessed: which clinical conditions should be included, the threshold for each quality parameter, the amount of financial incentives offered and how they will be provided. PMID:21605472

  1. Hydrostatic compaction of Microtherm HT.

    SciTech Connect

    Broome, Scott Thomas; Bauer, Stephen J.

    2010-09-01

    Two samples of jacketed Microtherm{reg_sign}HT were hydrostatically pressurized to maximum pressures of 29,000 psi to evaluate both pressure-volume response and change in bulk modulus as a function of density. During testing, each of the two samples exhibited large irreversible compactive volumetric strains with only small increases in pressure; however at volumetric strains of approximately 50%, the Microtherm{reg_sign}HT stiffened noticeably at ever increasing rates. At the maximum pressure of 29,000 psi, the volumetric strains for both samples were approximately 70%. Bulk modulus, as determined from hydrostatic unload/reload loops, increased by more than two-orders of magnitude (from about 4500 psi to over 500,000 psi) from an initial material density of {approx}0.3 g/cc to a final density of {approx}1.1 g/cc. An empirical fit to the density vs. bulk modulus data is K = 492769{rho}{sup 4.6548}, where K is the bulk modulus in psi, and {rho} is the material density in g/cm{sup 3}. The porosity decreased from 88% to {approx}20% indicating that much higher pressures would be required to compact the material fully.

  2. EE Cep observations requested for upcoming eclipse

    NASA Astrophysics Data System (ADS)

    Waagen, Elizabeth O.

    2014-07-01

    The AAVSO requests observations for the upcoming eclipse of EE Cephei, a long-period eclipsing variable. EE Cep has a period of 2,050 days, and shows strong variations in the eclipse light curve from one event to the next. Observations are needed to study the morphology of the upcoming eclipse, which will be used to better understand the shape of the eclipsing disk and how it precesses. Mid-eclipse is predicted to be August 23, 2014, but the early stages of the eclipse may begin as much as a month earlier. EE Cep is being observed by a number of amateur and professional astronomers using multiple telescopes at multiple wavelengths. Among these is a collaboration (see https://sites.google.com/site/eecep2014campaign/) headed by Cezary Galan at the Nicolaus Copernicus Astronomical Center in Poland; several individual AAVSO observers are already participating in this effort. The AAVSO is not currently a partner in that campaign, but all data submitted to the AAVSO will be publicly available. The AAVSO strongly encourages observers to begin following this star now, and to continue observations into October 2014 at least. Finder charts with sequence may be created using the AAVSO Variable Star Plotter (http://www.aavso.org/vsp). Observations should be submitted to the AAVSO International Database. See full Alert Notice for more details and observations.

  3. Systems biology and p4 medicine: past, present, and future.

    PubMed

    Hood, Leroy

    2013-04-01

    Studying complex biological systems in a holistic rather than a "one gene or one protein" at a time approach requires the concerted effort of scientists from a wide variety of disciplines. The Institute for Systems Biology (ISB) has seamlessly integrated these disparate fields to create a cross-disciplinary platform and culture in which "biology drives technology drives computation." To achieve this platform/culture, it has been necessary for cross-disciplinary ISB scientists to learn one another's languages and work together effectively in teams. The focus of this "systems" approach on disease has led to a discipline denoted systems medicine. The advent of technological breakthroughs in the fields of genomics, proteomics, and, indeed, the other "omics" is catalyzing striking advances in systems medicine that have and are transforming diagnostic and therapeutic strategies. Systems medicine has united genomics and genetics through family genomics to more readily identify disease genes. It has made blood a window into health and disease. It is leading to the stratification of diseases (division into discrete subtypes) for proper impedance match against drugs and the stratification of patients into subgroups that respond to environmental challenges in a similar manner (e.g. response to drugs, response to toxins, etc.). The convergence of patient-activated social networks, big data and their analytics, and systems medicine has led to a P4 medicine that is predictive, preventive, personalized, and participatory. Medicine will focus on each individual. It will become proactive in nature. It will increasingly focus on wellness rather than disease. For example, in 10 years each patient will be surrounded by a virtual cloud of billions of data points, and we will have the tools to reduce this enormous data dimensionality into simple hypotheses about how to optimize wellness and avoid disease for each individual. P4 medicine will be able to detect and treat perturbations in

  4. Differential interactions of dimethyltryptamine (DMT) with 5-HT1A and 5-HT2 receptors.

    PubMed

    Deliganis, A V; Pierce, P A; Peroutka, S J

    1991-06-01

    The interactions of the indolealkylamine N,N-dimethyltryptamine (DMT) with 5-hydroxytryptamine1A (5-HT1A) and 5-HT2 receptors in rat brain were analyzed using radioligand binding techniques and biochemical functional assays. The affinity of DMT for 5-HT1A sites labeled by [3H]-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]-8-OH-DPAT) was decreased in the presence of 10(-4) M GTP, suggesting agonist activity of DMT at this receptor. Adenylate cyclase studies in rat hippocampi showed that DMT inhibited forskolin-stimulated cyclase activity, a 5-HT1A agonist effect. DMT displayed full agonist activity with an EC50 of 4 x 10(-6) M in the cyclase assay. In contrast to the agonist actions of DMT at 5-HT1A receptors, DMT appeared to have antagonistic properties at 5-HT2 receptors. The ability of DMT to compete for [3H]-ketanserin-labeled 5-HT2 receptors was not affected by the presence of 10(-4) M GTP, suggesting antagonist activity of DMT at 5-HT2 receptors. In addition, DMT antagonized 5-HT2-receptor-mediated phosphatidylinositol (PI) turnover in rat cortex at concentrations above 10(-7) M, with 70% of the 5-HT-induced PI response inhibited at 10(-4) M DMT. Micromolar concentrations of DMT produced a slight PI stimulation that was not blocked by the 5-HT2 antagonist ketanserin. These studies suggest that DMT has opposing actions on 5-HT receptor subtypes, displaying agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2 receptors. PMID:1828347

  5. Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors.

    PubMed

    Cubeddu, L X; Bönisch, H; Göthert, M; Molderings, G; Racké, K; Ramadori, G; Miller, K J; Schwörer, H

    2000-01-01

    Nearly 30% of patients treated with metformin experience gastrointestinal side effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is associated with nausea, vomiting, and diarrhea, we examined whether metformin induces 5-HT release from the intestinal mucosa. In 40% of tissue biopsy specimens of human duodenal mucosa, metformin (1, 10, and 30 microM) caused an increase in 5-HT outflow by 35, 70, and 98%, respectively. Peak increases in 5-HT outflow were observed after 10-15 min exposure to metformin, returning to baseline levels after 25 min. Tetrodotoxin (1 microM) reduced by about 50% the metformin-evoked increase in 5-HT outflow (P<0.05). Metformin-evoked release was not affected by scopolamine + hexamethonium, propranolol, the 5-HT3 receptor antagonist dolasetron, naloxone, or the NK1 receptor antagonist L703606. In the presence of tetrodotoxin (1 microM), somatostatin (1 microM) further reduced metformin-induced 5-HT release by 15-20%. In view of the 5-HT releasing effects of selective 5-HT3 receptor agonists to which metformin (N-N-dimethylbiguanide) is structurally related, we investigated whether metformin directly interacts with 5-HT3 receptors. Receptor binding (inhibition of [3H]-GR65630 binding) and agonist effects (stimulation of [14C]-guanidinium influx) at 5-HT3 receptors were studied in murine neuroblastoma N1E-115 cells, which express functional 5-HT3 receptors. Metformin up to 0.3 mM failed to inhibit [3H]-GR65630 binding and to modify displacement of [3H]-GR65630 binding induced by 5-HT. 5-HT (3 microM) stimulated the influx of [14C]-guanidinium in intact N1E-115 cells. Metformin up to 1 mM failed to modify basal influx, 5-HT-induced influx, and 5-HT+ substance P-induced influx of [14C]-guanidinium. Our results indicate that metformin induces 5-HT3 receptor-independent release of 5-HT from human duodenal mucosa via neuronal and non-neuronal mechanisms. Part of the gastrointestinal side effects observed during treatment with

  6. p4-Linda: A portable implementation of Linda

    SciTech Connect

    Butler, R.M.; Leveton, A.L.; Lusk, E.L.

    1993-07-01

    Facilities such as interprocess communication and protection of shared resources have been added to operating systems to support multiprogramming and have since been adapted to exploit explicit multiprocessing within the scope of two models: the shared-memory model and the distributed (message-passing) model. When multiprocessors (or networks of heterogeneous processors) are used for explicit parallelism, the difference between these models is exposed to the programmer. The p4 tool set was originally developed to buffer the programmer from synchronization issues while offering an added advantage in portability, however two models are often still needed to develop parallel algorithms. We provide two implementations of Linda in an attempt to support a single high-level programming model on top of the existing paradigms in order to provide a consistent semantics regardless of the underlying model. Linda`s fundamental properties associated with generative communication eliminate the distinction between shared and distributed memory.

  7. LQCD Phase 1 Runs with P4RHMC

    SciTech Connect

    Soltz, R; Gupta, R

    2007-02-13

    These results represent the first set of runs of 10 {beta} values ranging from 2000-7000 trajectories with the p4rhmc code. This initial run sequence spanned roughly 2-weeks in late January and Early February, 2007. To manage the submission of dependent jobs: subSet.pl--submits a set of dependent jobs for a single run; rmSet.pl--removes a set of dependent jobs in reverse order of submission; and statSet.pl--runs pstat command and prints parsed output along with directory contents. The results of running the statSet.pl command are printed for three different times during the start up the next sequence of runs using the milc code.

  8. White Paper on P4 Concepts for Pediatric Imaging.

    PubMed

    Daldrup-Link, Heike E; Sammet, Christina; Hernanz-Schulman, Marta; Barsness, Katherine A; Cahill, Anne Marie; Chung, Ellen; Doria, Andrea S; Darge, Kassa; Krishnamurthy, Rajesh; Lungren, Matthew P; Moore, Sheila; Olivieri, Laura; Panigrahy, Ashok; Towbin, Alexander J; Trout, Andrew; Voss, Stephan

    2016-05-01

    Over the past decade, innovations in the field of pediatric imaging have been based largely on single-center and retrospective studies, which provided limited advances for the benefit of pediatric patients. To identify opportunities for potential "quantum-leap" progress in the field of pediatric imaging, the ACR-Pediatric Imaging Research (PIR) Committee has identified high-impact research directions related to the P4 concept of predictive, preventive, personalized, and participatory diagnosis and intervention. Input from 237 members of the Society for Pediatric Radiology was clustered around 10 priority areas, which are discussed in this article. Needs within each priority area have been analyzed in detail by ACR-PIR experts on these topics. By facilitating work in these priority areas, we hope to revolutionize the care of children by shifting our efforts from unilateral reaction to clinical symptoms, to interactive maintenance of child health. PMID:26850380

  9. Role of maternal 5-HT1A receptor in programming offspring emotional and physical development

    PubMed Central

    van Velzen, Annelies; Toth, Miklos

    2010-01-01

    Serotonin1A receptor (5-HT1AR) deficiency has been associated with anxiety and depression and mice with genetic receptor inactivation exhibit heightened anxiety. We have reported that 5-HT1AR is not only a genetic but also a maternal “environmental” factor in the development of anxiety in Swiss-Webster mice. Here we tested if the emergence of maternal genotype dependent adult anxiety is preceded by early behavioral abnormalities or if it is manifested following a normal emotional development. Pups born to null or heterozygote mothers had significantly reduced ultrasonic vocalization between postnatal day (P) 4 and 12 indicating an influence of the maternal genotype. The offspring’s own genotype had an effect limited to P4. Furthermore, we observed reduced weight gain in the null offspring of null but not heterozygote mothers indicating that a complete maternal receptor deficiency compromises offspring physical development. Except a short perinatal deficit during the dark period, heterozygote females displayed normal maternal behavior which, with the early appearance of ultrasonic vocalization deficit, suggests a role for 5-HT1AR during pre/perinatal development. Consistent with this notion, adult anxiety in the offspring is determined during the pre/perinatal period. In contrast to heterozygote females, null mothers exhibited impaired pup retrieval and nest building that may explain the reduced weight gain of their offspring. Taken together, our data indicate an important role for the maternal 5-HT1AR in regulating offspring emotional and physical development. Since reduced receptor binding has been reported in depression, including postpartum depression, reduced 5-HT1AR function in mothers may influence the emotional development of their offspring. PMID:20633050

  10. 5-HT6 receptors and Alzheimer's disease

    PubMed Central

    2013-01-01

    During the past 20 years, the 5-HT6 receptor has received increasing attention and become a promising target for improving cognition. Several studies with structurally different compounds have shown that not only antagonists but also 5-HT6 receptor agonists improve learning and memory in animal models. A large number of publications describing the development of ligands for this receptor have come to light, and it is now quite evident that 5-HT6 receptors have great pharmaceutical potential in terms of related patents. However, 5-HT6 receptor functionality is much more complex than initially defined. According to the existing data, different cellular pathways may be activated, depending on the drug being used. This article reviews preclinical and clinical evidence of the effects that 5-HT6 receptor compounds have on cognition. In addition, the biochemical and neurochemical mechanisms of action through which 5-HT6 receptor compounds can influence cognition will be described. Overall, several 5-HT6-targeted compounds can reasonably be regarded as powerful drug candidates for the treatment of Alzheimer's disease. PMID:23607787

  11. Characterization of a ( sub 3 H)-5-hydroxtyryptamine binding site in rabbit caudate nucleus that differs from the 5-HT sub 1A , 5-HT sub 1B , 5-HT sub 1C and 5-HT sub 1D subtypes

    SciTech Connect

    Xiong, Wencheng; Nelson, D.L. )

    1989-01-01

    ({sup 3}H)5-HT binding sites were analyzed in membranes prepared from the rabbit caudate nucleus (CN). ({sup 3}H)5-HT labeled both 5-HT{sub 1A} and 5-HT{sub 1C} recognition sites, defined by nanomolar affinity for 8-OH-DPAT and mesulergine respectively; however, these represented only a fraction of total specific ({sup 3}H)5-HT binding. Saturation experiments of ({sup 3}H)5-HT binding in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine to block 5-HT{sub 1A} and 5-HT{sub 1C} sites revealed that non-5-HT{sub 1A}/non-5-HT{sub 1C} sites represented about 60% of the total 5-HT{sub 1} sites and that they exhibited saturable, high affinity, and homogeneous binding. The pharmacological profile of the non-5-HT{sub 1A}/non-5-HT{sub 1C} sites (designated 5-HT{sub 1R}) also differed from that of 5-HT{sub 1B} and 5-HT{sub 2} sites, but was similar to that of the 5-HT{sub 1D} site. However, significant differences existed between the 5-HT{sub 1D} and 5-HT{sub 1B} sites for their K{sub i} values for spiperone, spirilene, metergoline, and methiothepin. The study of modulatory agents also showed differences between the 5-HT{sub 1R} and 5-HT{sub 1D} sites. In addition, calcium enhanced the effects of GTP on the 5-HT{sub 1R} sites, whereas calcium inhibited the GTP effect on the 5-HT{sub 1D} sites.

  12. Serotonin receptor diversity in the human colon: Expression of serotonin type 3 receptor subunits 5-HT3C, 5-HT3D, and 5-HT3E

    PubMed Central

    Kapeller, Johannes; Möller, Dorothee; Lasitschka, Felix; Autschbach, Frank; Hovius, Ruud; Rappold, Gudrun; Brüss, Michael; Gershon, Michael D.

    2011-01-01

    Since the first description of 5-HT3 receptors more than 50 years ago, there has been speculation about the molecular basis of their receptor heterogeneity. We have cloned the genes encoding novel 5-HT3 subunits 5-HT3C, 5-HT3D, and 5-HT3E and have shown that these subunits are able to form functional heteromeric receptors when coexpressed with the 5-HT3A subunit. However, whether these subunits are actually expressed in human tissue remained to be confirmed. In the current study, we performed immunocytochemistry to locate the 5-HT3A as well as the 5-HT3C, 5-HT3D, and 5-HT3E subunits within the human colon. Western blot analysis was used to confirm subunit expression, and RT-PCR was employed to detect transcripts encoding 5-HT3 receptor subunits in microdissected tissue samples. This investigation revealed, for the first time, that 5-HT3C, 5-HT3D, and 5-HT3E subunits are coexpressed with 5-HT3A in cell bodies of myenteric neurons. Furthermore, 5-HT3A and 5-HT3D were found to be expressed in submucosal plexus of the human large intestine. These data provide a strong basis for future studies of the roles that specific 5-HT3 receptor subtypes play in the function of the enteric and central nervous systems and the contribution that specific 5-HT3 receptors make to the pathophysiology of gastrointestinal disorders such as irritable bowel syndrome and dyspepsia. PMID:21192076

  13. RAFT polymerization kinetics and polymer characterization of P3HT rod-coil block copolymers and their uses to prepare hybrid nanocomposites

    NASA Astrophysics Data System (ADS)

    Kern, Melissa Robin

    group reactions result in P3HT homopolymer in the final sample. Therefore accurate characterization requires molecular weight determination of the block copolymer and quantification of the sample composition. Also presented in this work is the synthesis of amphiphilic rod-coil block copolymers of P3HT with poly(4-vinyl pyridine) (4VP) and poly(acrylic acid) (AA). Here, P3HT-b-PAA is prepared by the direct synthesis of acrylic acid with the macroRAFT agent using a binary solvent system of trichlorobenzene and dioxane to maintain polymer solubility throughout the polymerization. The micelle formation of the resulting block copolymer is detailed as the transparent micelle solution of P3HT-b-PAA exhibits the optical behavior of solid-state P3HT. Finally, the preparation of various nanocomposites from the synthesized P3HT homopolymer and block copolymers is presented. In the first method, the RAFT end group of the P3HT macroRAFT agent and the P3HT block copolymers is reduced to a thiol to allow for attachment to Au nanoparticles. While Au nanoparticles are not useful for photovoltaic applications, the surface modification demonstrates the utility of the P3HT macroRAFT agent, which is used to modify the surface with P3HT homopolymer and P3HT block copolymers. The second method to prepare P3HT hybrid nanocomposites is in-situ growth of CdS in P3HT-b-P4VP. With analysis by dynamic light scattering (DLS), Fourier-transform infrared (FT-IR) spectroscopy and transmission electron microscopy (TEM), it is concluded that a majority of the CdS growth in the P3HT-b-P4VP was confined to the P4VP block.

  14. Inversion by P4: polarization-picture post-processing.

    PubMed

    Schechner, Yoav Y

    2011-03-12

    Polarization may be sensed by imaging modules. This is done in various engineering systems as well as in biological systems, specifically by insects and some marine species. However, polarization per pixel is usually not the direct variable of interest. Rather, polarization-related data serve as a cue for recovering task-specific scene information. How should polarization-picture post-processing (P(4)) be done for the best scene understanding? Answering this question is not only helpful for advanced engineering (computer vision), but also to prompt hypotheses as to the processing occurring within biological systems. In various important cases, the answer is found by a principled expression of scene recovery as an inverse problem. Such an expression relies directly on a physics-based model of effects in the scene. The model includes analysis that depends on the different polarization components, thus facilitating the use of these components during the inversion, in a proper, even if non-trivial, manner. We describe several examples for this approach. These include automatic removal of path radiance in haze or underwater, overcoming partial semireflections and visual reverberations; three-dimensional recovery and distance-adaptive denoising. The resulting inversion algorithms rely on signal-processing methods, such as independent component analysis, deconvolution and optimization. PMID:21282167

  15. EE Cep Winks in Full Color

    NASA Astrophysics Data System (ADS)

    Walker, Gary E.

    2015-01-01

    We observe the long period (5.6 years) Eclipsing Binary Variable Star EE Cep during it's 2014 eclipse. It was observed on every clear night from the Maria Mitchell Observatory as well as remote sites for a total of 25 nights. Each night consisted of a detailed time series in BVRI looking for short term variations for a total of >9000 observations. The data was transformed to the Standard System. In addition, a time series was captured during the night of the eclipse. This data provides an alternate method to determine Time of Minimum than traditionally performed. The TOM varied with color. Several strong correlations are seen between colors substantiating the detection of variations on a time scale of hours. The long term light curve shows 5 interesting and different Phases with different characteristics.

  16. EE Cep Winks in Full Color (Abstract)

    NASA Astrophysics Data System (ADS)

    Walker, G.

    2015-06-01

    (Abstract only) We observe the long period (5.6 years) Eclipsing Binary Variable Star EE Cep during its 2014 eclipse. It was observed on every clear night from the Maria Mitchell Observatory as well as remote sites for a total of 25 nights. Each night consisted of a detailed time series in BVRI looking for short term variations for a total of >10,000 observations. The data was transformed to the Standard System. In addition, a time series was captured during the night of the eclipse. This data provides an alternate method to determine Time of Minimum than traditionally performed. The TOM varied with color. Several strong correlations are seen between colors substantiating the detection of variations on a time scale of hours. The long term light curve shows five interesting and different Phases with different characteristics.

  17. TARS-HT1 and TARS-HT2 heat-tolerant dry bean germplasm

    Technology Transfer Automated Retrieval System (TEKTRAN)

    TARS-HT1 (Reg no. __, PI ___) and TARS-HT2 (Reg no. __, PI ___) are heat tolerant dark red and light red, respectively, kidney beans (Phaseolus vulgaris L.) developed cooperatively by the USDA-ARS Tropical Agriculture Research Station (TARS), the University of Puerto Rico, Cornell University, and th...

  18. Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands.

    PubMed

    Ofori, Edward; Zhu, Xue Y; Etukala, Jagan R; Peprah, Kwakye; Jordan, Kamanski R; Adkins, Adia A; Bricker, Barbara A; Kang, Hye J; Huang, Xi-Ping; Roth, Bryan L; Ablordeppey, Seth Y

    2016-08-15

    5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin. PMID:27312422

  19. Lorcaserin, A 5-HT2C Receptor Agonist, Reduces Body Weight by Decreasing Energy Intake without Influencing Energy Expenditure

    PubMed Central

    Martin, Corby K.; Redman, Leanne M.; Zhang, Jinkun; Sanchez, Matilde; Anderson, Christen M.; Smith, Steven R.

    2011-01-01

    Context: Lorcaserin, a selective 5-hydroxytryptamine (5-HT)2C receptor agonist, reduces body weight. It is unclear whether weight loss is due to reduced energy intake (EI) or also to enhanced energy expenditure (EE). Objective: This study tested the effect of lorcaserin on EI and EE. Design, Participants, and Intervention: In a double-blind, randomized, placebo-controlled trial, 57 (39 women) overweight and obese (body mass index, 27–45 kg/m2) adults were randomized to placebo (n = 28) or 10 mg twice daily lorcaserin (n = 29) for 56 d. Weight maintenance was imposed during d 1–7. Beginning on d 8, participants followed a diet and exercise plan targeting a 600 kcal/d deficit. Outcomes: At baseline and after 7 and 56 d of treatment, we measured body weight, body composition (dual x-ray absorptiometry), blood pressure, heart rate, EI at lunch and dinner, subjective appetite ratings, and 24-h EE and 24-h-respiratory quotient (RQ), measured by indirect calorimetry in a respiratory chamber. Results: After 7 d of weight maintenance, EI was significantly (P < 0.01) reduced with lorcaserin but not placebo (mean ± sem for lorcaserin, −286 ± 86 kcal; placebo, −147 ± 89 kcal). After 56 d, lorcaserin resulted in significantly larger reductions in body weight (lorcaserin, −3.8 ± 0.4 kg; placebo, −2.2 ± 0.5 kg; P < 0.01), EI (lorcaserin, −470 ± 87 kcal; placebo, −205 ± 91 kcal; P < .05), and appetite ratings than in placebo. Changes in 24-h EE and 24-h RQ did not differ between groups, even after 24-h EE was adjusted for body weight and composition. Compared with placebo, lorcaserin had no effect on systolic or diastolic blood pressure or heart rate after 56 d. Conclusions: Lorcaserin reduces body weight through reduced EI, not altered EE or RQ. PMID:21190985

  20. The Co-Evolution of ESD and EE

    ERIC Educational Resources Information Center

    Monroe, Martha C.

    2012-01-01

    William B. Stapp, a major author of the founding documents of environmental education (EE), foreshadowed the triple concerns of education for sustainable development (ESD) with environment, social justice and economic health. Yet EE in the USA tended to follow the advocacy orientation of the environmental movement of the 1970s and later, following…

  1. Some Historical Thoughts on the ee-Learning Renaissance

    ERIC Educational Resources Information Center

    Nilles, Jack M.

    2007-01-01

    Jack Nilles surveys the evolution of ee-learning at the University of Southern California, together with the first formal telecommuting demonstration program, from its beginnings in the early 1970s to the relevant trends in 2006. Although the basic technologies of telecommuting and ee-learning were in evidence in the 1970s, subsequent…

  2. Intrathecal 5-methoxy-N,N-dimethyltryptamine in mice modulates 5-HT1 and 5-HT3 receptors.

    PubMed

    Alhaider, A A; Hamon, M; Wilcox, G L

    1993-11-01

    The antinociceptive effects of intrathecally administered 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent 5-HT receptor agonist, were studied in three behavioral tests in mice: the tail-flick test and the intrathecal substance P and N-methyl-D-aspartic acid (NMDA) assays. Intrathecal administration of 5-MeO-DMT (4.6-92 nmol/mouse) produced a significant prolongation of the tail-flick latency. This action was blocked by 5-HT3 and gamma-aminobutyric acidA (GABAA) receptor antagonists but not by 5-HT2, 5-HT1A, 5-HT1B or 5-HT1S receptor antagonists. Binding studies indicated that 5-MeO-DMT had very low affinity for 5-HT3 receptors. 5-MeO-DMT inhibited biting behavior while increasing scratching behavior induced by intrathecally administered substance P. The inhibition of biting behavior was antagonized by intrathecal co-administration of 5-HT1B and GABAA receptor antagonists while 5-HT1A, 5-HT1S, 5-HT2 and 5-HT3 receptor antagonists had no effect. 5-MeO-DMT-enhanced scratching behavior was inhibited by all the antagonists used except ketanserin and bicuculline, suggesting the involvement of 5-HT1A, 5-HT1B, 5-HT1S, 5-HT3 and GABAA receptors. NMDA-induced biting behavior was inhibited by 5-MeO-DMT pretreatment; this action was antagonized by 5-HT1B, 5-HT3 and GABAA receptor antagonists. The involvement of these receptors in 5-MeO-DMT action suggests that it may promote release of 5-HT (5-hydroxytryptamine, serotonin). PMID:7507056

  3. Measuring straight line segments using HT butterflies.

    PubMed

    Du, Shengzhi; Tu, Chunling; van Wyk, Barend J; Ochola, Elisha Oketch; Chen, Zengqiang

    2012-01-01

    This paper addresses the features of Hough Transform (HT) butterflies suitable for image-based segment detection and measurement. The full segment parameters such as the position, slope, width, length, continuity, and uniformity are related to the features of the HT butterflies. Mathematical analysis and experimental data are presented in order to demonstrate and build the relationship between the measurements of segments and the features of HT butterflies. An effective method is subsequently proposed to employ these relationships in order to discover the parameters of segments. Power line inspection is considered as an application of the proposed method. The application demonstrates that the proposed method is effective for power line inspection, especially for corner detection when they cross poles. PMID:22479442

  4. Transient failure behavior of HT9

    SciTech Connect

    Huang, F.H.

    1994-07-01

    Alloy HT9 has-been chosen as candidate materials for fast and fusion reactor applications because the.material exhibits excellent resistance to void swelling. However, ferritic alloys are known to undergo a ductile-brittle transition as the test temperature is decreased. This inherent problem has limited their applications to reactor component materials subjected to low neutron exposures. Despite the ductile-brittle transition problem, results show that the materials exhibit superior resistance to fracture under very high neutron fluences at irradiation temperatures above 380C. Results also show that the transient behavior for HT9 cladding specimens taken from the fuel column region and cladding taken from outside the fuel column or unirradiated cladding are the same. HT9 cladding maintained its transient strength with irradiation to a fluence of 9 {times} 10{sup 22} n/cm{sup 2} (E > 0.1 MeV).

  5. Constitutively Active 5-HT Receptors: An Explanation of How 5-HT Antagonists Inhibit Gut Motility in Species Where 5-HT is Not an Enteric Neurotransmitter?

    PubMed Central

    Spencer, Nick J.

    2015-01-01

    Antagonists of 5-Hydroxytryptamine (5-HT) receptors are well known to inhibit gastrointestinal (GI)-motility and transit in a variety of mammals, including humans. Originally, these observations had been interpreted by many investigators (including us) as evidence that endogenous 5-HT plays a major role in GI motility. This seemed a logical assumption. However, the story changed dramatically after recent studies revealed that 5-HT antagonists still blocked major GI motility patterns (peristalsis and colonic migrating motor complexes) in segments of intestine depleted of all 5-HT. Then, these results were further supported by Dr. Gershons' laboratory, which showed that genetic deletion of all genes that synthesizes 5-HT had minor, or no inhibitory effects on GI transit in vivo. If 5-HT was essential for GI motility patterns and transit, then one would expect major disruptions in motility and transit when 5-HT synthesis was genetically ablated. This does not occur. The inhibitory effects of 5-HT antagonists on GI motility clearly occur independently of any 5-HT in the gut. Evidence now suggests that 5-HT antagonists act on 5-HT receptors in the gut which are constitutively active, and don't require 5-HT for their activation. This would explain a long-standing mystery of how 5-HT antagonists inhibit gut motility in species like mice, rats, and humans where 5-HT is not an enteric neurotransmitter. Studies are now increasingly demonstrating that the presence of a neurochemical in enteric neurons does not mean they function as neurotransmitters. Caution should be exercised when interpreting any inhibitory effects of 5-HT antagonists on GI motility. PMID:26732863

  6. The 5-HT1-like receptors mediating inhibition of sympathetic vasopressor outflow in the pithed rat: operational correlation with the 5-HT1A, 5-HT1B and 5-HT1D subtypes

    PubMed Central

    Villalón, Carlos M; Centurión, David; Rabelo, Gonzalo; de Vries, Peter; Saxena, Pramod R; Sánchez-López, Araceli

    1998-01-01

    It has been suggested that the inhibition of sympathetically-induced vasopressor responses produced by 5-hydroxytryptamine (5-HT) in pithed rats is mediated by 5-HT1-like receptors. The present study has re-analysed this suggestion with regard to the classification schemes recently proposed by the NC-IUPHAR subcommittee on 5-HT receptors.Intravenous (i.v.) continuous infusions of 5-HT and the 5-HT1 receptor agonists, 8-OH-DPAT (5-HT1A), indorenate (5-HT1A), CP 93,129 (5-HT1B) and sumatriptan (5-HT1B/1D), resulted in a dose-dependent inhibition of sympathetically-induced vasopressor responses.The sympatho-inhibitory responses induced by 5-HT, 8-OH-DPAT, indorenate, CP 93,129 or sumatriptan were analysed before and after i.v. treatment with blocking doses of the putative 5-HT receptor antagonists, WAY 100635 (5-HT1A), cyanopindolol (5-HT1A/1B) or GR 127935 (5-HT1B/1D). Thus, after WAY 100635, the responses to 5-HT and indorenate, but not to 8-OH-DPAT, CP 93,129 and sumatriptan, were blocked. After cyanopindolol, the responses to 5-HT, indorenate and CP 93,129 were abolished, whilst those to 8-OH-DPAT and sumatriptan (except at the lowest frequency of stimulation) remained unaltered. In contrast, after GR 127935, the responses to 5-HT, CP 93,129 and sumatriptan, but not to 8-OH-DPAT and indorenate, were abolished.In additional experiments, the inhibition induced by 5-HT was not modified after 5-HT7 receptor blocking doses of mesulergine.The above results suggest that the 5-HT1-like receptors, which inhibit the sympathetic vasopressor outflow in pithed rats, display the pharmacological profile of the 5-HT1A, 5-HT1B and 5-HT1D, but not that of 5-HT7, receptors. PMID:9692787

  7. 5-HT4 and 5-HT2 receptors antagonistically influence gap junctional coupling between rat auricular myocytes.

    PubMed

    Derangeon, Mickaël; Bozon, Véronique; Defamie, Norah; Peineau, Nicolas; Bourmeyster, Nicolas; Sarrouilhe, Denis; Argibay, Jorge A; Hervé, Jean-Claude

    2010-01-01

    5-hydroxytryptamine-4 (5-HT(4)) receptors have been proposed to contribute to the generation of atrial fibrillation in human atrial myocytes, but it is unclear if these receptors are present in the hearts of small laboratory animals (e.g. rat). In this study, we examined presence and functionality of 5-HT(4) receptors in auricular myocytes of newborn rats and their possible involvement in regulation of gap junctional intercellular communication (GJIC, responsible for the cell-to-cell propagation of the cardiac excitation). Western-blotting assays showed that 5-HT(4) receptors were present and real-time RT-PCR analysis revealed that 5-HT(4b) was the predominant isoform. Serotonin (1 microM) significantly reduced cAMP concentration unless a selective 5-HT(4) inhibitor (GR113808 or ML10375, both 1 microM) was present. Serotonin also reduced the amplitude of L-type calcium currents and influenced the strength of GJIC without modifying the phosphorylation profiles of the different channel-forming proteins or connexins (Cxs), namely Cx40, Cx43 and Cx45. GJIC was markedly increased when serotonin exposure occurred in presence of a 5-HT(4) inhibitor but strongly reduced when 5-HT(2A) and 5-HT(2B) receptors were inhibited, showing that activation of these receptors antagonistically regulated GJIC. The serotoninergic response was completely abolished when 5-HT(4), 5-HT(2A) and 5-HT(2B) were simultaneously inhibited. A 24 h serotonin exposure strongly reduced Cx40 expression whereas Cx45 was less affected and Cx43 still less. In conclusion, this study revealed that 5-HT(4) (mainly 5-HT(4b)), 5-HT(2A) and 5-HT(2B) receptors coexisted in auricular myocytes of newborn rat, that 5-HT(4) activation reduced cAMP concentration, I(Ca)(L) and intercellular coupling whereas 5-HT(2A) or 5-HT(2B) activation conversely enhanced GJIC. PMID:19615378

  8. Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling.

    SciTech Connect

    Fang, Bin; Fu, Guoxing; Agniswamy, Johnson; Harrison, Robert W.; Weber, Irene T.

    2009-03-31

    Caspase-3 recognition of various P4 residues in its numerous protein substrates was investigated by crystallography, kinetics, and calculations on model complexes. Asp is the most frequent P4 residue in peptide substrates, although a wide variety of P4 residues are found in the cellular proteins cleaved by caspase-3. The binding of peptidic inhibitors with hydrophobic P4 residues, or no P4 residue, is illustrated by crystal structures of caspase-3 complexes with Ac-IEPD-Cho, Ac-WEHD-Cho, Ac-YVAD-Cho, and Boc-D(OMe)-Fmk at resolutions of 1.9-2.6 {angstrom}. The P4 residues formed favorable hydrophobic interactions in two separate hydrophobic regions of the binding site. The side chains of P4 Ile and Tyr form hydrophobic interactions with caspase-3 residues Trp206 and Trp214 within a non-polar pocket of the S4 subsite, while P4 Trp interacts with Phe250 and Phe252 that can also form the S5 subsite. These interactions of hydrophobic P4 residues are distinct from those for polar P4 Asp, which indicates the adaptability of caspase-3 for binding diverse P4 residues. The predicted trends in peptide binding from molecular models had high correlation with experimental values for peptide inhibitors. Analysis of structural models for the binding of 20 different amino acids at P4 in the aldehyde peptide Ac-XEVD-Cho suggested that the majority of hydrophilic P4 residues interact with Phe250, while hydrophobic residues interact with Trp206, Phe250, and Trp214. Overall, the S4 pocket of caspase-3 exhibits flexible adaptation for different residues and the new structures and models, especially for hydrophobic P4 residues, will be helpful for the design of caspase-3 based drugs.

  9. High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding.

    PubMed

    da Cunha-Bang, Sofi; Mc Mahon, Brenda; Fisher, Patrick MacDonald; Jensen, Peter Steen; Svarer, Claus; Knudsen, Gitte Moos

    2016-04-01

    Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145 for quantification of brain 5-HT4R binding. The Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females. PMID:26772668

  10. 5-Hydroxytryptamine (5-HT) Cellular Sequestration during Chronic Exposure Delays 5-HT3 Receptor Resensitization due to Its Subsequent Release*

    PubMed Central

    Hothersall, J. Daniel; Alexander, Amy; Samson, Andrew J.; Moffat, Christopher; Bollan, Karen A.; Connolly, Christopher N.

    2014-01-01

    The serotonergic synapse is dynamically regulated by serotonin (5-hydroxytryptamine (5-HT)) with elevated levels leading to the down-regulation of the serotonin transporter and a variety of 5-HT receptors, including the 5-HT type-3 (5-HT3) receptors. We report that recombinantly expressed 5-HT3 receptor binding sites are reduced by chronic exposure to 5-HT (IC50 of 154.0 ± 45.7 μm, t½ = 28.6 min). This is confirmed for 5-HT3 receptor-induced contractions in the guinea pig ileum, which are down-regulated after chronic, but not acute, exposure to 5-HT. The loss of receptor function does not involve endocytosis, and surface receptor levels are unaltered. The rate and extent of down-regulation is potentiated by serotonin transporter function (IC50 of 2.3 ± 1.0 μm, t½ = 3.4 min). Interestingly, the level of 5-HT uptake correlates with the extent of down-regulation. Using TX-114 extraction, we find that accumulated 5-HT remains soluble and not membrane-bound. This cytoplasmically sequestered 5-HT is readily releasable from both COS-7 cells and the guinea pig ileum. Moreover, the 5-HT level released is sufficient to prevent recovery from receptor desensitization in the guinea pig ileum. Together, these findings suggest the existence of a novel mechanism of down-regulation where the chronic release of sequestered 5-HT prolongs receptor desensitization. PMID:25281748

  11. Serotonin (5-HT) and 5-HT2A receptor agonists suppress lipolysis in primary rat adipose cells.

    PubMed

    Hansson, Björn; Medina, Anya; Fryklund, Claes; Fex, Malin; Stenkula, Karin G

    2016-05-27

    Serotonin (5-HT) is a biogenic monoamine that functions both as a neurotransmitter and a circulating hormone. Recently, the metabolic effects of 5-HT have gained interest and peripheral 5-HT has been proposed to influence lipid metabolism in various ways. Here, we investigated the metabolic effects of 5-HT in isolated, primary rat adipose cells. Incubation with 5-HT suppressed β-adrenergically stimulated glycerol release and decreased phosphorylation of protein kinase A (PKA)-dependent substrates, hormone sensitive lipase (Ser563) and perilipin (Ser522). The inhibitory effect of 5-HT on lipolysis enhanced the anti-lipolytic effect of insulin, but sustained in the presence of phosphodiesterase inhibitors, OPC3911 and isobuthylmethylxanthine (IBMX). The relative expression of 5-HT1A, -2B and -4 receptor class family were significantly higher in adipose tissue compared to adipose cells, whereas 5-HT1D, -2A and -7 were highly expressed in isolated adipose cells. Similar to 5-HT, 5-HT2 receptor agonists reduced lipolysis while 5-HT1 receptor agonists rather decreased non-stimulated and insulin-stimulated glucose uptake. Together, these data provide evidence of a direct effect of 5-HT on adipose cells, where 5-HT suppresses lipolysis and glucose uptake, which could contribute to altered systemic lipid- and glucose metabolism. PMID:27109474

  12. 40 CFR Table 1 to Subpart Ee of... - Applicability of General Provisions to Subpart EE

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...) Yes. 63.4(b) Yes. 63.4(c) Yes. 63.5(a) Yes. 63.5(b)(1) Yes. 63.5(b)(3)-(6) Yes. 63.5(d) Yes. 63.5(e.... 63.6(f)(1) No § 63.701(f) of subpart EE specifies when the standards apply. 63.6(f)(2)(i)-(ii) Yes...)(2)(i) Yes. 63.6(h)(2)(iii) Yes. 63.6(h)(4) Yes This requirement applies only for the...

  13. Experiment 2030. EE-2 Temperature Log and Downhole Water Sample

    SciTech Connect

    Grigsby, Charles O.

    1983-07-29

    A temperature log and downhole water sample run were conducted in EE-2 on July 13, 1983. The temperature log was taken to show any changes which had occurred in the fracture-to-wellbore intersections as a result of the Experiment 2020 pumping and to locate fluid entries for taking the water sample. The water sample was requested primarily to determine the arsenic concentration in EE-2 fluids (see memo from C.Grigsby, June 28, 1983 concerning arsenic in EE-3 samples.) The temperature log was run using the thermistor in the ESS-6 water samples.

  14. Circadian 5-HT production regulated by adrenergic signaling

    PubMed Central

    Sun, Xing; Deng, Jie; Liu, Tiecheng; Borjigin, Jimo

    2002-01-01

    Using on-line microdialysis, we have characterized in vivo dynamics of pineal 5-hydroxytryptamine (5-HT; serotonin) release. Daily pineal 5-HT output is triphasic: (i) 5-HT levels are constant and high during the day; (ii) early in the night, there is a novel sharp rise in 5-HT synthesis and release, which precedes the nocturnal rise in melatonin synthesis; and (iii) late in the night, levels are low. This triphasic 5-HT production persists in constant darkness and is influenced strongly by intrusion of light at night. We demonstrate that both diurnal 5-HT synthesis and 5-HT release are activated by sympathetic innervation from the superior cervical ganglion and show that these processes are controlled by distinct receptors. The increase in 5-HT synthesis is controlled by β-adrenergic receptors, whereas the increase in 5-HT release is mediated by α-adrenergic signaling. On the other hand, the marked decrease in 5-HT content and release late at night is a passive process, influenced by the extent of melatonin synthesis. In the absence of melatonin synthesis, the late-night decline in 5-HT release is prevented, reaching levels roughly twice as high as that of the day value. In summary, our results demonstrate that 5-HT levels display marked circadian rhythms that depend on adrenergic signaling. PMID:11917109

  15. Recombinant HT.sub.m4 gene, protein and assays

    DOEpatents

    Lim, Bing; Adra, Chaker N.; Lelias, Jean-Michel

    1996-01-01

    The invention relates to a recombinant DNA molecule which encodes a HT.sub.m4 protein, a transformed host cell which has been stably transfected with a DNA molecule which encodes a HT.sub.m4 protein and a recombinant HT.sub.m4 protein. The invention also relates to a method for detecting the presence of a hereditary atopy.

  16. Antibodies specific for HT.sub.m4

    DOEpatents

    Lim, Bing; Adra, Chaker N.; Lelias, Jean-Michel

    1998-01-01

    The invention relates to a recombinant DNA molecule which encodes a HT.sub.m4 protein, a transformed host cell which has been stably transfected with a DNA molecule which encodes a HT.sub.m4 protein and a recombinant HT.sub.m4 protein. The invention also relates to a method for detecting the presence of a hereditary atopy.

  17. Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists.

    PubMed

    Kim, Jeeyeon; Kim, Youngjae; Tae, Jinsung; Yeom, Miyoung; Moon, Bongjin; Huang, Xi-Ping; Roth, Bryan L; Lee, Kangho; Rhim, Hyewhon; Choo, Il Han; Chong, Youhoon; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah

    2013-11-01

    The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 R. Among the synthesized compounds, 1-([2'-methoxy-(1,1'-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function. PMID:24039134

  18. The 5-HT3B subunit affects high-potency inhibition of 5-HT3 receptors by morphine

    PubMed Central

    Baptista-Hon, Daniel T; Deeb, Tarek Z; Othman, Nidaa A; Sharp, Douglas; Hales, Tim G

    2012-01-01

    BACKGROUND AND PURPOSE Morphine is an antagonist at 5-HT3A receptors. 5-HT3 and opioid receptors are expressed in many of the same neuronal pathways where they modulate gut motility, pain and reinforcement. There is increasing interest in the 5-HT3B subunit, which confers altered pharmacology to 5-HT3 receptors. We investigated the mechanisms of inhibition by morphine of 5-HT3 receptors and the influence of the 5-HT3B subunit. EXPERIMENTAL APPROACH 5-HT-evoked currents were recorded from voltage-clamped HEK293 cells expressing human 5-HT3A subunits alone or in combination with 5-HT3B subunits. The affinity of morphine for the orthosteric site of 5-HT3A or 5-HT3AB receptors was assessed using radioligand binding with the antagonist [3H]GR65630. KEY RESULTS When pre-applied, morphine potently inhibited 5-HT-evoked currents mediated by 5-HT3A receptors. The 5-HT3B subunit reduced the potency of morphine fourfold and increased the rates of inhibition and recovery. Inhibition by pre-applied morphine was insurmountable by 5-HT, was voltage-independent and occurred through a site outside the second membrane-spanning domain. When applied simultaneously with 5-HT, morphine caused a lower potency, surmountable inhibition of 5-HT3A and 5-HT3AB receptors. Morphine also fully displaced [3H]GR65630 from 5-HT3A and 5-HT3AB receptors with similar potency. CONCLUSIONS AND IMPLICATIONS These findings suggest that morphine has two sites of action, a low-affinity, competitive site and a high-affinity, non-competitive site that is not available when the channel is activated. The affinity of morphine for the latter is reduced by the 5-HT3B subunit. Our results reveal that morphine causes a high-affinity, insurmountable and subunit-dependent inhibition of human 5-HT3 receptors. PMID:21740409

  19. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats.

    PubMed

    Martin-Gronert, Malgorzata S; Stocker, Claire J; Wargent, Edward T; Cripps, Roselle L; Garfield, Alastair S; Jovanovic, Zorica; D'Agostino, Giuseppe; Yeo, Giles S H; Cawthorne, Michael A; Arch, Jonathan R S; Heisler, Lora K; Ozanne, Susan E

    2016-04-01

    Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist. PMID:26769798

  20. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

    PubMed Central

    Martin-Gronert, Malgorzata S.; Stocker, Claire J.; Wargent, Edward T.; Cripps, Roselle L.; Garfield, Alastair S.; Jovanovic, Zorica; D'Agostino, Giuseppe; Yeo, Giles S. H.; Cawthorne, Michael A.; Arch, Jonathan R. S.; Heisler, Lora K.; Ozanne, Susan E.

    2016-01-01

    ABSTRACT Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus of in utero growth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist. PMID:26769798

  1. The P4 truss is moved to a workstand in the SSPF

    NASA Technical Reports Server (NTRS)

    2000-01-01

    In the Space Station Processing Facility, workers get ready to lower the International Space Station's P4 truss onto a workstand. Part of the 10-truss, girder-like structure that will ultimately extend the length of a football field, the P4 is the second port truss segment that will attach to the first port truss segment (P1 truss). The P4 is scheduled for mission 12A in September 2002.

  2. The P4 truss is moved to a workstand in the SSPF

    NASA Technical Reports Server (NTRS)

    2000-01-01

    In the Space Station Processing Facility, workers oversee the removal of the P4 truss from the truck that transported it from Tulsa, Okla. Part of the 10-truss, girder-like structure that will ultimately extend the length of a football field on the International Space Station, the P4 is the second port truss segment that will attach to the first port truss segment (P1 truss). The P4 is scheduled for mission 12A in September 2002.

  3. The P4 truss is moved to a workstand in the SSPF

    NASA Technical Reports Server (NTRS)

    2000-01-01

    In the Space Station Processing Facility, an overhead crane moves the P4 truss to a workstand. Part of the 10-truss, girder-like structure that will ultimately extend the length of a football field on the International Space Station, the P4 is the second port truss segment that will attach to the first port truss segment (P1 truss). The P4 is scheduled for mission 12A in September 2002.

  4. Mechanisms of genome propagation and helper exploitation by satellite phage P4.

    PubMed Central

    Lindqvist, B H; Dehò, G; Calendar, R

    1993-01-01

    Temperate coliphage P2 and satellite phage P4 have icosahedral capsids and contractile tails with side tail fibers. Because P4 requires all the capsid, tail, and lysis genes (late genes) of P2, the genomes of these phages are in constant communication during P4 development. The P4 genome (11,624 bp) and the P2 genome (33.8 kb) share homologous cos sites of 55 bp which are essential for generating 19-bp cohesive ends but are otherwise dissimilar. P4 turns on the expression of helper phage late genes by two mechanisms: derepression of P2 prophage and transactivation of P2 late-gene promoters. P4 also exploits the morphopoietic pathway of P2 by controlling the capsid size to fit its smaller genome. The P4 sid gene product is responsible for capsid size determination, and the P2 capsid gene product, gpN, is used to build both sizes. The P2 capsid contains 420 capsid protein subunits, and P4 contains 240 subunits. The size reduction appears to involve a major change of the whole hexamer complex. The P4 particles are less stable to heat inactivation, unless their capsids are coated with a P4-encoded decoration protein (the psu gene product). P4 uses a small RNA molecule as its immunity factor. Expression of P4 replication functions is prevented by premature transcription termination effected by this small RNA molecule, which contains a sequence that is complementary to a sequence in the transcript that it terminates. Images PMID:8246844

  5. The Top 10 Things I LOVE about p4c Hawai'i

    ERIC Educational Resources Information Center

    Ikeda, Jolyn

    2012-01-01

    In 2001, Dr. Thomas Jackson, or Dr. J as the author and her colleagues affectionately call him, spoke to the faculty at Waikiki Elementary. He described philosophy for children (p4c) Hawai'i and encouraged them to try P4C if something about it "resonated" with them. In the beginning, Dr. J held a p4t (philosophy for teachers) after-school seminar…

  6. The P4 truss is moved to a workstand in the SSPF

    NASA Technical Reports Server (NTRS)

    2000-01-01

    After its move across the Space Station Processing Facility, the International Space Station's P4 truss rests in its workstand. Part of the 10-truss, girder-like structure that will ultimately extend the length of a football field, the P4 is the second port truss segment that will attach to the first port truss segment (P1 truss). The P4 is scheduled for mission 12A in September 2002.

  7. Arterial expression of 5-HT2B and 5-HT1B receptors during development of DOCA-salt hypertension

    PubMed Central

    Banes, Amy KL; Watts, Stephanie W

    2003-01-01

    Background 5-hydroxytryptamine (5-HT)2B and 5-HT1B receptors are upregulated in arteries from hypertensive DOCA-salt rats and directly by mineralocorticoids. We hypothesized that increased 5-HT2B and 5-HT1B receptor density and contractile function would precede increased blood pressure in DOCA-high salt rats. We performed DOCA-salt time course (days 1, 3, 5 and 7) studies using treatment groups of: DOCA-high salt, DOCA-low salt, Sham and Sham-high salt rats. Results In isolated-tissue baths, DOCA-high salt aorta contracted to the 5-HT2B receptor agonist BW723C86 on day 1; Sham aorta did not contract. The 5-HT1B receptor agonist CP93129 had no effect in arteries from any group. On days 3, 5 and 7 CP93129 and BW723C86 contracted DOCA-high salt and Sham-high salt aorta; Sham and DOCA-low salt aorta did not respond. Western analysis of DOCA-high salt aortic homogenates revealed increased 5-HT2B receptor levels by day 3; 5-HT1B receptor density was unchanged. Aortic homogenates from the other groups showed unchanged 5-HT2B and 5-HT1B receptor levels. Conclusion These data suggest that functional changes of 5-HT2B but not 5-HT1B receptors may play a role in the development of DOCA-salt hypertension. PMID:12974983

  8. Chronic activation of 5-HT4 receptors or blockade of 5-HT6 receptors improve memory performances.

    PubMed

    Quiedeville, Anne; Boulouard, Michel; Hamidouche, Katia; Da Silva Costa-Aze, Virginie; Nee, Gerald; Rochais, Christophe; Dallemagne, Patrick; Fabis, Frédéric; Freret, Thomas; Bouet, Valentine

    2015-10-15

    5-HT4 and 5-HT6 serotonergic receptors are located in brain structures involved in memory processes. Neurochemical and behavioural studies have demonstrated that acute activation of 5-HT4 receptors (5-HT4R) or blockade of 5-HT6 receptors (5-HT6R) improves memory. To evaluate the potential of these two receptors as targets in the treatment of memory disorders encountered in several situations (ageing, Alzheimer's disease, schizophrenia, etc.), it is necessary to assess whether their beneficial effects occur after chronic administration, and if such treatment induces adverse effects. The goal of this study was to assess the effects of chronic 5-HT4R or 5-HT6R modulation on recognition memory, and to observe the possible manifestation of side effects (modification of weight gain, locomotor activity or exploratory behaviour, etc.). Mice were treated for 14 days with a 5-HT4R partial agonist (RS-67333) or a 5-HT6R antagonist (SB-271046) at increasing doses. Memory performances, locomotor activity, and exploration were assessed. Both chronic 5-HT4R activation and 5-HT6R blockade extended memory traces in an object recognition test, and were not associated with any adverse effects in the parameters assessed. Chronic modulation of one or both of these receptors thus seems promising as a potential strategy for the treatment memory deficits. PMID:26187692

  9. Experiment 2039 – Diagnostic Logging in EE-3

    SciTech Connect

    Dash, Zora V.; Grigsby, Charles O.; Murphy, Hugh D.

    1984-06-19

    Experiment 2039, diagnostic logging in EE-3, was conducted in two parts. Part A, temperature and collar locator surveys while injecting water was run from ~16:00, 4-Apr-84 through ~11:00, 5-Apr-84. Part B, tracer surveys, run from ~8:15 - 21:00, 6-Apr-84. The purpose of the surveys was to determine fluid entry locations in the open hole sections of EE-3

  10. Synergism Between a Serotonin 5-HT2A Receptor (5-HT2AR) Antagonist and 5-HT2CR Agonist Suggests New Pharmacotherapeutics for Cocaine Addiction

    PubMed Central

    2012-01-01

    Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT2A receptor (5-HT2AR) and 5-HT2CR; either a selective 5-HT2AR antagonist or a 5-HT2CR agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT2AR antagonist plus 5-HT2CR agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT2AR antagonist M100907 plus the 5-HT2CR agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT2AR antagonist plus a 5-HT2CR agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules. PMID:23336050

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

    PubMed

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

    2013-01-16

    Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT(2A)R antagonist M100907 plus the 5-HT(2C)R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT(2A)R antagonist plus a 5-HT(2C)R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules. PMID:23336050

  12. 5-HT spatial distribution imaging with multiphoton excitation of 5-HT correlative visible fluorescence in live cells

    NASA Astrophysics Data System (ADS)

    Zhang, Zhihong; Zeng, Shaoqun; Liu, Yafeng; Zhou, Wei; Chen, Tongsheng; Luo, Qingming

    2002-04-01

    The autofluorescence of 5-Hydroxytryptamine (5-HT) loaded rat mucosal mast cells (RBL-2H3 cells) is imaged with multiphoton excitation laser scanning microscope (MPELSM). 5-HT correlative visible fluorescence (Fco-vis) excited with 740-nm multiphoton excitation is observed in live cells for the first time, and the generating mechanism of 5-HT Fco-vis is studied. The spatial distribution of 5-HT in live cells is imaged at high spatial resolution in our experiment, which provides a new way to study the correlation between 5-HT spatial distribution and content, and the cellular functional state in live tissue or cells.

  13. p-(4-Azipentyl)-propofol: A Potent Photoreactive General Anesthetic Derivative of Propofol

    PubMed Central

    Stewart, Deirdre S.; Savechenkov, Pavel Y.; Dostalova, Zuzana; Chiara, David C.; Ge, Rile; Raines, Douglas E.; Cohne, Jonathan B.; Forman, Stuart A.; Bruzik, Karol S.; Miller, Keith W.

    2013-01-01

    We synthesized 2,6-Diisopropyl-4-[3-(3-methyl-3H-diazirin-3-yl)-propyl]-phenol (p-(4-azipentyl)-propofol), or p-4-AziC5-Pro, a novel photoactivable derivative of the general anesthetic propofol. p-4-AziC5-Pro has an anesthetic potency similar to propofol. Like propofol, the compound potentiates inhibitory GABAA receptor current responses and allosterically modulates binding to both agonist and benzodiazepine sites, assayed on heterologously expressed GABAA receptors. p-4-AziC5-Pro inhibits excitatory current responses of nACh receptors expressed in Xenopus oocytes and photoincorporates into native nACh receptor-enriched Torpedo membranes. Thus p-4-AziC5-Pro is a functional general anesthetic that both modulates and photoincorporates into Cys-loop ligand-gated ion channels, making it an excellent candidate for use in identifying propofol binding sites. PMID:22029276

  14. Recombinant saphenous vein 5-HT1B receptors of the rabbit: comparative pharmacology with human 5-HT1B receptors.

    PubMed

    Wurch, T; Palmier, C; Colpaert, F C; Pauwels, P J

    1997-01-01

    1. The rabbit recombinant saphenous vein 5-hydroxytryptamine1B (r 5-HT1B) receptor stably transfected in rat C6-glial cells was characterized by measuring adenosine 3':5'-cyclic monophosphate (cycle AMP) formation upon exposure to various 5-HT receptor ligands. The effects of agonists and antagonists were compared with their effects determined previously at the human cloned 5-HT1B (h 5-HT1B) receptor under similar experimental conditions. 2. Intact C6-glial cells expressing rb HT1B receptors exhibited [3H]-5-carboxamidotryptamine (5-CT) binding sites with a Kd of 0.80 +/- 0.13 nM and a Bmax between 225 to 570 fmol mg-1 protein. The binding affinities of a series of 5-HT receptor ligands determined in a membrane preparation with [3H]-5-CT or [3H]-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(-4 -pyridyl) benzamide (GR 125,743) were similar. With the exception of ketanserin, ligand affinities were comparable to those determined at the clones h 5-HT1B receptor site. 3. rb 5-HT1B receptors were negatively coupled to cyclic AMP formation upon stimulation with 5-HT agonists. Of the several 5-HT agonists tested, 5-CT was the most potent, the potency rank order being: 5-CT > 5-HT > zolmitriptan > naratriptan > rizatriptan > sumatriptan > R (+)-8-(hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The maximal responses of these agonists were similar to those induced by 5-HT. The potency of these agonists showed a positive correlation (r2 = 0.87; P < 0.002) with their potency at the cloned h 5-HT1B receptor subtype. 4. 2'-Methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-e-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127,935), methiothepin and ketanserin each behaved as silent, competitive antagonists at rb 5HT1B receptors; pKB values were 8.41, 8.32 and 7.05, respectively when naratriptan was used as an agonist. These estimates accorded with their binding affinities and the potencies found on 5-HT and/or sumatriptan

  15. Antibacterial Activity of Recombinant Pig Intestinal Parasite Cecropin P4 Peptide Secreted from Pichia pastoris

    PubMed Central

    Song, Ki-Duk; Lee, Woon-Kyu

    2014-01-01

    Cecropins (Cec) are antibacterial peptides and their expression is induced in a pig intestinal parasite Ascaris suum by bacterial infection. To explore the usefulness of its activity as an antibiotic, CecP4 cDNA was prepared and cloned into the pPICZ B expression vector and followed by the integration into AOX1 locus in Pichia pastoris. The supernatants from cell culture were collected after methanol induction and concentrated for the test of antimicrobial activity. The recombinant P. patoris having CecP4 showed antimicrobial activity when tested against Staphyllococcus aureus in disc diffusion assay. We selected one of the CecP4 clones (CecP4-2) and performed further studies with it. The growth of recombinant P. pastoris was optimized using various concentration of methanol, and it was found that 2% methanol in the culture induced more antibacterial activity, compared to 1% methanol. We extended the test of antimicrobial activity by applying the concentrated supernatant of CecP4 culture to Pseudomonas aeruginosa and E. coli respectively. Recombinant CecP4 also showed antimicrobial activity against both Pseudomona and E. coli, suggesting the broad spectrum of its antimicrobial activity. After improvements for the scale-up, it will be feasible to use recombinant CecP4 for supplementation to the feed to control microbial infections in young animals, such as piglets. PMID:25049952

  16. Antibacterial Activity of Recombinant Pig Intestinal Parasite Cecropin P4 Peptide Secreted from Pichia pastoris.

    PubMed

    Song, Ki-Duk; Lee, Woon-Kyu

    2014-02-01

    Cecropins (Cec) are antibacterial peptides and their expression is induced in a pig intestinal parasite Ascaris suum by bacterial infection. To explore the usefulness of its activity as an antibiotic, CecP4 cDNA was prepared and cloned into the pPICZ B expression vector and followed by the integration into AOX1 locus in Pichia pastoris. The supernatants from cell culture were collected after methanol induction and concentrated for the test of antimicrobial activity. The recombinant P. patoris having CecP4 showed antimicrobial activity when tested against Staphyllococcus aureus in disc diffusion assay. We selected one of the CecP4 clones (CecP4-2) and performed further studies with it. The growth of recombinant P. pastoris was optimized using various concentration of methanol, and it was found that 2% methanol in the culture induced more antibacterial activity, compared to 1% methanol. We extended the test of antimicrobial activity by applying the concentrated supernatant of CecP4 culture to Pseudomonas aeruginosa and E. coli respectively. Recombinant CecP4 also showed antimicrobial activity against both Pseudomona and E. coli, suggesting the broad spectrum of its antimicrobial activity. After improvements for the scale-up, it will be feasible to use recombinant CecP4 for supplementation to the feed to control microbial infections in young animals, such as piglets. PMID:25049952

  17. Haemophilus influenzae P4 Interacts With Extracellular Matrix Proteins Promoting Adhesion and Serum Resistance.

    PubMed

    Su, Yu-Ching; Mukherjee, Oindrilla; Singh, Birendra; Hallgren, Oskar; Westergren-Thorsson, Gunilla; Hood, Derek; Riesbeck, Kristian

    2016-01-15

    Interaction with the extracellular matrix (ECM) is one of the successful colonization strategies employed by nontypeable Haemophilus influenzae (NTHi). Here we identified Haemophilus lipoprotein e (P4) as a receptor for ECM proteins. Purified recombinant P4 displayed a high binding affinity for laminin (Kd = 9.26 nM) and fibronectin (Kd = 10.19 nM), but slightly less to vitronectin (Kd = 16.51 nM). A P4-deficient NTHi mutant showed a significantly decreased binding to these ECM components. Vitronectin acquisition conferred serum resistance to both P4-expressing NTHi and Escherichia coli transformants. P4-mediated bacterial adherence to pharynx, type II alveolar, and bronchial epithelial cells was mainly attributed to fibronectin. Importantly, a significantly reduced bacterial infection was observed in the middle ear of the Junbo mouse model when NTHi was devoid of P4. In conclusion, our data provide new insight into the role of P4 as an important factor for Haemophilus colonization and subsequent respiratory tract infection. PMID:26153407

  18. Convergence of melatonin and serotonin (5-HT) signaling at MT2/5-HT2C receptor heteromers.

    PubMed

    Kamal, Maud; Gbahou, Florence; Guillaume, Jean-Luc; Daulat, Avais M; Benleulmi-Chaachoua, Abla; Luka, Marine; Chen, Patty; Kalbasi Anaraki, Dina; Baroncini, Marc; Mannoury la Cour, Clotilde; Millan, Mark J; Prevot, Vincent; Delagrange, Philippe; Jockers, Ralf

    2015-05-01

    Inasmuch as the neurohormone melatonin is synthetically derived from serotonin (5-HT), a close interrelationship between both has long been suspected. The present study reveals a hitherto unrecognized cross-talk mediated via physical association of melatonin MT2 and 5-HT2C receptors into functional heteromers. This is of particular interest in light of the "synergistic" melatonin agonist/5-HT2C antagonist profile of the novel antidepressant agomelatine. A suite of co-immunoprecipitation, bioluminescence resonance energy transfer, and pharmacological techniques was exploited to demonstrate formation of functional MT2 and 5-HT2C receptor heteromers both in transfected cells and in human cortex and hippocampus. MT2/5-HT2C heteromers amplified the 5-HT-mediated Gq/phospholipase C response and triggered melatonin-induced unidirectional transactivation of the 5-HT2C protomer of MT2/5-HT2C heteromers. Pharmacological studies revealed distinct functional properties for agomelatine, which shows "biased signaling." These observations demonstrate the existence of functionally unique MT2/5-HT2C heteromers and suggest that the antidepressant agomelatine has a distinctive profile at these sites potentially involved in its therapeutic effects on major depression and generalized anxiety disorder. Finally, MT2/5-HT2C heteromers provide a new strategy for the discovery of novel agents for the treatment of psychiatric disorders. PMID:25770211

  19. The P4 truss is moved to a workstand in the SSPF

    NASA Technical Reports Server (NTRS)

    2000-01-01

    Suspended by an overhead crane in the Space Station Processing Facility, the International Space Station's P4 truss moves toward a workstand. Below and behind it on the floor is the Multi- Purpose Logistics Module Raffaello, another segment of the Space Station. Part of the 10-truss, girder-like structure that will ultimately extend the length of a football field, the P4 is the second port truss segment that will attach to the first port truss segment (P1 truss). The P4 is scheduled for mission 12A in September 2002.

  20. Antibodies specific for HT{sub m4}

    DOEpatents

    Lim, B.; Adra, C.N.; Lelias, J.M.

    1998-01-06

    The invention relates to a recombinant DNA molecule which encodes a HT{sub m4} protein, a transformed host cell which has been stably transfected with a DNA molecule which encodes a HT{sub m4} protein and a recombinant HT{sub m4} protein. The invention also relates to a method for detecting the presence of a hereditary atopy. 2 figs.

  1. Recombinant HT{sub m4} gene, protein and assays

    DOEpatents

    Lim, B.; Adra, C.N.; Lelias, J.M.

    1996-09-03

    The invention relates to a recombinant DNA molecule which encodes a HT{sub m4} protein, a transformed host cell which has been stably transfected with a DNA molecule which encodes a HT{sub m4} protein and a recombinant HT{sub m4} protein. The invention also relates to a method for detecting the presence of a hereditary atopy. 2 figs.

  2. Phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ), a lipid signalling enigma.

    PubMed

    Giudici, Maria-Luisa; Clarke, Jonathan H; Irvine, Robin F

    2016-05-01

    The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are an important family of enzymes, whose physiological roles are being teased out by a variety of means. Phosphatidylinositol-5-phosphate 4-kinase γ (PI5P4Kγ) is especially intriguing as its in vitro activity is very low. Here we review what is known about this enzyme and discuss some recent advances towards an understanding of its physiology. Additionally, the effects of the ATP-competitive inhibitor I-OMe Tyrphostin AG-538 on all three mammalian PI5P4Ks was explored, including two PI5P4Kγ mutants with altered ATP- or PI5P-binding sites. The results suggest a strategy for targeting non-ATP binding sites on inositol lipid kinases. PMID:26710750

  3. P4-ATPases as Phospholipid Flippases-Structure, Function, and Enigmas.

    PubMed

    Andersen, Jens P; Vestergaard, Anna L; Mikkelsen, Stine A; Mogensen, Louise S; Chalat, Madhavan; Molday, Robert S

    2016-01-01

    P4-ATPases comprise a family of P-type ATPases that actively transport or flip phospholipids across cell membranes. This generates and maintains membrane lipid asymmetry, a property essential for a wide variety of cellular processes such as vesicle budding and trafficking, cell signaling, blood coagulation, apoptosis, bile and cholesterol homeostasis, and neuronal cell survival. Some P4-ATPases transport phosphatidylserine and phosphatidylethanolamine across the plasma membrane or intracellular membranes whereas other P4-ATPases are specific for phosphatidylcholine. The importance of P4-ATPases is highlighted by the finding that genetic defects in two P4-ATPases ATP8A2 and ATP8B1 are associated with severe human disorders. Recent studies have provided insight into how P4-ATPases translocate phospholipids across membranes. P4-ATPases form a phosphorylated intermediate at the aspartate of the P-type ATPase signature sequence, and dephosphorylation is activated by the lipid substrate being flipped from the exoplasmic to the cytoplasmic leaflet similar to the activation of dephosphorylation of Na(+)/K(+)-ATPase by exoplasmic K(+). How the phospholipid is translocated can be understood in terms of a peripheral hydrophobic gate pathway between transmembrane helices M1, M3, M4, and M6. This pathway, which partially overlaps with the suggested pathway for migration of Ca(2+) in the opposite direction in the Ca(2+)-ATPase, is wider than the latter, thereby accommodating the phospholipid head group. The head group is propelled along against its concentration gradient with the hydrocarbon chains projecting out into the lipid phase by movement of an isoleucine located at the position corresponding to an ion binding glutamate in the Ca(2+)- and Na(+)/K(+)-ATPases. Hence, the P4-ATPase mechanism is quite similar to the mechanism of these ion pumps, where the glutamate translocates the ions by moving like a pump rod. The accessory subunit CDC50 may be located in close association

  4. P4-ATPases as Phospholipid Flippases—Structure, Function, and Enigmas

    PubMed Central

    Andersen, Jens P.; Vestergaard, Anna L.; Mikkelsen, Stine A.; Mogensen, Louise S.; Chalat, Madhavan; Molday, Robert S.

    2016-01-01

    P4-ATPases comprise a family of P-type ATPases that actively transport or flip phospholipids across cell membranes. This generates and maintains membrane lipid asymmetry, a property essential for a wide variety of cellular processes such as vesicle budding and trafficking, cell signaling, blood coagulation, apoptosis, bile and cholesterol homeostasis, and neuronal cell survival. Some P4-ATPases transport phosphatidylserine and phosphatidylethanolamine across the plasma membrane or intracellular membranes whereas other P4-ATPases are specific for phosphatidylcholine. The importance of P4-ATPases is highlighted by the finding that genetic defects in two P4-ATPases ATP8A2 and ATP8B1 are associated with severe human disorders. Recent studies have provided insight into how P4-ATPases translocate phospholipids across membranes. P4-ATPases form a phosphorylated intermediate at the aspartate of the P-type ATPase signature sequence, and dephosphorylation is activated by the lipid substrate being flipped from the exoplasmic to the cytoplasmic leaflet similar to the activation of dephosphorylation of Na+/K+-ATPase by exoplasmic K+. How the phospholipid is translocated can be understood in terms of a peripheral hydrophobic gate pathway between transmembrane helices M1, M3, M4, and M6. This pathway, which partially overlaps with the suggested pathway for migration of Ca2+ in the opposite direction in the Ca2+-ATPase, is wider than the latter, thereby accommodating the phospholipid head group. The head group is propelled along against its concentration gradient with the hydrocarbon chains projecting out into the lipid phase by movement of an isoleucine located at the position corresponding to an ion binding glutamate in the Ca2+- and Na+/K+-ATPases. Hence, the P4-ATPase mechanism is quite similar to the mechanism of these ion pumps, where the glutamate translocates the ions by moving like a pump rod. The accessory subunit CDC50 may be located in close association with the

  5. Discovery of γ-MnP4 and the Polymorphism of Manganese Tetraphosphide.

    PubMed

    Henge, Dennis B; Hermus, Martin; Litterscheid, Christian F; Wagner, Norbert; Beck, Johannes; Albert, Barbara; Brgoch, Jakoah

    2015-09-01

    A new polymorph of MnP4 was prepared by reaction of the elements via chemical vapor transport with iodine as transporting agent. The crystal structure was refined using single-crystal diffraction data (space group Cc, no. 9, a = 5.1049(8) Å, b = 10.540(2) Å, c = 10.875(2) Å, β = 93.80(2)°). The phase is called γ-MnP4 as it is isostructural with γ-FeP4. It is the fourth reported binary polymorph in the MnP4 system, all of which are stacking variants of nets built with manganese and phosphorus atoms. In γ-MnP4, there are two Mn-Mn distances (2.93 and 3.72 Å) arising from a Peierls-like distortion effectively forming Mn2 dumbbells in the structure. Magnetic and electrical conductivity measurements show diamagnetism and a small anisotropic band gap (100-200 meV) with significantly enhanced conductivity along the crystallographic a axis. Calculations of the electronic and vibrational (phonon) structures show the P-P and Mn-P bonds within the nets are mainly responsible for the stability of the phase. The similar bonding motifs of the polymorphs give rise to the existence of numerous dynamically stable variants. The calculated Helmholtz energy shows the polymorph formation to be closely tied to temperature with the 6-MnP4 structure favorable at low temperatures, the 2-MnP4 favorable between approximately 800 and 2000 K, and 8-MnP4 preferred at high temperatures. PMID:26266629

  6. TMPyP4, a Stabilizer of Nucleic Acid Secondary Structure, Is a Novel Acetylcholinesterase Inhibitor

    PubMed Central

    Fujiwara, Nana; Mazzola, Michael; Cai, Elizabeth; Wang, Meng; Cave, John W.

    2015-01-01

    The porphyrin compound, TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine), is widely used as a photosensitizer and a modulator of nucleic acid secondary structure stability. Our group recently showed in cultured cells and forebrain slice cultures that this compound can also down regulate expression of Tyrosine hydroxylase (Th), which encodes the rate-limiting enzyme in catecholamine biosynthesis, by stabilizing DNA secondary structures in the Th proximal promoter. The current study sought to establish whether treatment with TMPyP4 could modify mouse Th expression levels in vivo. Intraperitoneal administration of low TMPyP4 doses (10mg/kg), similar to those used for photosensitization, did not significantly reduce Th transcript levels in several catecholaminergic regions. Administration of a high dose (40 mg/kg), similar to those used for tumor xenograph reduction, unexpectedly induced flaccid paralysis in an age and sex-dependent manner. In vitro analyses revealed that TMPyP4, but not putative metabolites, inhibited Acetylcholinesterase activity and pre-treatment of TMPyP4 with Hemeoxygenase-2 (HO-2) rescued Acetylcholinesterase function. Age-dependent differences in HO-2 expression levels may account for some of the variable in vivo effects of high TMPyP4 doses. Together, these studies indicate that only low doses of TMPyP4, such as those typically used for photosensitization, are well tolerated in vivo. Thus, despite its widespread use in vitro, TMPyP4 is not ideal for modifying neuronal gene expression in vivo by manipulating nucleic acid secondary structure stability, which highlights the need to identify more clinically suitable compounds that can modulate nucleic acid secondary structure and gene expression. PMID:26402367

  7. Cellular resilience: 5-HT neurons in Tph2(-/-) mice retain normal firing behavior despite the lack of brain 5-HT.

    PubMed

    Montalbano, Alberto; Waider, Jonas; Barbieri, Mario; Baytas, Ozan; Lesch, Klaus-Peter; Corradetti, Renato; Mlinar, Boris

    2015-11-01

    Considerable evidence links dysfunction of serotonin (5-hydroxytryptamine, 5-HT) transmission to neurodevelopmental and psychiatric disorders characterized by compromised "social" cognition and emotion regulation. It is well established that the brain 5-HT system is under autoregulatory control by its principal transmitter 5-HT via its effects on activity and expression of 5-HT system-related proteins. To examine whether 5-HT itself also has a crucial role in the acquisition and maintenance of characteristic rhythmic firing of 5-HT neurons, we compared their intrinsic electrophysiological properties in mice lacking brain 5-HT, i.e. tryptophan hydroxylase-2 null mice (Tph2(-/-)) and their littermates, Tph2(+/-) and Tph2(+/+), by using whole-cell patch-clamp recordings in a brainstem slice preparation and single unit recording in anesthetized animals. We report that the active properties of dorsal raphe nucleus (DRN) 5-HT neurons in vivo (firing rate magnitude and variability; the presence of spike doublets) and in vitro (firing in response to depolarizing current pulses; action potential shape) as well as the resting membrane potential remained essentially unchanged across Tph2 genotypes. However, there were subtle differences in subthreshold properties, most notably, an approximately 25% higher input conductance in Tph2(-/-) mice compared with Tph2(+/-) and Tph2(+/+) littermates (p<0.0001). This difference may at least in part be a consequence of slightly bigger size of the DRN 5-HT neurons in Tph2(-/-) mice (approximately 10%, p<0.0001). Taken together, these findings show that 5-HT neurons acquire and maintain their signature firing properties independently of the presence of their principal neurotransmitter 5-HT, displaying an unexpected functional resilience to complete brain 5-HT deficiency. PMID:26409296

  8. Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system.

    PubMed

    Swinford-Jackson, S E; Anastasio, N C; Fox, R G; Stutz, S J; Cunningham, K A

    2016-06-01

    Intensification of craving elicited by drug-associated cues during abstinence occurs over time in human cocaine users while elevation of cue reactivity ("incubation") is observed in rats exposed to extended forced abstinence from cocaine self-administration. Incubation in rodents has been linked to time-dependent neuronal plasticity in the medial prefrontal cortex (mPFC). We tested the hypothesis that incubation of cue reactivity during abstinence from cocaine self-administration is accompanied by lower potency and/or efficacy of the selective serotonin (5-HT) 5-HT2C​ receptor (5-HT2CR) agonist WAY163909 to suppress cue reactivity and a shift in the subcellular localization profile of the mPFC 5-HT2CR protein. We observed incubation of cue reactivity (measured as lever presses reinforced by the discrete cue complex) between Day 1 and Day 30 of forced abstinence from cocaine relative to sucrose self-administration. Pharmacological and biochemical analyses revealed that the potency of the selective 5-HT2CR agonist WAY163909 to suppress cue reactivity, the expression of synaptosomal 5-HT2CR protein in the mPFC, and the membrane to cytoplasmic expression of the 5-HT2CR in mPFC were lower on Day 30 vs. Day 1 of forced abstinence from cocaine self-administration. Incubation of cue reactivity assessed during forced abstinence from sucrose self-administration did not associate with 5-HT2CR protein expression in the mPFC. Collectively, these outcomes are the first indication that neuroadaptations in the 5-HT2CR system may contribute to incubation of cocaine cue reactivity. PMID:26926963

  9. Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors

    PubMed Central

    Watson, J; Brough, S; Coldwell, M C; Gager, T; Ho, M; Hunter, A J; Jerman, J; Middlemiss, D N; Riley, G J; Brown, A M

    1998-01-01

    Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] has been reported to act as a functionally selective muscarinic partial agonist with potential use in the treatment of Alzheimer's disease. This study examined the functional activity of xanomeline at 5-HT1 and 5-HT2 receptors in native tissue and/or human cloned receptors.Xanomeline had affinity for muscarinic receptors in rat cortical membranes where the ratio of the displacement affinity of [3H]-Quinuclidinyl benzilate vs that of [3H]-Oxotremorine-M was 16, indicative of partial agonist activity. Radioligand binding studies on human cloned receptors confirmed that xanomeline had substantial affinity for M1, M2, M3, M4, M5 receptors and also for 5-HT1 and 5-HT2 receptor subtypes.Carbachol and xanomeline stimulated basal [35S]-GTPγS binding in rat cortical membranes with micromolar affinity. The response to carbachol was attenuated by himbacine and pirenzepine with pA2 of 8.2, 6.9 respectively consistent with the response being mediated, predominantly, via M2 and M4 receptors. Xanomeline-induced stimulation of [35S]-GTPγS binding was inhibited by himbacine with an apparent pKb of 6.3, was not attenuated by pirenzepine up to 3 μM and was inhibited by the selective 5-HT1A antagonist WAY100635 with an apparent pKb of 9.4. These data suggest the agonist effect of xanomeline in this tissue is, in part, via 5-HT1A receptors. Similar studies on human cloned receptors confirmed that xanomeline is an agonist at human cloned 5-HT1A and 5-HT1B receptors.In studies using the fluorescent cytoplasmic Ca2+ indicator FLUO-3AM, xanomeline induced an increase in cytoplasmic Ca2+ concentration in SH-SY5Y cells expressing recombinant human 5-HT2C receptors. Atropine antagonized this response, consistent with mediation via endogenously-expressed muscarinic receptors. In the presence of atropine, xanomeline antagonized 5-HT-induced cytoplasmic changes in Ca2+ concentration in cells expressing h5

  10. Does Cisapride, as a 5HT(4) Receptor Agonist, Aggravate the Severity of TNBS-Induced Colitis in Rat?

    PubMed

    Motavallian, Azadeh; Minaiyan, Mohsen; Rabbani, Mohammad; Mahzouni, Parvin; Andalib, Sasan; Abed, Alireza; Babavalian, Mohammad Reza

    2012-01-01

    There is a pressing need for research that will lead to the reveal of targets designed to analyse the possible pathways for the treatment of IBD. Because of the probable involvement of serotonin in inflammatory conditions of intestine and the important role of 5HT(4) receptors in GI function, the investigation of the role of 5HT(4) receptors in the pathogenesis of IBD will be interesting. The aim of this study was to investigate the effects of cisapride, a 5HT(4) receptor agonist, in trinitrobenzenesulfonic-acid-(TNBS) induced rat colitis. Two hours subsequent to induction of colitis using TNBS in rats, cisapride (2 mg/kg, intraperitoneally (i.p); 4 mg/kg, orally (p.o)) and dexamethasone (1 mg/kg, i.p; 2 mg/kg, p.o) were administrated for 6 days. Animals were thereafter euthanized; macroscopic, histological, and biochemical assessments and ELISA test were carried out on distal colon samples. Our data showed that dexamethasone treatment (i.p, p.o) significantly decreased macroscopic and microscopic damage and also biochemical markers, but there were no significant differences in aforementioned parameters between cisapride (i.p or p.o) and TNBS-treated rats. It can be deduced that because the severity of colitis produced by TNBS is massive (through various pathways), cisapride could not bring about more colitis damages through 5HT(4) receptors. Based on the present study further researches are required for investigating the exact roles of 5HT(4) receptors in the pathogenesis of ulcerative colitis. PMID:22888336

  11. 32. SECTIONS AA, BB, CC, DD, AND EE WASTE CALCINATION ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    32. SECTIONS A-A, B-B, C-C, D-D, AND E-E WASTE CALCINATION FACILITY SHOWING RELATIONSHIPS OF DIFFERENT FLOOR LEVELS TO ONE ANOTHER. INEEL DRAWING NUMBER 200-0633-00-287-106353. FLUOR NUMBER 5775-CPP-633-A-3. - Idaho National Engineering Laboratory, Old Waste Calcining Facility, Scoville, Butte County, ID

  12. ee-Learning: The Best Road to Adulthood?

    ERIC Educational Resources Information Center

    Chisholm, Linda

    2007-01-01

    In this article, Linda Chisholm discusses the potential of ee-learning to address some of the endemic problems of college campuses. In an era of large campuses and large classes, students are removed from the positive examples once provided by faculty who lived in the campus community. The result is as evident in the woeful skills of some college…

  13. Research Trends in the United States: EE to ESD

    ERIC Educational Resources Information Center

    Heimlich, Joe E.

    2007-01-01

    Research on education for sustainable development (ESD) is not a unified body of work and, much like the literature for environmental education (EE), research is published in many arenas. The trends, however, capture some of the major foci of the research that is emerging on ESD, especially in the early years of the Decade of Education for…

  14. Designing ee-Learning Environments: Lessons from an Online Workshop

    ERIC Educational Resources Information Center

    Godwin, Lindsey; Kaplan, Soren

    2008-01-01

    Based on their work leading three experiential, online workshops with over 180 participants from around the world, Lindsey Godwin and Soren Kaplan share reflections on designing and conducting successful ee-learning courses. The workshops sought to translate a popular face-to-face seminar in appreciative inquiry, an increasingly popular…

  15. EE and ESD: Two Paradigms, One Crucial Goal

    ERIC Educational Resources Information Center

    McKeown, Rosalyn; Hopkins, Chuck

    2005-01-01

    The launch of the United Nations Decade of Education for Sustainable Development (UNDESD) gives the education community opportunity to reflect on and discuss major issues that will affect the future well-being of the world. The goals and dreams of environmental education (EE) are similar to those of educators involved in education for sustainable…

  16. Spinal 5-HT1A, not the 5-HT1B or 5-HT3 receptors, mediates descending serotonergic inhibition for late-phase mechanical allodynia of carrageenan-induced peripheral inflammation.

    PubMed

    Kim, Joung Min; Jeong, Seong Wook; Yang, Jihoon; Lee, Seong Heon; Kim, Woon Mo; Jeong, Seongtae; Bae, Hong Beom; Yoon, Myung Ha; Choi, Jeong Il

    2015-07-23

    Previous electrophysiological studies demonstrated a limited role of 5-hydroxytryptamine 3 receptor (5-HT3R), but facilitatory role of 5-HT1AR and 5-HT1BR in spinal nociceptive processing of carrageenan-induced inflammatory pain. The release of spinal 5-HT was shown to peak in early-phase and return to baseline in late-phase of carrageenan inflammation. We examined the role of the descending serotonergic projections involving 5-HT1AR, 5-HT1BR, and 5-HT3R in mechanical allodynia of early- (first 4h) and late-phase (24h after) carrageenan-induced inflammation. Intrathecal administration of 5-HT produced a significant anti-allodynic effect in late-phase, but not in early-phase. Similarly, intrathecal 5-HT1AR agonist (8-OH-DPAT) attenuated the intensity of late-phase allodynia in a dose dependent fashion which was antagonized by 5-HT1AR antagonist (WAY-100635), but produced no effect on the early-phase allodynia. However, other agonists or antagonists of 5-HT1BR (CP-93129, SB-224289) and 5-HT3R (m-CPBG, ondansetron) did not produce any anti- or pro-allodynic effect in both early- and late- phase allodynia. These results suggest that spinal 5-HT1A, but not 5-HT1B or 5-HT3 receptors mediate descending serotonergic inhibition on nociceptive processing of late-phase mechanical allodynia in carrageenan-induced inflammation. PMID:26037417

  17. Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors.

    PubMed

    Smith, R L; Canton, H; Barrett, R J; Sanders-Bush, E

    1998-11-01

    Extensive behavioral and biochemical evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacological properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor density and cellular microenvironment, we also examined the properties of DMT in native preparations using a behavioral and biochemical approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacological studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT. Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native preparation. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT. PMID:9768567

  18. Pharmacological Characterization of 5-HT1A Autoreceptor-Coupled GIRK Channels in Rat Dorsal Raphe 5-HT Neurons

    PubMed Central

    Montalbano, Alberto; Corradetti, Renato; Mlinar, Boris

    2015-01-01

    G protein-activated inwardly rectifying potassium (GIRK) channels in 5-HT neurons are assumed to be principal effectors of 5-hydroxytryptamine 1A (5-HT1A) autoreceptors, but their pharmacology, subunit composition and the role in regulation of 5-HT neuron activity have not been fully elucidated. We sought for a pharmacological tool for assessing the functional role of GIRK channels in 5-HT neurons by characterizing the effects of drugs known to block GIRK channels in the submicromolar range of concentrations. Whole-cell voltage-clamp recording in brainstem slices were used to determine concentration-response relationships for the selected GIRK channel blockers on 5-HT1A autoreceptor-activated inwardly rectifying K+ conductance in rat dorsal raphe 5-HT neurons. 5-HT1A autoreceptor-activated GIRK conductance was completely blocked by the nonselective inwardly rectifying potassium channels blocker Ba2+ (EC50 = 9.4 μM, full block with 100 μM) and by SCH23390 (EC50 = 1.95 μM, full block with 30 μM). GIRK-specific blocker tertiapin-Q blocked 5-HT1A autoreceptor-activated GIRK conductance with high potency (EC50 = 33.6 nM), but incompletely, i.e. ~16% of total conductance resulted to be tertiapin-Q-resistant. U73343 and SCH28080, reported to block GIRK channels with submicromolar EC50s, were essentially ineffective in 5-HT neurons. Our data show that inwardly rectifying K+ channels coupled to 5-HT1A autoreceptors display pharmacological properties generally expected for neuronal GIRK channels, but different from GIRK1-GIRK2 heteromers, the predominant form of brain GIRK channels. Distinct pharmacological properties of GIRK channels in 5-HT neurons should be explored for the development of new therapeutic agents for mood disorders. PMID:26460748

  19. Exploration of the ligand binding site of the human 5-HT4 receptor by site-directed mutagenesis and molecular modeling

    PubMed Central

    Mialet, Jeanne; Dahmoune, Yamina; Lezoualc'h, Frank; Berque-Bestel, Isabelle; Eftekhari, Pierre; Hoebeke, Johan; Sicsic, Sames; Langlois, Michel; Fischmeister, Rodolphe

    2000-01-01

    Among the five human 5-HT4 (h5-HT4) receptor isoforms, the h5-HT4(a) receptor was studied with a particular emphasis on the molecular interactions involved in ligand binding. For this purpose, we used site-directed mutagenesis of the transmembrane domain. Twelve mutants were constructed with a special focus on the residue P4.53 of helix IV which substitutes in h5-HT4 receptors the highly conserved S residue among the rhodopsin family receptors. The mutated receptors were transiently expressed in COS-7 cells.Ligand binding or competition studies with two h5-HT4 receptor agonists, serotonin and ML10302 and two h5-HT4 receptor antagonists, [3H]-GR113808 and ML10375 were performed on wild type and mutant receptors. Functional activity of the receptors was evaluated by measuring the ability of serotonin to stimulate adenylyl cyclase.Ligand binding experiments revealed that [3H]-GR113808 did not bind to mutants P4.53A, S5.43A, F6.51A, Y7.43A and to double mutant F6.52V/N6.55L. On the other hand mutations D3.32N, S5.43A and Y7.43A appeared to promote a dramatic decrease of h5-HT4(a) receptor functional activity. From these studies, S5.43 and Y7.43 clearly emerged as common anchoring sites to antagonist [3H]-GR113808 and to serotonin.According to these results, we propose ligand-receptor complex models with serotonin and [3H]-GR113808. For serotonin, three interaction points were selected including ionic interaction with D3.32, a stabilizing interaction of this ion pair by Y7.43 and a hydrogen bond with S5.43. [3H]-GR113808 was also docked, based on the same type of interactions with S5.43 and D3.32: the proposed model suggested a possible role of P4.53 in helix IV structure allowing the involvement of a close hydrophobic residue, W4.50, in a hydrophobic pocket for hydrophobic interactions with the indole ring of [3H]-GR113808. PMID:10821780

  20. An improved limit for Γee of X (3872) and Γee measurement of ψ (3686)

    NASA Astrophysics Data System (ADS)

    Ablikim, M.; Achasov, M. N.; Ai, X. C.; Albayrak, O.; Albrecht, M.; Ambrose, D. J.; Amoroso, A.; An, F. F.; An, Q.; Bai, J. Z.; Baldini Ferroli, R.; Ban, Y.; Bennett, D. W.; Bennett, J. V.; Bertani, M.; Bettoni, D.; Bian, J. M.; Bianchi, F.; Boger, E.; Bondarenko, O.; Boyko, I.; Briere, R. A.; Cai, H.; Cai, X.; Cakir, O.; Calcaterra, A.; Cao, G. F.; Cetin, S. A.; Chang, J. F.; Chelkov, G.; Chen, G.; Chen, H. S.; Chen, H. Y.; Chen, J. C.; Chen, M. L.; Chen, S. J.; Chen, X.; Chen, X. R.; Chen, Y. B.; Cheng, H. P.; Chu, X. K.; Cibinetto, G.; Cronin-Hennessy, D.; Dai, H. L.; Dai, J. P.; Dbeyssi, A.; Dedovich, D.; Deng, Z. Y.; Denig, A.; Denysenko, I.; Destefanis, M.; De Mori, F.; Ding, Y.; Dong, C.; Dong, J.; Dong, L. Y.; Dong, M. Y.; Du, S. X.; Duan, P. F.; Fan, J. Z.; Fang, J.; Fang, S. S.; Fang, X.; Fang, Y.; Fava, L.; Feldbauer, F.; Felici, G.; Feng, C. Q.; Fioravanti, E.; Fritsch, M.; Fu, C. D.; Gao, Q.; Gao, X. Y.; Gao, Y.; Gao, Z.; Garzia, I.; Geng, C.; Goetzen, K.; Gong, W. X.; Gradl, W.; Greco, M.; Gu, M. H.; Gu, Y. T.; Guan, Y. H.; Guo, A. Q.; Guo, L. B.; Guo, Y.; Guo, Y. P.; Haddadi, Z.; Hafner, A.; Han, S.; Han, Y. L.; Hao, X. Q.; Harris, F. A.; He, K. L.; He, Z. Y.; Held, T.; Heng, Y. K.; Hou, Z. L.; Hu, C.; Hu, H. M.; Hu, J. F.; Hu, T.; Hu, Y.; Huang, G. M.; Huang, G. S.; Huang, H. P.; Huang, J. S.; Huang, X. T.; Huang, Y.; Hussain, T.; Ji, Q.; Ji, Q. P.; Ji, X. B.; Ji, X. L.; Jiang, L. L.; Jiang, L. W.; Jiang, X. S.; Jiao, J. B.; Jiao, Z.; Jin, D. P.; Jin, S.; Johansson, T.; Julin, A.; Kalantar-Nayestanaki, N.; Kang, X. L.; Kang, X. S.; Kavatsyuk, M.; Ke, B. C.; Kliemt, R.; Kloss, B.; Kolcu, O. B.; Kopf, B.; Kornicer, M.; Kühn, W.; Kupsc, A.; Lai, W.; Lange, J. S.; Lara, M.; Larin, P.; Leng, C.; Li, C. H.; Li, Cheng; Li, D. M.; Li, F.; Li, G.; Li, H. B.; Li, J. C.; Li, Jin; Li, K.; Li, K.; Li, Lei; Li, P. R.; Li, T.; Li, W. D.; Li, W. G.; Li, X. L.; Li, X. M.; Li, X. N.; Li, X. Q.; Li, Z. B.; Liang, H.; Liang, Y. F.; Liang, Y. T.; Liao, G. R.; Lin, D. X.; Liu, B. J.; Liu, C. X.; Liu, F. H.; Liu, Fang; Liu, Feng; Liu, H. B.; Liu, H. H.; Liu, H. H.; Liu, H. M.; Liu, J.; Liu, J. P.; Liu, J. Y.; Liu, K.; Liu, K. Y.; Liu, L. D.; Liu, P. L.; Liu, Q.; Liu, S. B.; Liu, X.; Liu, X. X.; Liu, Y. B.; Liu, Z. A.; Liu, Zhiqiang; Liu, Zhiqing; Loehner, H.; Lou, X. C.; Lu, H. J.; Lu, J. G.; Lu, R. Q.; Lu, Y.; Lu, Y. P.; Luo, C. L.; Luo, M. X.; Luo, T.; Luo, X. L.; Lv, M.; Lyu, X. R.; Ma, F. C.; Ma, H. L.; Ma, L. L.; Ma, Q. M.; Ma, S.; Ma, T.; Ma, X. N.; Ma, X. Y.; Maas, F. E.; Maggiora, M.; Malik, Q. A.; Mao, Y. J.; Mao, Z. P.; Marcello, S.; Messchendorp, J. G.; Min, J.; Min, T. J.; Mitchell, R. E.; Mo, X. H.; Mo, Y. J.; Morales Morales, C.; Moriya, K.; Muchnoi, N. Yu.; Muramatsu, H.; Nefedov, Y.; Nerling, F.; Nikolaev, I. B.; Ning, Z.; Nisar, S.; Niu, S. L.; Niu, X. Y.; Olsen, S. L.; Ouyang, Q.; Pacetti, S.; Patteri, P.; Pelizaeus, M.; Peng, H. P.; Peters, K.; Pettersson, J.; Ping, J. L.; Ping, R. G.; Poling, R.; Pu, Y. N.; Qi, M.; Qian, S.; Qiao, C. F.; Qin, L. Q.; Qin, N.; Qin, X. S.; Qin, Y.; Qin, Z. H.; Qiu, J. F.; Rashid, K. H.; Redmer, C. F.; Ren, H. L.; Ripka, M.; Rong, G.; Ruan, X. D.; Santoro, V.; Sarantsev, A.; Savrié, M.; Schoenning, K.; Schumann, S.; Shan, W.; Shao, M.; Shen, C. P.; Shen, P. X.; Shen, X. Y.; Sheng, H. Y.; Song, W. M.; Song, X. Y.; Sosio, S.; Spataro, S.; Sun, G. X.; Sun, J. F.; Sun, S. S.; Sun, Y. J.; Sun, Y. Z.; Sun, Z. J.; Sun, Z. T.; Tang, C. J.; Tang, X.; Tapan, I.; Thorndike, E. H.; Tiemens, M.; Toth, D.; Ullrich, M.; Uman, I.; Varner, G. S.; Wang, B.; Wang, B. L.; Wang, D.; Wang, D. Y.; Wang, K.; Wang, L. L.; Wang, L. S.; Wang, M.; Wang, P.; Wang, P. L.; Wang, Q. J.; Wang, S. G.; Wang, W.; Wang, X. F.; Wang, Y. D.; Wang, Y. F.; Wang, Y. Q.; Wang, Z.; Wang, Z. G.; Wang, Z. H.; Wang, Z. Y.; Weber, T.; Wei, D. H.; Wei, J. B.; Weidenkaff, P.; Wen, S. P.; Wiedner, U.; Wolke, M.; Wu, L. H.; Wu, Z.; Xia, L. G.; Xia, Y.; Xiao, D.; Xiao, Z. J.; Xie, Y. G.; Xiu, Q. L.; Xu, G. F.; Xu, L.; Xu, Q. J.; Xu, Q. N.; Xu, X. P.; Yan, L.; Yan, W. B.; Yan, W. C.; Yan, Y. H.; Yang, H. X.; Yang, L.; Yang, Y.; Yang, Y. X.; Ye, H.; Ye, M.; Ye, M. H.; Yin, J. H.; Yu, B. X.; Yu, C. X.; Yu, H. W.; Yu, J. S.; Yuan, C. Z.; Yuan, W. L.; Yuan, Y.; Yuncu, A.; Zafar, A. A.; Zallo, A.; Zeng, Y.; Zhang, B. X.; Zhang, B. Y.; Zhang, C.; Zhang, C. C.; Zhang, D. H.; Zhang, H. H.; Zhang, H. Y.; Zhang, J. J.; Zhang, J. L.; Zhang, J. Q.; Zhang, J. W.; Zhang, J. Y.; Zhang, J. Z.; Zhang, K.; Zhang, L.; Zhang, S. H.; Zhang, X. Y.; Zhang, Y.; Zhang, Y. H.; Zhang, Y. T.; Zhang, Z. H.; Zhang, Z. P.; Zhang, Z. Y.; Zhao, G.; Zhao, J. W.; Zhao, J. Y.; Zhao, J. Z.; Zhao, Lei; Zhao, Ling; Zhao, M. G.; Zhao, Q.; Zhao, Q. W.; Zhao, S. J.; Zhao, T. C.; Zhao, Y. B.; Zhao, Z. G.; Zhemchugov, A.; Zheng, B.; Zheng, J. P.; Zheng, W. J.; Zheng, Y. H.; Zhong, B.; Zhou, L.; Zhou, Li; Zhou, X.; Zhou, X. K.; Zhou, X. R.; Zhou, X. Y.; Zhu, K.; Zhu, K. J.; Zhu, S.; Zhu, X. L.; Zhu, Y. C.; Zhu, Y. S.; Zhu, Z. A.; Zhuang, J.; Zotti, L.; Zou, B. S.; Zou, J. H.

    2015-10-01

    Using the data sets taken at center-of-mass energies above 4 GeV by the BESIII detector at the BEPCII storage ring, we search for the reaction e+e- →γISR X (3872) →γISRπ+π- J / ψ via the Initial State Radiation technique. The production of a resonance with quantum numbers JPC =1++ such as the X (3872) via single photon e+e- annihilation is forbidden, but is allowed by a next-to-leading order box diagram. We do not observe a significant signal of X (3872), and therefore give an upper limit for the electronic width times the branching fraction ΓeeX (3872) B (X (3872) →π+π- J / ψ) < 0.13 eV at the 90% confidence level. This measurement improves upon existing limits by a factor of 46. Using the same final state, we also measure the electronic width of the ψ (3686) to be Γeeψ (3686) = 2213 ±18stat ±99sys eV.

  1. Sirh7/Ldoc1 knockout mice exhibit placental P4 overproduction and delayed parturition.

    PubMed

    Naruse, Mie; Ono, Ryuichi; Irie, Masahito; Nakamura, Kenji; Furuse, Tamio; Hino, Toshiaki; Oda, Kanako; Kashimura, Misho; Yamada, Ikuko; Wakana, Shigeharu; Yokoyama, Minesuke; Ishino, Fumitoshi; Kaneko-Ishino, Tomoko

    2014-12-01

    Sirh7/Ldoc1 [sushi-ichi retrotransposon homolog 7/leucine zipper, downregulated in cancer 1, also called mammalian retrotransposon-derived 7 (Mart7)] is one of the newly acquired genes from LTR retrotransposons in eutherian mammals. Interestingly, Sirh7/Ldoc1 knockout (KO) mice exhibited abnormal placental cell differentiation/maturation, leading to an overproduction of placental progesterone (P4) and placental lactogen 1 (PL1) from trophoblast giant cells (TGCs). The placenta is an organ that is essential for mammalian viviparity and plays a major endocrinological role during pregnancy in addition to providing nutrients and oxygen to the fetus. P4 is an essential hormone in the preparation and maintenance of pregnancy and the determination of the timing of parturition in mammals; however, the biological significance of placental P4 in rodents is not properly recognized. Here, we demonstrate that mouse placentas do produce P4 in mid-gestation, coincident with a temporal reduction in ovarian P4, suggesting that it plays a role in the protection of the conceptuses specifically in this period. Pregnant Sirh7/Ldoc1 knockout females also displayed delayed parturition associated with a low pup weaning rate. All these results suggest that Sirh7/Ldoc1 has undergone positive selection during eutherian evolution as a eutherian-specific acquired gene because it impacts reproductive fitness via the regulation of placental endocrine function. PMID:25468940

  2. Sirh7/Ldoc1 knockout mice exhibit placental P4 overproduction and delayed parturition

    PubMed Central

    Naruse, Mie; Ono, Ryuichi; Irie, Masahito; Nakamura, Kenji; Furuse, Tamio; Hino, Toshiaki; Oda, Kanako; Kashimura, Misho; Yamada, Ikuko; Wakana, Shigeharu; Yokoyama, Minesuke; Ishino, Fumitoshi; Kaneko-Ishino, Tomoko

    2014-01-01

    Sirh7/Ldoc1 [sushi-ichi retrotransposon homolog 7/leucine zipper, downregulated in cancer 1, also called mammalian retrotransposon-derived 7 (Mart7)] is one of the newly acquired genes from LTR retrotransposons in eutherian mammals. Interestingly, Sirh7/Ldoc1 knockout (KO) mice exhibited abnormal placental cell differentiation/maturation, leading to an overproduction of placental progesterone (P4) and placental lactogen 1 (PL1) from trophoblast giant cells (TGCs). The placenta is an organ that is essential for mammalian viviparity and plays a major endocrinological role during pregnancy in addition to providing nutrients and oxygen to the fetus. P4 is an essential hormone in the preparation and maintenance of pregnancy and the determination of the timing of parturition in mammals; however, the biological significance of placental P4 in rodents is not properly recognized. Here, we demonstrate that mouse placentas do produce P4 in mid-gestation, coincident with a temporal reduction in ovarian P4, suggesting that it plays a role in the protection of the conceptuses specifically in this period. Pregnant Sirh7/Ldoc1 knockout females also displayed delayed parturition associated with a low pup weaning rate. All these results suggest that Sirh7/Ldoc1 has undergone positive selection during eutherian evolution as a eutherian-specific acquired gene because it impacts reproductive fitness via the regulation of placental endocrine function. PMID:25468940

  3. Object-Oriented Version of Glenn-HT Code Released: Glenn-HT2000

    NASA Technical Reports Server (NTRS)

    Heidmann, James D.; Ameri, Ali A.; Rigby, David I.; Garg, Vijay K.; Fabian, John C.; Lucci, Barbara L.; Steinthorsson, Erlendur

    2005-01-01

    NASA Glenn Research Center s General Multi-Block Navier-Stokes Convective Heat Transfer Code (Glenn-HT) has been used extensively to predict heat transfer and fluid flow for a variety of steady gas turbine engine problems. Efforts have focused on turbine heat transfer, where computations have modeled tip clearance, internal coolant, and film cooling flows. Excellent agreement has been achieved for a variety of experimental test cases, and results have been published in over 40 technical publications. The code is available to U.S. industry and has been used by several domestic gas turbine engine companies. The following figure shows a typical flow solution from the Glenn-HT code for a film-cooled turbine blade.

  4. Pilot Fullerton dons EES anti-gravity suit lower torso on middeck

    NASA Technical Reports Server (NTRS)

    1982-01-01

    Pilot Fullerton dons ejection escape suit (EES) anti-gravity (anti-g) suit lower torso on forward port side middeck above potable water tank. Anti-g suit is an olive drab inner garment that complements EES.

  5. E × e Jahn-Teller effect in the P4+ cation and its signatures in the photoelectron spectrum of P4

    NASA Astrophysics Data System (ADS)

    Bhattacharyya, Swarnendu; Opalka, Daniel; Domcke, Wolfgang

    2015-10-01

    The Jahn-Teller effect in the electronic ground state of the P4+ radical cation, which is one of the strongest E × e Jahn-Teller effects known in nature, has been revisited in this work with computational methods. The relevance of the Jahn-Teller coupling terms beyond second order in normal-mode displacements has been investigated. An elegant and efficient scheme based on polynomial invariant theory has been employed to expand the E × e potential energy matrix up to arbitrarily high orders in normal mode displacements. Using the state-averaged complete-active-space self-consistent-field method and a correlation consistent double- ζ basis set, an accurate ab initio adiabatic E × e Jahn-Teller potential-energy surface was obtained. It is shown that a polynomial expansion of least up to sixth order is necessary to account for the pronounced anharmonicity of the ab initio potential-energy surface for large amplitude displacements of the Jahn-Teller active vibrational mode. The vibronic structure of the X ˜ 2 E band of the photoelectron spectrum of P4 has been computed using a time-dependent wave-packet propagation method. The results reveal the significance of the higher-order Jahn-Teller coupling terms for the high-resolution vibronic spectrum as well as for the low-resolution band shape.

  6. (1R, 3S)-(−)-Trans-PAT: A novel full-efficacy serotonin 5-HT2C receptor agonist with 5-HT2A and 5-HT2B receptor inverse agonist/antagonist activity

    PubMed Central

    Booth, Raymond G.; Fang, Lijuan; Huang, Yingsu; Wilczynski, Andrzej; Sivendran, Sashikala

    2009-01-01

    The serotonin 5-HT2A, 5-HT2B, and 5-HT2C G protein-coupled receptors signal primarily through Gαq to activate phospholipase C (PLC) and formation of inositol phosphates (IP) and diacylglycerol. The human 5-HT2C receptor, expressed exclusively in the central nervous system, is involved in several physiological and psychological processes. Development of 5-HT2C agonists that do not also activate 5-HT2A or 5-HT2B receptors is challenging because transmembrane domain identity is about 75% among 5-HT2 subtypes. This paper reports 5-HT2 receptor affinity and function of (1R,3S)-(−)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT), a small molecule that produces anorexia and weight-loss after peripheral administration to mice. (−)-Trans-PAT is a stereoselective full-efficacy agonist at human 5-HT2C receptors, plus, it is a 5-HT2A/5-HT2B inverse agonist and competitive antagonist. The Ki of (−)-trans-PAT at 5-HT2A, 5-HT2B, and 5-HT2C receptors is 410, 1200, and 37 nM, respectively. Functional studies measured activation of PLC/[3H]-IP formation in clonal cells expressing human 5-HT2 receptors. At 5-HT2C receptors, (−)-trans-PAT is an agonist (EC50 = 20 nM) comparable to serotonin in potency and efficacy. At 5-HT2A and 5-HT2B receptors, (−)-trans-PAT is an inverse agonist (IC50 = 490 and 1,000 nM, respectively) and competitive antagonist (KB = 460 and 1400 nM, respectively) of serotonin. Experimental results are interpreted in light of molecular modeling studies indicating the (−)-trans-PAT protonated amine can form an ionic bond with D3.32 of 5-HT2A and 5-HT2C receptors, but, not with 5-HT2B receptors. In addition to probing 5-HT2 receptor structure and function, (−)-trans-PAT is a novel lead regarding 5-HT2C agonist/5-HT2A inverse agonist drug development for obesity and neuropsychiatric disorders. PMID:19397907

  7. The action of SDZ 205,557 at 5-hydroxytryptamine (5-HT3 and 5-HT4) receptors.

    PubMed Central

    Eglen, R. M.; Alvarez, R.; Johnson, L. G.; Leung, E.; Wong, E. H.

    1993-01-01

    1. The interaction of the novel antagonist, SDZ 205,557 (2-methoxy-4-amino-5-chloro benzoic acid 2-(diethylamino) ethyl ester), at 5-HT3 and 5-HT4 receptors has been assessed in vitro and in vivo. 2. In guinea-pig hippocampus and in the presence of 0.4 microM 5-carboxamidotryptamine, 5-HT4-mediated stimulation of adenylyl cyclase was competitively antagonized by SDZ 205,557, with a pA2 value of 7.5, and a Schild slope of 0.81. In rat carbachol-contracted oesophagus, 5-HT4-receptor mediated relaxations were surmountably antagonized by SDZ 205,557 with a similar pA2 value (7.3). This value was agonist-independent with the exception of (R)-zacopride, against which a significantly lower value (6.4) was observed. 3. In functional studies of 5-HT3 receptors, SDZ 205,557 exhibited an affinity of 6.2 in guinea-pig ileum compared with 6.9 at binding sites labelled by [3H]-quipazine in NG108-15 cells. In the anaesthetized, vagotomized micropig, SDZ 205,557 produced only a transient blockade of 5-HT4-mediated tachycardia. This contrasted with tropisetron, which was active for over 60 min after administration. The half-lives for the inhibitory responses of SDZ 205,557 and tropisetron were 23 and 116 min, respectively. 4. In conclusion, SDZ 205,557 has similar affinity for 5-HT3 and 5-HT4 receptors. The apparent selectivity observed in guinea-pig is due to the atypical nature of the 5-HT3 receptor in this species. The short duration of action of this novel antagonist may complicate its use in vivo. SDZ 205,557 should, therefore, be used with appropriate caution in studies defining the 5-HT4 receptor. PMID:8448587

  8. Specific Noncompetitive Immunoassay for HT-2 Mycotoxin Detection.

    PubMed

    Arola, Henri O; Tullila, Antti; Kiljunen, Harri; Campbell, Katrina; Siitari, Harri; Nevanen, Tarja K

    2016-02-16

    Here we demonstrate a novel homogeneous one-step immunoassay, utilizing a pair of recombinant antibody antigen-binding fragments (Fab), that is specific for HT-2 toxin and has a positive readout. Advantages over the conventional competitive immunoassay formats such as enzyme-linked immunosorbent assay (ELISA) are the specificity, speed, and simplicity of the assay. Recombinant antibody HT2-10 Fab recognizing both HT-2 and T-2 toxins was developed from a phage display antibody library containing 6 × 10(7) different antibody clones. Specificity of the immunoassay was introduced by an anti-immune complex (IC) antibody binding the primary antibody-HT-2 toxin complex. When the noncompetitive immune complex assay was compared to the traditional competitive assay, an over 10-fold improvement in sensitivity was observed. Although the HT2-10 antibody has 100% cross-reactivity for HT-2 and T-2 toxins, the immune complex assay is highly specific for HT-2 alone. The assay performance with real samples was evaluated using naturally contaminated wheat reference material. The half-maximal effective concentration (EC50) value of the time-resolved fluorescence resonance energy transfer (TR-FRET) assay was 9.6 ng/mL, and the limit of detection (LOD) was 0.38 ng/mL (19 μg/kg). The labeled antibodies can be predried to the assay vials, e.g., microtiter plate wells, and readout is ready in 10 min after the sample application. PMID:26785138

  9. The 5-HT(7) receptor in learning and memory.

    PubMed

    Roberts, Amanda J; Hedlund, Peter B

    2012-04-01

    The 5-HT(7) receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood. The present paper reviews to what extent the use of animal models of learning and memory and other techniques have implicated the 5-HT(7) receptor in such processes. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior and cellular mechanisms. In tests such as the Barnes maze, contextual fear conditioning and novel location recognition that involve spatial learning and memory there is a considerable amount of evidence supporting an involvement of the 5-HT(7) receptor. Supporting evidence has also been obtained in studies of mRNA expression and cellular signaling as well as in electrophysiological experiments. Especially interesting are the subtle but distinct effects observed in hippocampus-dependent models of place learning where impairments have been described in mice lacking the 5-HT(7) receptor or after administration of a selective antagonist. While more work is required, it appears that 5-HT(7) receptors are particularly important in allocentric representation processes. In instrumental learning tasks both procognitive effects and impairments in memory have been observed using pharmacological tools targeting the 5-HT(7) receptor. In conclusion, the use of pharmacological and genetic tools in animal studies of learning and memory suggest a potentially important role for the 5-HT(7) receptor in cognitive processes. PMID:21484935

  10. Experiment 2003 – First Pressurization of EE-2

    SciTech Connect

    Murphy, Hugh D.; Matsunaga, Isao; Kuriyagawa, Michio

    1982-01-07

    Water was pumped into EE-2 at a nominal rate of 9gpm, to a final pressure of 2070 psi. The wellbore was exceptionally tight we might just have well pumped into a steel pressure vessel not only was there no evidence of breakdown, but only a total of about 30 gallons of water permeated the rock during the 2-1/2 hour-long pressurization.

  11. Influence of the nacnac Ligand in Iron(I)-Mediated P4 Transformations.

    PubMed

    Spitzer, Fabian; Graßl, Christian; Balázs, Gábor; Zolnhofer, Eva M; Meyer, Karsten; Scheer, Manfred

    2016-03-18

    A study of P4 transformations at low-valent iron is presented using β-diketiminato (L) Fe(I) complexes [LFe(tol)] (tol=toluene; L=L(1) (1 a), L(2) (1 b), L(3) (1 c)) with different combinations of aromatic and backbone substituents at the ligand. The products [(LFe)4 (μ4 -η(2) :η(2) :η(2) :η(2) -P8 )] (L=L(1) (2 a), L(2) (2 b)) containing a P8 core were obtained by the reaction of 1 a,b with P4 in toluene at room temperature. Using a slightly more sterically encumbered ligand in 1 c results in the formation of [(L(3) Fe)2 (μ-η(4) :η(4) -P4 )] (2 c), possessing a cyclo-P4 moiety. Compounds 2 a-c were comprehensively characterized and their electronic structures investigated by SQUID magnetization and (57) Fe Mössbauer spectroscopy as well as by DFT methods. PMID:26924606

  12. FROM "CANAL BRIDGE, F.A.P. 4C, MAR. 1938." SHOWING WAIKELE BRIDGE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    FROM "CANAL BRIDGE, F.A.P. 4-C, MAR. 1938." SHOWING WAIKELE BRIDGE PLAN AND ELEVATION. Hawaii Department of Transportation, Design Branch, Project ID 7101-001, drawing 4449.27. - Waikele Canal Bridge and Highway Overpass, Farrington Highway and Waikele Stream, Waipahu, Honolulu County, HI

  13. A P4-ATPase gene GbPATP of cotton confers chilling tolerance in plants.

    PubMed

    Liu, Tingli; Guo, Shiwei; Lian, Ziyi; Chen, Fei; Yang, Yuwen; Chen, Tianzi; Ling, Xitie; Liu, Aiming; Wang, Rongfu; Zhang, Baolong

    2015-03-01

    Members of the P4 subfamily of P-type ATPases are implicated in generating lipid asymmetry between the two lipid leaflets of the plasma membrane in Arabidopsis and are important for resistance to low temperatures, but the function of P4-ATPases in cotton remains unclear. In this study, we found using quantitative reverse transcription-PCR analysis that the expression of the P4-ATPase gene GbPATP in cotton was induced at low temperatures. In addition, GbPATP-silenced cotton plants were more sensitive to low temperatures and exhibited greater malondialdehyde (MDA) content and lower catalase (CAT) activity than the control plants. GbPATP transgenic tobacco plants showed better chilling tolerance, had a lower MDA content and had higher CAT activity than wild-type plants under low-temperature treatment. The green fluorescent protein (GFP)-GbPATP fusion protein was found to be localized to the cell plasma membrane. Collectively, the results suggest that GbPATP functions as a P4-ATPase and plays an important role in improving chilling tolerance in plant. PMID:25520408

  14. From integrative disease modeling to predictive, preventive, personalized and participatory (P4) medicine

    PubMed Central

    2013-01-01

    With the significant advancement of high-throughput technologies and diagnostic techniques throughout the past decades, molecular underpinnings of many disorders have been identified. However, translation of patient-specific molecular mechanisms into tailored clinical applications remains a challenging task, which requires integration of multi-dimensional molecular and clinical data into patient-centric models. This task becomes even more challenging when dealing with complex diseases such as neurodegenerative disorders. Integrative disease modeling is an emerging knowledge-based paradigm in translational research that exploits the power of computational methods to collect, store, integrate, model and interpret accumulated disease information across different biological scales from molecules to phenotypes. We argue that integrative disease modeling will be an indispensable part of any P4 medicine research and development in the near future and that it supports the shift from descriptive to causal mechanistic diagnosis and treatment of complex diseases. For each ‘P’ in predictive, preventive, personalized and participatory (P4) medicine, we demonstrate how integrative disease modeling can contribute to addressing the real-world issues in development of new predictive, preventive, personalized and participatory measures. With the increasing recognition that application of integrative systems modeling is the key to all activities in P4 medicine, we envision that translational bioinformatics in general and integrative modeling in particular will continue to open up new avenues of scientific research for current challenges in P4 medicine. PMID:24195840

  15. Influence of the nacnac Ligand in Iron(I)‐Mediated P4 Transformations

    PubMed Central

    Spitzer, Fabian; Graßl, Christian; Balázs, Gábor; Zolnhofer, Eva M.; Meyer, Karsten

    2016-01-01

    Abstract A study of P4 transformations at low‐valent iron is presented using β‐diketiminato (L) FeI complexes [LFe(tol)] (tol=toluene; L=L1 (1 a), L2 (1 b), L3 (1 c)) with different combinations of aromatic and backbone substituents at the ligand. The products [(LFe)4(μ4‐η2:η2:η2:η2‐P8)] (L=L1 (2 a), L2 (2 b)) containing a P8 core were obtained by the reaction of 1 a,b with P4 in toluene at room temperature. Using a slightly more sterically encumbered ligand in 1 c results in the formation of [(L3Fe)2(μ‐η4:η4‐P4)] (2 c), possessing a cyclo‐P4 moiety. Compounds 2 a–c were comprehensively characterized and their electronic structures investigated by SQUID magnetization and 57Fe Mössbauer spectroscopy as well as by DFT methods. PMID:26924606

  16. P4 radiology of hepatobiliary diseases with gadoxetic acid-enhanced MRI as a biomarker.

    PubMed

    Ba-Ssalamah, Ahmed; Qayyum, Aliya; Bastati, Nina; Fakhrai, Negar; Herold, Christian J; Caseiro Alves, Filipe

    2014-02-01

    A recent paradigm shift in radiology has focused on the globalization of so-called P4 radiology. P4 radiology represents delivery of imaging results that are predictive, personalized, pre-emptive and participatory. The combination of the P4 approach and biomarkers is particularly pertinent to MRI, especially with technological advances such as diffusion-weighted imaging. The development of new liver-specific MRI contrast media, particularly gadoxetic acid, demonstrate specific pharmacokinetic properties, which provide combined morphologic and functional information in the same setting. The evaluation of hepatobiliary pathology beyond morphology gives rise to the possibilty of using gadoxetic acid-enhanced MRI as an imaging biomarker of hepatobiliary diseases. The integration of functional imaging with an understanding of complex disease mechanisms forms the basis for P4 radiology, which may ultimately lead to individualized, cost-effective, targeted therapy for patients. This will enable radiologists to determine the prognosis of the disease and estimate early response to treatment, with the participation of all the required medical disciplines. PMID:24417263

  17. 26 CFR 301.6103(p)(4)-1 - Procedures relating to safeguards for returns or return information.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... or return information. 301.6103(p)(4)-1 Section 301.6103(p)(4)-1 Internal Revenue INTERNAL REVENUE... Information and Returns Returns and Records § 301.6103(p)(4)-1 Procedures relating to safeguards for returns..., see § 301.6103(p)(7)-1....

  18. 26 CFR 301.6103(p)(4)-1 - Procedures relating to safeguards for returns or return information.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... or return information. 301.6103(p)(4)-1 Section 301.6103(p)(4)-1 Internal Revenue INTERNAL REVENUE... Information and Returns Returns and Records § 301.6103(p)(4)-1 Procedures relating to safeguards for returns..., see § 301.6103(p)(7)-1....

  19. 26 CFR 301.6103(p)(4)-1 - Procedures relating to safeguards for returns or return information.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... or return information. 301.6103(p)(4)-1 Section 301.6103(p)(4)-1 Internal Revenue INTERNAL REVENUE... Information and Returns Returns and Records § 301.6103(p)(4)-1 Procedures relating to safeguards for returns..., see § 301.6103(p)(7)-1....

  20. 26 CFR 301.6103(p)(4)-1 - Procedures relating to safeguards for returns or return information.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... or return information. 301.6103(p)(4)-1 Section 301.6103(p)(4)-1 Internal Revenue INTERNAL REVENUE... Information and Returns Returns and Records § 301.6103(p)(4)-1 Procedures relating to safeguards for returns..., see § 301.6103(p)(7)-1....

  1. 26 CFR 301.6103(p)(4)-1 - Procedures relating to safeguards for returns or return information.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... or return information. 301.6103(p)(4)-1 Section 301.6103(p)(4)-1 Internal Revenue INTERNAL REVENUE... Information and Returns Returns and Records § 301.6103(p)(4)-1 Procedures relating to safeguards for returns..., see § 301.6103(p)(7)-1....

  2. Application of the Dimensional Reduction Formalism to Pb12[Li2(P2O7)2(P4O13)2](P4O13): a Phosphate Containing Three Types of Isolated P-O Groups.

    PubMed

    Zhang, Xiangyu; Wu, Hongping; Wang, Ying; Dong, Xiaoyu; Han, Shujuan; Pan, Shilie

    2016-08-01

    A new phosphate, Pb12[Li2(P2O7)2(P4O13)2](P4O13), containing three types of isolated polyphosphate anionic groups [P2O7], and two types of [P4O13] has been successfully synthesized by using Li2O as dimensional reduction agent to dismantle Pb3P4O13. The isolation of [P2O7] and two types of [P4O13] with different symmetries in the title compound mainly benefits from the large number and flexible coordination of the Pb(2+) cations. PMID:27399881

  3. Adaptation of antenna profiles for control of MR guided hyperthermia (HT) in a hybrid MR-HT system

    SciTech Connect

    Weihrauch, Mirko; Wust, Peter; Weiser, Martin; Nadobny, Jacek; Eisenhardt, Steffen; Budach, Volker; Gellermann, Johanna

    2007-12-15

    A combined numerical-experimental iterative procedure, based on the Gauss-Newton algorithm, has been developed for control of magnetic resonance (MR)-guided hyperthermia (HT) applications in a hybrid MR-HT system BSD 2000 3D-MRI. In this MR-HT system, composed of a 3-D HT applicator Sigma-Eye placed inside a tunnel-type MR tomograph Siemens MAGNETOM Symphony (1.5 T), the temperature rise due to the HT radiation can be measured on-line in three dimensions by use of the proton resonance frequency shift (PRFS) method. The basic idea of our iterative procedure is the improvement of the system's characterization by a step-by-step modification of the theoretical HT antenna profiles (electric fields radiated by single antennas). The adaptation of antenna profiles is efficient if the initial estimates are radiation fields calculated from a good a priori electromagnetic model. Throughout the iterative procedure, the calculated antenna fields (FDTD) are step-by-step modified by comparing the calculated and experimental data, the latter obtained using the PRFS method. The procedure has been experimentally tested on homogeneous and inhomogeneous phantoms. It is shown that only few comparison steps are necessary for obtaining a dramatic improvement of the general predictability and quality of the specific absorption rate (SAR) inside the MR-HT hybrid system.

  4. Evidence for 5-HT7 receptors mediating relaxation of human colonic circular smooth muscle

    PubMed Central

    Prins, Nicolaas H; Briejer, Michel R; Van Bergen, Patrick J E; Akkermans, Louis M A; Schuurkes, Jan A J

    1999-01-01

    5-HT4 receptors mediate relaxation of human colon circular muscle. However, after 5-HT4 receptor blockade (SB 204070 10 nM), 5-HT still induced a relaxation (pEC50 6.3). 5-HT4 receptors were sufficiently blocked, as the curves to 5-HT obtained in the presence of 10 and 100 nM SB 204070 were indistinguishable. This 5-HT-induced relaxation was tetrodotoxin-insensitive, indicative of a smooth muscle relaxant 5-HT receptor. This, and the rank order of potency (5-CT=5-MeOT=5-HT) suggested involvement of 5-HT1 or 5-HT7 receptors. Mesulergine, a 5-HT7 receptor antagonist at nanomolar concentrations, and a 5-HT1 receptor antagonist at micromolar concentrations, competitively antagonized the 5-HT-induced relaxation (pKB 8.3) and antagonized the relaxation to 5-CT. Methysergide antagonized the 5-HT-induced relaxation (pA2 7.6). It is concluded that the profile of the smooth muscle inhibitory 5-HT receptor resembles that of the 5-HT7 receptor. These data provide the first evidence for functional human 5-HT7 receptors. PMID:10556917

  5. RU 24969-induced emesis in the cat - 5-HT1 sites other than 5-HT1A, 5-HT1B or 5-HT1C implicated

    NASA Technical Reports Server (NTRS)

    Lucot, James B.

    1990-01-01

    RU 24969 was administered s.c. to cats and found to elicit emesis with a maximally effective dose of 1.0 mg/kg 5-Methoxytryptamine was found to have lower efficacy and to produce a higher incidence of nonspecific effects while trifluoromethylphenylpiperizine (TFMPP) was devoid of emetic effects. The emesis elicited by 1.0 mg/kg of RU 24969 was not altered by pretreatment with phentolamine, haloperidol, yohimbine or (-)-propranolol, indicating that catecholamines played no role in this response. The emesis was prevented by metergoline and methysergide but not by ketanserin, cyproheptadine, mesulergine, ICS 205 930, methiothepin, trimethobenzamide or BMY 7378. An indirect argument is presented that implicates a role for 5-HT1D sites. This conclusion must remain tentative until drugs selective for this site are synthesized and tested. The emesis was also prevented by 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT), confirming that this drug has a general antiemetic effect in cats.

  6. Ion permeation and conduction in a human recombinant 5-HT3 receptor subunit (h5-HT3A)

    PubMed Central

    Brown, A M; Hope, A G; Lambert, J J; Peters, J A

    1998-01-01

    A human recombinant homo-oligomeric 5-HT3 receptor (h5-HT3A) expressed in a human embryonic kidney cell line (HEK 293) was characterized using the whole-cell recording configuration of the patch clamp technique. 5-HT evoked transient inward currents (EC50 = 3.4 μm; Hill coefficient = 1.8) that were blocked by the 5-HT3 receptor antagonist ondansetron (IC50 = 103 pm) and by the non-selective agents metoclopramide (IC50 = 69 nm), cocaine (IC50 = 459 nm) and (+)-tubocurarine (IC50 = 2.8 μm). 5-HT-induced currents rectified inwardly and reversed in sign (E5-HT) at a potential of −2.2 mV. N-Methyl-d-glucamine was finitely permeant. Permeability ratios PNa/PCs and PNMDG/PCs were 0.90 and 0.083, respectively. Permeability towards divalent cations was assessed from measurements of E5-HT in media where Ca2+ and Mg2+ replaced Na+. PCa/PCs and PMg/PCs were calculated to be 1.00 and 0.61, respectively. Single channel chord conductance (γ) estimated from fluctuation analysis of macroscopic currents increased with membrane hyperpolarization from 243 fS at −40 mV to 742 fS at −100 mV. Reducing [Ca2+]o from 2 to 0.1 mm caused an increase in the whole-cell current evoked by 5-HT. A concomitant reduction in [Mg2+]o produced further potentiation. Fluctuation analysis indicates that a voltage-independent augmentation of γ contributes to this phenomenon. The data indicate that homo-oligomeric receptors composed of h5-HT3A subunits form inwardly rectifying cation-selective ion channels of low conductance that are permeable to Ca2+ and Mg2+. PMID:9508827

  7. Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation.

    PubMed

    Jensen, Jesper Bornø; du Jardin, Kristian Gaarn; Song, Dekun; Budac, David; Smagin, Gennady; Sanchez, Connie; Pehrson, Alan Lars

    2014-01-01

    Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities. PMID:24284262

  8. Performance of HT9 clad metallic fuel at high temperature

    SciTech Connect

    Pahl, R.G.; Lahm, C.E.; Hayes, S.L.

    1992-12-01

    Steady-state testing of HT9 clad metallic fuel at high temperatures was initiated in EBR-II in November of 1987. At that time U-10 wt. % Zr fuel clad with the low-swelling ferritic/martensitic alloy HT9 was being considered as driver fuel options for both EBR-II and FFTF. The objective of the X447 test described here was to determine the lifetime of HT9 cladding when operated with metallic fuel at beginning of life inside wall temperatures approaching {approximately}660{degree}C. Though stress-temperature design limits for HT9 preclude its use for high burnup applications under these conditions due to excessive thermal creep, the X447 test was carried out to obtain data on high temperature breach phenomena involving metallic fuel since little data existed in that area.

  9. Performance of HT9 clad metallic fuel at high temperature

    SciTech Connect

    Pahl, R.G.; Lahm, C.E.; Hayes, S.L.

    1992-01-01

    Steady-state testing of HT9 clad metallic fuel at high temperatures was initiated in EBR-II in November of 1987. At that time U-10 wt. % Zr fuel clad with the low-swelling ferritic/martensitic alloy HT9 was being considered as driver fuel options for both EBR-II and FFTF. The objective of the X447 test described here was to determine the lifetime of HT9 cladding when operated with metallic fuel at beginning of life inside wall temperatures approaching [approximately]660[degree]C. Though stress-temperature design limits for HT9 preclude its use for high burnup applications under these conditions due to excessive thermal creep, the X447 test was carried out to obtain data on high temperature breach phenomena involving metallic fuel since little data existed in that area.

  10. Therapeutic Potential of 5-HT6 Receptor Agonists.

    PubMed

    Karila, Delphine; Freret, Thomas; Bouet, Valentine; Boulouard, Michel; Dallemagne, Patrick; Rochais, Christophe

    2015-10-22

    Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox. PMID:26099069

  11. Selective 5-HT2C agonists as potential antidepressants.

    PubMed

    Leysen, D C

    1999-02-01

    The antidepressants currently used need improvement, especially in terms of efficacy, relapse rate and onset of action. In this review the clinical and experimental data which support the rationale for 5-HT2C agonists in the treatment of depression are listed. Next, the results obtained with the non-selective 5-HT2C agonists on the market and in clinical development are described. Finally, the preclinical data on the more selective 5-HT2C agonists are summarized. These recent preclinical results reveal a greater potency and effect size compared to fluoxetine, good tolerability and no evidence of tolerance development. Selective 5-HT2C agonists might become innovative drugs for the treatment of depression, panic, obsessive-compulsive disorder (OCD), some forms of aggression and eating disorders. PMID:16160946

  12. Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism.

    PubMed

    du Jardin, Kristian Gaarn; Jensen, Jesper Bornø; Sanchez, Connie; Pehrson, Alan L

    2014-01-01

    We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (∼80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (∼25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (∼25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism. PMID:23916504

  13. 5-HT3 Receptor Brain-Type B-Subunits are Differentially Expressed in Heterologous Systems

    PubMed Central

    2015-01-01

    Genes for five different 5-HT3 receptor subunits have been identified. Most of the subunits have multiple isoforms, but two isoforms of the B subunits, brain-type 1 (Br1) and brain-type 2 (Br2) are of particular interest as they appear to be abundantly expressed in human brain, where 5-HT3B subunit RNA consists of approximately 75% 5-HT3Br2, 24% 5-HT3Br1, and <1% 5-HT3B. Here we use two-electrode voltage-clamp, radioligand binding, fluorescence, whole cell, and single channel patch-clamp studies to characterize the roles of 5-HT3Br1 and 5-HT3Br2 subunits on function and pharmacology in heterologously expressed 5-HT3 receptors. The data show that the 5-HT3Br1 transcriptional variant, when coexpressed with 5-HT3A subunits, alters the EC50, nH, and single channel conductance of the 5-HT3 receptor, but has no effect on the potency of competitive antagonists; thus, 5-HT3ABr1 receptors have the same characteristics as 5-HT3AB receptors. There were some differences in the shapes of 5-HT3AB and 5-HT3ABr1 receptor responses, which were likely due to a greater proportion of homomeric 5-HT3A versus heteromeric 5-HT3ABr1 receptors in the latter, as expression of the 5-HT3Br1 compared to the 5-HT3B subunit is less efficient. Conversely, the 5-HT3Br2 subunit does not appear to form functional channels with the 5-HT3A subunit in either oocytes or HEK293 cells, and the role of this subunit is yet to be determined. PMID:25951416

  14. P3HT-based nanoarchitectural Fano solar cells.

    PubMed

    Liao, Wen-Pin; Su, Yen-Hsun; Huang, Yun-Kai; Yeh, Chen-Sheng; Huang, Li-Wen; Wu, Jih-Jen

    2014-10-22

    The finite difference time domain simulation shows the existence of an asymmetric quadrupole of Fano resonance on the surface of a gold-silica core-shell (Au@silica) nanoparticle (NP) as being incorporated into the metal oxide nanoarchitecture/P3HT hybrid. Compared to the metal oxide nanoarchitecture/P3HT hybrid solar cell, a 30% enrichment of the short-circuit current density (Jsc) is attained in the P3HT-based nanoarchitectural Fano solar cell with the Au@silica NPs. The enhancement of charge separation in the cell by the electric field of the Fano resonance is directly evidenced by time-resolved photoluminescence measurements. The increase of the degree of P3HT order in the hybrid by the incorporation of Au@silica NPs into the hybrid active layer may also contribute to the enhancement in the Jsc. Charge carrier dynamic measurements show that an electron collection efficiency of ∼97% can be maintained in the P3HT-based nanoarchitectural Fano solar cell. Significant improvement of the efficiency of the inverted metal oxide/P3HT hybrid solar cell is therefore achieved. PMID:25223500

  15. The 5-HT[subscript 3A] Receptor Is Essential for Fear Extinction

    ERIC Educational Resources Information Center

    Kondo, Makoto; Nakamura, Yukiko; Ishida, Yusuke; Yamada, Takahiro; Shimada, Shoichi

    2014-01-01

    The 5-HT [subscript 3] receptor, the only ionotropic 5-HT receptor, is expressed in limbic regions, including the hippocampus, amygdala, and cortex. However, it is not known whether it has a role in fear memory processes. Analysis of 5-HT [subscript 3A] receptor knockout mice in fear conditioning paradigms revealed that the 5-HT [subscript 3A]…

  16. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mice lacking 5-HT 2C receptors displayed hepatic insulin resistance, a phenotype normalized by re-expression of 5-HT2CRs only in pro-opiomelanocortin (POMC) neurons. 5-HT2CR deficiency also abolished the anti-diabetic effects of meta-chlorophenylpiperazine (a 5-HT2CR agonist); these effects were re...

  17. Ferrenberg Swendsen Analysis of LLNL and NYBlue BG/L p4rhms Data

    SciTech Connect

    Soltz, R

    2007-12-05

    These results are from the continuing Lattice Quantum Chromodynamics runs on BG/L. These results are from the Ferrenberg-Swendsen analysis [?] of the combined data from LLNL and NYBlue BG/L runs for 32{sup 3} x 8 runs with the p4rhmc v2.0 QMP-MPI.X (semi-optimized p4 code using qmp over mpi). The jobs include beta values ranging from 3.525 to 3.535 with an alternate analysis extending to 3.540. The NYBlue data sets are from 9k trajectories from Oct 2007, and the LLNL data are from two independent streams of {approx}5k each, taking from the July 2007 runs. The following outputs are produced by the fs-2+1-chiub.c program. All outputs have had checksums produced by addCks.pl and checked by the checkCks.pl perl script after scanning.

  18. Nonessential region of bacteriophage P4: DNA sequence, transcription, gene products, and functions.

    PubMed Central

    Ghisotti, D; Finkel, S; Halling, C; Dehò, G; Sironi, G; Calendar, R

    1990-01-01

    We sequenced the leftmost 2,640 base pairs of bacteriophage P4 DNA, thus completing the sequence of the 11,627-base-pair P4 genome. The newly sequenced region encodes three nonessential genes, which are called gop, beta, and cII (in order, from left to right). The gop gene product kills Escherichia coli when the beta protein is absent; the gop and beta genes are transcribed rightward from the same promoter. The cII gene is transcribed leftward to a rho-independent terminator. Mutation of this terminator creates a temperature-sensitive phenotype, presumably owing to a defect in expression of the beta gene. Images PMID:2403440

  19. Spectroscopic properties of Eu3+ doped RbLaP4O12 powders.

    PubMed

    Mesfar, M; Horchani-Naifer, K; Abdelhedi, M; Dammak, M; Ferid, M

    2013-10-01

    Monophasic RbLaP4O12 possessing monoclinic symmetry with varied Eu(3+) concentrations was synthesized by flux method. The obtained cyclotetraphosphate exhibits very small crystals and the dopant Eu(3+) ions were successfully incorporated into the sites of La(3+) ions of the host lattice. These compounds were characterized by infrared and Raman spectroscopy, X-ray diffraction (XRD) and luminescence spectroscopy. The spectroscopy properties confirm the potentiality of present RbLaP4O12 doped with Eu(3+) ions as luminophore host materials to produce an intense red luminescence at 616 nm corresponding to (5)D0→(7)F2 emission level and have significant importance in the development of emission optical systems. PMID:23770502

  20. Development of a HT seismic downhole tool.

    SciTech Connect

    Maldonado, Frank P.; Greving, Jeffrey J.; Henfling, Joseph Anthony; Chavira, David J.; Uhl, James Eugene; Polsky, Yarom

    2009-06-01

    Enhanced Geothermal Systems (EGS) require the stimulation of the drilled well, likely through hydraulic fracturing. Whether fracturing of the rock occurs by shear destabilization of natural fractures or by extensional failure of weaker zones, control of the fracture process will be required to create the flow paths necessary for effective heat mining. As such, microseismic monitoring provides one method for real-time mapping of the fractures created during the hydraulic fracturing process. This monitoring is necessary to help assess stimulation effectiveness and provide the information necessary to properly create the reservoir. In addition, reservoir monitoring of the microseismic activity can provide information on reservoir performance and evolution over time. To our knowledge, no seismic tool exists that will operate above 125 C for the long monitoring durations that may be necessary. Replacing failed tools is costly and introduces potential errors such as depth variance, etc. Sandia has designed a high temperature seismic tool for long-term deployment in geothermal applications. It is capable of detecting microseismic events and operating continuously at temperatures up to 240 C. This project includes the design and fabrication of two High Temperature (HT) seismic tools that will have the capability to operate in both temporary and long-term monitoring modes. To ensure the developed tool meets industry requirements for high sampling rates (>2ksps) and high resolution (24-bit Analog-to-Digital Converter) two electronic designs will be implemented. One electronic design will utilize newly developed 200 C electronic components. The other design will use qualified Silicon-on-Insulator (SOI) devices and will have a continuous operating temperature of 240 C.

  1. XP-PCM Calculations of High Pressure Structural and Vibrational Properties of P4S3.

    PubMed

    Pagliai, Marco; Cammi, Roberto; Cardini, Gianni; Schettino, Vincenzo

    2016-07-14

    The structure and the vibrational properties of the P4S3 crystal at high pressures are discussed by application of the XP-PCM method. The vibrational assignment has been clarified. The structure and the electron distribution changes as a function of pressure are analyzed. The pressure effect on the vibrational frequencies is satisfactorily reproduced and discussed in terms of confinement and structure relaxation contributions. PMID:26943701

  2. Care and Do Not Harm: Possible Misunderstandings With Quaternary Prevention (P4)

    PubMed Central

    Widmer, Daniel

    2015-01-01

    The discussion between general practitioners (GPs) and healthcare delivery organizations necessitates a common language. The presentation of the 4 types of GP’s activities, opens dialogue but can lead to possible misunderstandings between the micro- and macro-level of the healthcare system. This commentary takes 4 examples: costs reduction by P4, priority of beneficence or nonmaleficence, role of evidence-based medicine (EBM) and use of a constructivist model. PMID:26340401

  3. Modulation of dopamine transmission by 5HT2C and 5HT3 receptors: a role in the antidepressant response.

    PubMed

    Dremencov, Eliyahu; Weizmann, Yifat; Kinor, Noa; Gispan-Herman, Iris; Yadid, Gal

    2006-02-01

    Dopaminergic mesolimbic and mesocortical systems are fundamental in hedonia and motivation. Therefore their regulation should be central in understanding depression treatment. This review highlights the dopaminergic activity in relation to depressive behavior and suggests two putative receptors as potential targets for research and development of future antidepressants. In this article we review data that describe the role of serotonin in regulating dopamine release, via 5HT2C and 5HT3 receptors. This action of serotonin appears to be linked to depressive-like behavior and to onset of behavioral effects of antidepressants in an animal model of depression. We suggest that drugs or strategies that decrease 5HT2C and increase 5HT3 receptor-mediated dopamine release in the limbic areas of the brain may provide a fast onset of therapeutic effect. Clinical and basic research data supporting this hypothesis are discussed. PMID:16475958

  4. Negative magnetoresistance in a magnetic semiconducting Zintl phase: Eu(3)In(2)P(4).

    PubMed

    Jiang, Jiong; Olmstead, Marilyn M; Kauzlarich, Susan M; Lee, Han-Oh; Klavins, Peter; Fisk, Zachary

    2005-07-25

    A new rare earth metal Zintl phase, Eu(3)In(2)P(4), was synthesized by utilizing a metal flux method. The compound crystallizes in the orthorhombic space group Pnnm with the cell parameters a = 16.097(3) A, b = 6.6992(13) A, c = 4.2712(9) A, and Z = 2 (T = 90(2) K, R1 = 0.0159, wR2 = 0.0418 for all data). It is isostructural to Sr(3)In(2)P(4). The structure consists of tetrahedral dimers, [In(2)P(2)P(4/2)](6-), that form a one-dimensional chain along the c axis. Three europium atoms interact via a Eu-Eu distance of 3.7401(6) A to form a straight line triplet. Single-crystal magnetic measurements show anisotropy at 30 K and a magnetic transition at 14.5 K. High-temperature data give a positive Weiss constant, which suggests ferromagnetism, while the shape of susceptibility curves (chi vs T) suggests antiferromagnetism. Heat capacity shows a magnetic transition at 14.5 K that is suppressed with field. This compound is a semiconductor according to the temperature-dependent resistivity measurements with a room-temperature resistivity of 0.005(1) Omega m and E(g) = 0.452(4) eV. It shows negative magnetoresistance below the magnetic ordering temperature. The maximum magnetoresistance (Deltarho/rho(H)) is 30% at 2 K with H = 5 T. PMID:16022530

  5. Positive selection in AvrP4 avirulence gene homologues across the genus Melampsora

    PubMed Central

    Van der Merwe, Marlien M.; Kinnear, Mark W.; Barrett, Luke G.; Dodds, Peter N.; Ericson, Lars; Thrall, Peter H.; Burdon, Jeremy J.

    2009-01-01

    Pathogen genes involved in interactions with their plant hosts are expected to evolve under positive Darwinian selection or balancing selection. In this study a single copy avirulence gene, AvrP4, in the plant pathogen Melampsora lini, was used to investigate the evolution of such a gene across species. Partial translation elongation factor 1-alpha sequences were obtained to establish phylogenetic relationships among the Melampsora species. We amplified AvrP4 homologues from species pathogenic on hosts from different plant families and orders, across the inferred phylogeny. Translations of the AvrP4 sequences revealed a predicted signal peptide and towards the C-terminus of the protein, six identically spaced cysteines were identified in all sequences. Maximum likelihood analysis of synonymous versus non-synonymous substitution rates indicated that positive selection played a role in the evolution of the gene during the diversification of the genus. Fourteen codons under significant positive selection reside in the C-terminal 28 amino acid region, suggesting that this region interacts with host molecules in most sequenced accessions. Selection pressures on the gene may be either due to the pathogenicity or avirulence function of the gene or both. PMID:19457888

  6. Neutrino mass matrices with M{sub ee}=0

    SciTech Connect

    BenTov, Yoni; Zee, A.

    2011-10-01

    Motivated by the possibility that the amplitude for neutrinoless double beta decay may be much smaller than the planned sensitivity of future experiments, we study Ansaetze for the neutrino mass matrix with M{sub ee}=0. For the case in which CP is conserved, we consider two classes of real-valued mass matrices: ''Class I'' defined by |M{sub e{mu}|}=|M{sub e{tau}|}, and ''Class II'' defined by |M{sub {mu}{mu}|}=|M{sub {tau}{tau}|}. The important phenomenological distinction between the two is that Class I permits only small values of V{sub e3} up to {approx}0.03, while Class II admits large values of V{sub e3} up to its empirical upper limit of 0.22. Then we introduce CP-violating complex phases into the mass matrix. We show that it is possible to have tribimaximal mixing with M{sub ee}=0 and |M{sub {mu}{tau}|}=|M{sub {mu}{mu}|}=|M{sub {tau}{tau}|} if the Majorana phase angles are {+-}{pi}/4. Alternatively, for smaller values of |M{sub {mu}{tau}|}=|M{sub {mu}{mu}|}=|M{sub {tau}{tau}|} it is possible to obtain |V{sub e3}|{approx}0.2 and generate relatively large CP-violating amplitudes. To eliminate phase redundancy, we emphasize rephasing any mass matrix with M{sub ee}=0 into a standard form with two complex phases. The discussion alternates between analytical and numerical but remains purely phenomenological, without any attempt to derive mass matrices from a fundamental theory.

  7. Effects of dominance status on conditioned defeat and expression of 5-HT1A and 5-HT2A receptors

    PubMed Central

    Morrison, Kathleen E.; Swallows, Cody L.; Cooper, Matthew A.

    2011-01-01

    Past experience can alter how individuals respond to stressful events. The brain serotonin system is a key factor modulating stress-related behavior and may contribute to individual variation in coping styles. In this study we investigated whether dominant and subordinate hamsters respond differently to social defeat and whether their behavioral responses are associated with changes in 5-HT1A and 5-HT2A receptor immunoreactivity in several limbic brain regions. We paired weight-matched hamsters in daily aggressive encounters for two weeks so that they formed a stable dominance relationship. We also included controls that were exposed to an empty cage each day for two weeks. Twenty-four hours after the final pairing or empty cage exposure, subjects were socially defeated in 3, 5-min encounters with a more aggressive hamster. Twenty-four hours after social defeat, animals were tested for conditioned defeat in a 5-min social interaction test with a non-aggressive intruder. We collected brains following conditioned defeat testing and performed immunohistochemistry for 5-HT1A and 5-HT2A receptors. We found that dominants showed less submissive and defensive behavior at conditioned defeat testing compared to both subordinates and controls. Additionally, both dominants and subordinates had an increased number of 5-HT1A immunopositive cells in the basolateral amygdala compared to controls. Subordinates also had more 5-HT1A immunopositive cells in the dorsal medial amygdala than did controls. Finally, dominants had fewer 5-HT1A immunopositive cells in the paraventricular nucleus of the hypothalamus compared to controls. Our results indicate that dominant social status results in a blunted conditioned defeat response and a distinct pattern of 5-HT1A receptor expression, which may contribute to resistance to conditioned defeat. PMID:21362435

  8. Preclinical profile of the mixed 5-HT1A/5-HT2A receptor antagonist S 21,357.

    PubMed

    Griebel, G; Blanchard, D C; Rettori, M C; Guardiola-Lemaître, B; Blanchard, R J

    1996-06-01

    This study evaluated the pharmacological and behavioral effects of S 21,357, a drug with high affinity for both 5-HT1A and 5-HT2A receptors. The drug behaved as antagonist at both 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors, as it prevented the inhibitory effect of lesopitron on the electrical discharge of the dorsal raphé nucleus (DRN) 5-HT neurons and the activity of forskolin-stimulated adenylate cyclase in hippocampal homogenates. In addition, S 21,357 (4 and 128 mg/kg, PO) inhibited 5-HTP-induced head-twitch responses in mice, indicating that it possesses 5-HT2A antagonistic properties. In a test battery designed to assess defensive behaviors of Swiss-Webster mice to the presence of, or situations associated with, a natural threat stimulus (i.e., rat), S 21,357 (0.12-2 mg/kg, IP) reduced contextual defense reactions after the rat was removed, risk assessment activities when the subject was chased, and finally, defensive attack behavior. These behavioral changes are consistent with fear/anxiety reduction. Furthermore, the drug strongly reduced flight reactions in response to the approaching rat. This last finding, taken together with recent results with panic-modulating drugs, suggest that S 21,357 may have potential efficacy against panic attack. Finally, our results suggest that compounds sharing high affinities for both 5-HT1A and 5-HT2A receptors may directly or synergistically increase the range of defensive behaviors affected. PMID:8743616

  9. Testosterone and its metabolites modulate 5HT1A and 5HT1B agonist effects on intermale aggression.

    PubMed

    Simon, N G; Cologer-Clifford, A; Lu, S F; McKenna, S E; Hu, S

    1998-01-01

    Our understanding of the neurochemical and neuroendocrine systems' regulating the display of offensive intermale aggression has progressed substantially over the past twenty years. Pharmacological studies have shown that serotonin, via its action at 5HT1A and/or 5HT1B receptor sites, modulates the display of intermale aggressive behavior and that its effects serve to decrease behavioral expression. Neuroendocrine investigations, in turn, have demonstrated that male-typical aggression is testosterone-dependent and studies of genetic effects, metabolic function and steroid receptor binding have shown that facilitation of behavioral displays can occur via independent androgen-sensitive or estrogen-sensitive pathways. Remarkably, there have been virtually no studies that examined the interrelationship between these facilitative and inhibitory systems. As an initial step toward characterizing the interaction between the systems, studies were conducted that assessed hormonal modulation of serotonin function at 5HT1A and 5HT1B receptor sites. They demonstrated: (1) that the androgenic and estrogenic metabolites of testosterone differentially modulate the ability of systemically administered 8-OH-DPAT (a 5HT1A agonist) and CGS12066B (a 5HT1B agonist) to decrease offensive aggression; and (2) when microinjected into the lateral septum (LS) or medial preoptic area (MPO), the aggression-attenuating effects of 1A and 1B agonists differ regionally and vary with the steroidal milieu. In general, the results suggest that estrogens establish a restrictive environment for attenuation of T-dependent aggression by 8-OH-DPAT and CGS 12066B, while androgens either do not inhibit, or perhaps even facilitate, the ability of 5HT1A and 5HT1B agonists to reduce aggression. Potential mechanisms involved in the production of these steroidal effects are discussed and emerging issues that may impact on efforts to develop an integrative neurobiological model of offensive, intermale aggression

  10. Search of EeV Protons of Galactic Origin

    NASA Astrophysics Data System (ADS)

    Ivanov, Dmitri; Telescope Array Collaboration

    2016-03-01

    Cosmic rays in 1 to 3 EeV range have been shown to have a light, most likely protonic, mass composition. To establish their origin, one can search for anisotropy in their arrival directions: extragalactic protons should be isotropic, but those originating within the Galaxy should be concentrated along the galactic plane, and there should be a shortage of events near the galactic anticenter. Guided by the latest models of the galactic magnetic field, which indicate these effects, we search for the anisotropy in the data collected by the surface detector of the Telescope Array experiment.

  11. EE-2 Fracture Initiation by Simultaneous Wellbore Cooling and Pressurization

    SciTech Connect

    Brown, Donald W.

    1982-03-11

    One of the more significant though generally unrecognized technical achievements of the HDR program has been the demonstration of multiple fracture initiation by simulations wellbore cooling and pressurization. This technique, if applied to the Phase II reservoir, would undoubtedly result in the formation of numerous incipient fractures along the entire EE-2 openhole section. This simple and straightforward method of developing a multiply-fractured HDR reservoir could have a profound influence on the cost of reservoir development, and the economics of the HDR concept in general.

  12. An exclusive event generator for e+e- scan experiments

    NASA Astrophysics Data System (ADS)

    Ping, Rong-Gang

    2014-08-01

    An exclusive event generator is designed for e+e- scan experiments, including initial state radiation effects up to the second order correction. The generator is coded within the framework of BesEvtGen. There are seventy hadronic decay modes available, with effective center-of-mass energy coverage from the two pion mass threshold up to about 6 GeV. The accuracy achieved for the initial state radiation correction reaches the level achieved by the KKMC generator. The uncertainty associated with the calculation of the correction factor to the initial state radiation is dominated by the measurements of the energy-dependent Born cross section.

  13. Experiment 2043: EE-3 Fracture Exploration with Tracer

    SciTech Connect

    Brown, Donald W.; Grigsby, Charles O.; Hendron, Robert H.

    1984-06-19

    Early during Experiment 2042, flow communication was established between the high-pressure injection interval below the liner in EE-3, and the low-pressure fracture zone between the casing and the liner (the latter region being open to the annulus.) As Experiment 2042 progressed, it became apparent that this flow connection was not via a packer leak or a direct bypass around the cemented-in liner. This was inferred from the very slow pressure equilibration behavior of the flow connection under shut-in conditions, implying that the communication was through a relatively high impedance flow path more typical of a fracture connection or connections.

  14. First Study of Rapidity Gaps in e+e- Annihilation

    NASA Astrophysics Data System (ADS)

    Abe, K.; Abe, K.; Abt, I.; Akagi, T.; Allen, N. J.; Ash, W. W.; Aston, D.; Baird, K. G.; Baltay, C.; Band, H. R.; Barakat, M. B.; Baranko, G.; Bardon, O.; Barklow, T.; Bashindzhagyan, G. L.; Bazarko, A. O.; Ben-David, R.; Benvenuti, A. C.; Bilei, G. M.; Bisello, D.; Blaylock, G.; Bogart, J. R.; Bolton, T.; Bower, G. R.; Brau, J. E.; Breidenbach, M.; Bugg, W. M.; Burke, D.; Burnett, T. H.; Burrows, P. N.; Busza, W.; Calcaterra, A.; Caldwell, D. O.; Calloway, D.; Camanzi, B.; Carpinelli, M.; Cassell, R.; Castaldi, R.; Castro, A.; Cavalli-Sforza, M.; Chou, A.; Church, E.; Cohn, H. O.; Coller, J. A.; Cook, V.; Cotton, R.; Cowan, R. F.; Coyne, D. G.; Crawford, G.; D'Oliveira, A.; Damerell, C. J.; Daoudi, M.; de Sangro, R.; de Simone, P.; dell'Orso, R.; Dervan, P. J.; Dima, M.; Dong, D. N.; Du, P. Y.; Dubois, R.; Eisenstein, B. I.; Elia, R.; Etzion, E.; Falciai, D.; Fan, C.; Fero, M. J.; Frey, R.; Furuno, K.; Gillman, T.; Gladding, G.; Gonzalez, S.; Hallewell, G. D.; Hart, E. L.; Hasan, A.; Hasegawa, Y.; Hasuko, K.; Hedges, S.; Hertzbach, S. S.; Hildreth, M. D.; Huber, J.; Huffer, M. E.; Hughes, E. W.; Hwang, H.; Iwasaki, Y.; Jackson, D. J.; Jacques, P.; Jaros, J.; Johnson, A. S.; Johnson, J. R.; Johnson, R. A.; Junk, T.; Kajikawa, R.; Kalelkar, M.; Kang, H. J.; Karliner, I.; Kawahara, H.; Kendall, H. W.; Kim, Y.; King, M. E.; King, R.; Kofler, R. R.; Krishna, N. M.; Kroeger, R. S.; Labs, J. F.; Langston, M.; Lath, A.; Lauber, J. A.; Leith, D. W.; Lia, V.; Liu, M. X.; Liu, X.; Loreti, M.; Lu, A.; Lynch, H. L.; Ma, J.; Mancinelli, G.; Manly, S.; Mantovani, G.; Markiewicz, T. W.; Maruyama, T.; Massetti, R.; Masuda, H.; Mazzucato, E.; McKemey, A. K.; Meadows, B. T.; Messner, R.; Mockett, P. M.; Moffeit, K. C.; Mours, B.; Muller, D.; Nagamine, T.; Narita, S.; Nauenberg, U.; Neal, H.; Nussbaum, M.; Ohnishi, Y.; Osborne, L. S.; Panvini, R. S.; Park, H.; Pavel, T. J.; Peruzzi, I.; Piccolo, M.; Piemontese, L.; Pieroni, E.; Pitts, K. T.; Plano, R. J.; Prepost, R.; Prescott, C. Y.; Punkar, G. D.; Quigley, J.; Ratcliff, B. N.; Reeves, T. W.; Reidy, J.; Rensing, P. E.; Rochester, L. S.; Rowson, P. C.; Russell, J. J.; Saxton, O. H.; Schalk, T.; Schindler, R. H.; Schumm, B. A.; Sen, S.; Serbo, V. V.; Shaevitz, M. H.; Shank, J. T.; Shapiro, G.; Sherden, D. J.; Shmakov, K. D.; Simopoulos, C.; Sinev, N. B.; Smith, S. R.; Snyder, J. A.; Stamer, P.; Steiner, H.; Steiner, R.; Strauss, M. G.; Su, D.; Suekane, F.; Sugiyama, A.; Suzuki, S.; Swartz, M.; Szumilo, A.; Takahashi, T.; Taylor, F. E.; Torrence, E.; Trandafir, A. I.; Turk, J. D.; Usher, T.; Va'Vra, J.; Vannini, C.; Vella, E.; Venuti, J. P.; Verdier, R.; Verdini, P. G.; Wagner, S. R.; Waite, A. P.; Watts, S. J.; Weidemann, A. W.; Weiss, E. R.; Whitaker, J. S.; White, S. L.; Wickens, F. J.; Williams, D. A.; Williams, D. C.; Williams, S. H.; Willocq, S.; Wilson, R. J.; Wisniewski, W. J.; Woods, M.; Word, G. B.; Wyss, J.; Yamamoto, R. K.; Yamartino, J. M.; Yang, X.; Yellin, S. J.; Young, C. C.; Yuta, H.; Zapalac, G.; Zdarko, R. W.; Zeitlin, C.; Zhou, J.

    1996-06-01

    We present the first study of rapidity gaps in e+e- annihilations, using Z0 decays collected by the SLAC Linear Collider Large Detector experiment. Our measured rapidity gap spectra fall exponentially with increasing gap size over five decades, and we observe no anomalous class of events containing large gaps. This supports the interpretation of the large-gap events measured in pp¯ and ep collisions in terms of exchange of color-singlet objects. The presence of heavy flavors or additional jets does not affect these conclusions.

  15. Hypoxia-inducible Factor 1 (HIF-1) Promotes Extracellular Matrix Remodeling under Hypoxic Conditions by Inducing P4HA1, P4HA2, and PLOD2 Expression in Fibroblasts*

    PubMed Central

    Gilkes, Daniele M.; Bajpai, Saumendra; Chaturvedi, Pallavi; Wirtz, Denis; Semenza, Gregg L.

    2013-01-01

    Extracellular matrix (ECM) composition, organization, and compliance provide both architectural and chemical cues that modulate tissue structure and function. ECM produced by stromal fibroblasts plays a key role in breast cancer invasion and metastasis, which are also stimulated by intratumoral hypoxia. Here, we demonstrate that hypoxia-inducible factor 1 (HIF-1) is a critical regulator of ECM remodeling by fibroblasts under hypoxic conditions. HIF-1 activates expression of genes encoding collagen prolyl (P4HA1 and P4HA2) and lysyl (PLOD2) hydroxylases. P4HA1 and P4HA2 are required for collagen deposition, whereas PLOD2 is required for ECM stiffening and collagen fiber alignment. Together P4HA1, P4HA2, and PLOD2 mediate remodeling of ECM composition, alignment, and mechanical properties in response to hypoxia. HIF-1-dependent ECM remodeling by hypoxic fibroblasts induces changes in breast cancer cell morphology, adhesion, and motility that promote invasion and metastasis. PMID:23423382

  16. 31 CFR 351.70 - How are redemption values calculated for book-entry Series EE savings bonds?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... for book-entry Series EE savings bonds? 351.70 Section 351.70 Money and Finance: Treasury Regulations... DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.70 How are redemption values calculated for book-entry Series EE savings bonds? We base current...

  17. 31 CFR 351.60 - How are book-entry Series EE savings bonds purchased and held?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 2 2011-07-01 2011-07-01 false How are book-entry Series EE savings... OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.60 How are book-entry Series EE savings bonds purchased and held? Book-entry bonds must be purchased and held...

  18. 31 CFR 351.65 - What amount of book-entry Series EE savings bonds may I acquire per year?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 2 2011-07-01 2011-07-01 false What amount of book-entry Series EE... DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.65 What amount of book-entry Series EE savings bonds may I acquire per year? The principal amount of...

  19. 31 CFR 351.70 - How are redemption values calculated for book-entry Series EE savings bonds?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... for book-entry Series EE savings bonds? 351.70 Section 351.70 Money and Finance: Treasury Regulations... DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.70 How are redemption values calculated for book-entry Series EE savings bonds? We base current...

  20. 31 CFR 351.63 - How are redemption payments made for my redeemed book-entry Series EE savings bonds?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... my redeemed book-entry Series EE savings bonds? 351.63 Section 351.63 Money and Finance: Treasury... PUBLIC DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.63 How are redemption payments made for my redeemed book-entry Series EE savings bonds? We will...

  1. 31 CFR 351.66 - What book-entry Series EE savings bonds are included in the computation?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 2 2011-07-01 2011-07-01 false What book-entry Series EE savings... DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.66 What book-entry Series EE savings bonds are included in the computation? (a) We include all bonds...

  2. 31 CFR 351.61 - What are the denominations and prices of book-entry Series EE savings bonds?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... of book-entry Series EE savings bonds? 351.61 Section 351.61 Money and Finance: Treasury Regulations... DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.61 What are the denominations and prices of book-entry Series EE savings bonds? Book-entry bonds...

  3. 31 CFR 351.62 - How is payment made for purchases of book-entry Series EE savings bonds?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... book-entry Series EE savings bonds? 351.62 Section 351.62 Money and Finance: Treasury Regulations... DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.62 How is payment made for purchases of book-entry Series EE savings bonds? You may only purchase...

  4. 31 CFR 351.61 - What are the denominations and prices of book-entry Series EE savings bonds?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... of book-entry Series EE savings bonds? 351.61 Section 351.61 Money and Finance: Treasury Regulations... DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.61 What are the denominations and prices of book-entry Series EE savings bonds? Book-entry bonds...

  5. 31 CFR 351.65 - What amount of book-entry Series EE savings bonds may I acquire per year?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false What amount of book-entry Series EE... DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.65 What amount of book-entry Series EE savings bonds may I acquire per year? The principal amount of...

  6. 31 CFR 351.60 - How are book-entry Series EE savings bonds purchased and held?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false How are book-entry Series EE savings... OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.60 How are book-entry Series EE savings bonds purchased and held? Book-entry bonds must be purchased and held...

  7. 31 CFR 351.62 - How is payment made for purchases of book-entry Series EE savings bonds?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... book-entry Series EE savings bonds? 351.62 Section 351.62 Money and Finance: Treasury Regulations... DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.62 How is payment made for purchases of book-entry Series EE savings bonds? You may only purchase...

  8. 31 CFR 351.66 - What book-entry Series EE savings bonds are included in the computation?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false What book-entry Series EE savings... DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.66 What book-entry Series EE savings bonds are included in the computation? (a) We include all bonds...

  9. 31 CFR 351.63 - How are redemption payments made for my redeemed book-entry Series EE savings bonds?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... my redeemed book-entry Series EE savings bonds? 351.63 Section 351.63 Money and Finance: Treasury... PUBLIC DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.63 How are redemption payments made for my redeemed book-entry Series EE savings bonds? We will...

  10. 31 CFR 351.7 - May Series EE savings bonds be called for redemption prior to final maturity?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false May Series EE savings bonds be called... Yields of Series EE Savings Bonds General Provisions § 351.7 May Series EE savings bonds be called for redemption prior to final maturity? The Secretary of the Treasury may not call Series EE bonds for...

  11. A search for point sources of EeV photons

    SciTech Connect

    Aab, A.; Abreu, P.; Andringa, S.; Aglietta, M.; Ahlers, M.; Ahn, E. J.; Al Samarai, I.; Albuquerque, I. F. M.; Allekotte, I.; Allen, J.; Allison, P.; Almela, A.; Castillo, J. Alvarez; Alvarez-Muñiz, J.; Batista, R. Alves; Ambrosio, M.; Aramo, C.; Aminaei, A.; Anchordoqui, L.; Arqueros, F.; Collaboration: Pierre Auger Collaboration102; and others

    2014-07-10

    Measurements of air showers made using the hybrid technique developed with the fluorescence and surface detectors of the Pierre Auger Observatory allow a sensitive search for point sources of EeV photons anywhere in the exposed sky. A multivariate analysis reduces the background of hadronic cosmic rays. The search is sensitive to a declination band from –85° to +20°, in an energy range from 10{sup 17.3} eV to 10{sup 18.5} eV. No photon point source has been detected. An upper limit on the photon flux has been derived for every direction. The mean value of the energy flux limit that results from this, assuming a photon spectral index of –2, is 0.06 eV cm{sup –2} s{sup –1}, and no celestial direction exceeds 0.25 eV cm{sup –2} s{sup –1}. These upper limits constrain scenarios in which EeV cosmic ray protons are emitted by non-transient sources in the Galaxy.

  12. Signal of doubly charged Higgs at e+e- colliders

    NASA Astrophysics Data System (ADS)

    Hue, L. T.; Huong, D. T.; Long, H. N.; Hung, H. T.; Thao, N. H.

    2015-11-01

    The masses and signals of the production of doubly charged Higgses (DCH) in the framework of the supersymmetric reduced minimal 3-3-1 model are investigated. In the DCH sector, we prove that there always exists a region of the parameter space where the mass of the lightest DCH is of the order of O(100) GeV even when all other new particles are very heavy. The lightest DCH mainly decays to two same-sign leptons while the dominant decay channels of the heavy DCHs are those decaying to heavy particles. We analyze each production cross section for e^+e^- ⇒ H^{++} H^{-} as a function of a few kinematic variables, which are useful to discuss the creation of DCHs in e^+e^- colliders as an indicator of new physics beyond the Standard Model. A numerical study shows that the cross sections for creating the lightest DCH can reach values of a few pb. The other two DCHs are too heavy, beyond the observable range of experiments. The lightest DCH may be detected by the International Linear Collider or the Compact Linear Collider by searching for its decay to a same-sign charged lepton pair.

  13. Effect of 5-HT2A and 5-HT2C receptors on temporal discrimination by mice.

    PubMed

    Halberstadt, Adam L; Sindhunata, Ivan S; Scheffers, Kees; Flynn, Aaron D; Sharp, Richard F; Geyer, Mark A; Young, Jared W

    2016-08-01

    Timing deficits are observed in patients with schizophrenia. Serotonergic hallucinogens can also alter the subjective experience of time. Characterizing the mechanism through which the serotonergic system regulates timing will increase our understanding of the linkage between serotonin (5-HT) and schizophrenia, and will provide insight into the mechanism of action of hallucinogens. We investigated whether interval timing in mice is altered by hallucinogens and other 5-HT2 receptor ligands. C57BL/6J mice were trained to perform a discrete-trials temporal discrimination task. In the discrete-trials task, mice were presented with two levers after a variable interval. Responding on lever A was reinforced if the interval was <6.5 s, and responding on lever B was reinforced if the interval was >6.5 s. A 2-parameter logistic function was fitted to the proportional choice for lever B (%B responding), yielding estimates of the indifference point (T50) and the Weber fraction (a measure of timing precision). The 5-HT2A antagonist M100907 increased T50, whereas the 5-HT2C antagonist SB-242,084 reduced T50. The results indicate that 5-HT2A and 5-HT2C receptors have countervailing effects on the speed of the internal pacemaker. The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI; 3 mg/kg IP), a 5-HT2 agonist, flattened the response curve at long stimulus intervals and shifted it to the right, causing both T50 and the Weber fraction to increase. The effect of DOI was antagonized by M100907 (0.03 mg/kg SC) but was unaffected by SB-242,084 (0.1 mg/kg SC). Similar to DOI, the selective 5-HT2A agonist 25CN-NBOH (6 mg/kg SC) reduced %B responding at long stimulus intervals, and increased T50 and the Weber fraction. These results demonstrate that hallucinogens alter temporal perception in mice, effects that are mediated by the 5-HT2A receptor. It appears that 5-HT regulates temporal perception, suggesting that altered serotonergic signaling may contribute to the timing deficits

  14. Opposing actions of 5HT1A and 5HT2-like serotonin receptors on modulations of the electric signal waveform in the electric fish Brachyhypopomus pinnicaudatus

    PubMed Central

    Allee, Susan J.; Markham, Michael R.; Salazar, Vielka L.; Stoddard, Philip K.

    2008-01-01

    Serotonin (5-HT) is an indirect modulator of the electric organ discharge (EOD) in the weakly electric gymnotiform fish, Brachyhypopomus pinnicaudatus. Injections of 5-HT enhance EOD waveform “masculinity”, increasing both waveform amplitude and the duration of the second phase. This study investigated the pharmacological identity of 5-HT receptors that regulate the electric waveform and their effects on EOD amplitude and duration. We present evidence that two sets of serotonin receptors modulate the EOD in opposite directions. We found that the 5HT1AR agonist 8-OH-DPAT diminishes EOD duration and amplitude while the 5HT1AR antagonist WAY100635 increases these parameters. In contrast, the 5HT2R agonist α-Me-5-HT increases EOD amplitude but not duration, yet 5-HT-induced increases in EOD duration can be inhibited by blocking 5HT2A/2C-like receptors with ketanserin. These results show that 5-HT exerts bi-directional control of EOD modulations in B. pinnicaudatus via action at receptors similar to mammalian 5HT1A and 5HT2 receptors. The discordant amplitude and duration response suggests separate mechanisms for modulating these waveform parameters. PMID:18206154

  15. Long-term Stress with Hyperglucocorticoidemia-induced Hepatic Steatosis with VLDL Overproduction Is Dependent on both 5-HT2 Receptor and 5-HT Synthesis in Liver

    PubMed Central

    Fu, Jihua; Ma, Shaoxin; Li, Xin; An, Shanshan; Li, Tao; Guo, Keke; Lin, Min; Qu, Wei; Wang, Shanshan; Dong, Xinyue; Han, Xiaoyu; Fu, Ting; Huang, Xinping; Wang, Tianying; He, Siyu

    2016-01-01

    Hepatic triglycerides production and adipose lipolysis are pivotal for long-term stress (LTS) or hyperglucocorticoidemia-induced insulin resistance. 5-hydroxytryptamine (5-HT) has been demonstrated to induce hepatic lipid metabolic abnormality by activating mammalian target of rapamycin (mTOR). In present study, we explored whether 5-HT is involved in LTS effects in liver using restraint stress-exposed rats and cultured primary rat hepatocytes and HepG2 cells. LTS with hyperglucocorticoidemia induced hepatic 5-HT synthetic increase with tryptophan hydroxylase 1 (Tph1) up-regulation, and 5-HT2 receptor (5-HT2R, including 5-HT2A, 2B receptor) up-regulation in liver and visceral adipose, as well as hepatic mTOR activation with triglycerides and VLDL overproduction with steatosis, and visceral adipose lipolytic increase with high blood free fatty acids (FFAs) level. 5-HT exposure exhibited LTS-like effects in both tissues, and both LTS and 5-HT effects could be abolished significantly by blocking 5-HT2R. In HepG2 cells dexamethasone or palmitate-induced mTOR activation with triglycerides and VLDL overproduction were accompanied by up-regulations of 5-HT synthesis and 5-HT2R, which were significantly abolished by gene silencing Tph1 or 5-HT2R and were almost fully abolished by co-silencing of both, especially on VLDL overproduction. Chemical inhibition of Tph1 or/and 5-HT2R in both hepatocytes exhibited similar abolishment with genetic inhibition on dexamethason-induced effects. 5-HT-stimulated effects in both hepatocytes were fully abolished by blocking 5-HT2R, while 5-HT itself also up-regulated 5-HT2R. In conclusion, up-regulated hepatic 5-HT synthesis and 5-HT2R induced by both glucocorticoid and FFAs are crucial for LTS-induced hepatic steatosis with VLDL overproduction, while 5-HT by acting on 5-HT2R mediates mTOR activation in liver. PMID:26884719

  16. Evidence for 5-HT1-like receptor-mediated vasoconstriction in human pulmonary artery.

    PubMed Central

    MacLean, M. R.; Clayton, R. A.; Templeton, A. G.; Morecroft, I.

    1996-01-01

    1. The 5-hydroxytryptamine (5-HT) receptors mediating contraction of human isolated pulmonary artery rings were investigated. Responses to the agonists 5-carboximidotryptamine (5-CT, non-selective 5-HT1 agonist), sumatriptan (5-HT1D-like receptor agonist), 5-HT and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 5-HT1A receptor agonist) were studied. Responses to 5-HT and sumatriptan in the presence of the antagonists, methiothepin (non-selective 5-HT1+2-receptor antagonist), ketanserin (5-HT2A receptor antagonist) and the novel antagonist, GR55562 (5-HT1D receptor antagonist) were also studied. 2. All agonists contracted human pulmonary artery ring preparations in the following order of potency 5-CT > 5-HT = sumatriptan > 8-OH-DPAT. Maximum responses to 5-HT, 5-CT and sumatriptan were not significantly different. 3. Methiothepin 1 nM and 10 nM, but not 0.1 nM reduced the maximum contractile responses to 5-HT but did not alter tissue sensitivity to 5-HT. Methiothepin 0.1 nM, 1 nM and 10 nM had a similar effect on responses to sumatriptan. 4. The 5-HT2A receptor antagonist ketanserin (10 nM, 100 nM and 1 microM) also reduced the maximum contractile response to both 5-HT and sumatriptan without affecting tissue sensitivity to these agonists. 5. The novel 5-HT1D receptor antagonist, GR55562, inhibited responses to 5-HT and sumatriptan in a true competitive fashion. 6. The results suggest that the human pulmonary artery has a functional population of 5-HT1D-like receptors which are involved in the contractile response to 5-HT. PMID:8886409

  17. Functional characterization of 5-HT1D autoreceptors on the modulation of 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex.

    PubMed Central

    el Mansari, M.; Blier, P.

    1996-01-01

    1. The aims of the present study were (i) to characterize further the pharmacology of 5-HT1D autoreceptors modulating 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex; (ii) to determine whether 5-HT1D receptors in the mesencephalic raphe are located on 5-HT neurones; (iii) to determine whether 5-HT1D autoreceptors are coupled to G proteins; and (iv) to assess their sensitivity following long-term 5-HT reuptake blockade and inhibition of type-A monoamine oxidase. 2. In mesencephalic raphe, hippocampus and frontal cortex slices, the 5-HT1D/1B receptor agonist, sumatriptan and the 5-HT1 receptor agonist, 5-methoxytryptamine (5-MeOT) but not the 5-HT1B receptor agonist, CP93129, inhibited electrically the evoked release of [3H]-5-HT in a concentration-dependent manner. This effect was antagonized by the 5-HT1D/1B receptor antagonist GR127935 in the three structures, but not by the 5-HT1A receptor antagonist, (+)-WAY100635 in mesencephalic raphe slices. These results confirm the presence of functional 5-HT1D autoreceptors controlling 5-HT release within the mesencephalic raphe as well as in terminal regions. 3. The inhibitory effect of sumatriptan on K(+)-evoked release of [3H]-5-HT was not reduced by the addition of the Na+ channel blocker, tetrodotoxin to the superfusion medium, suggesting that these 5-HT1D receptors in the mesencephalic raphe are located on 5-HT neurones and may be considered autoreceptors. 4. The in vitro treatment with the alkylating agent N-ethylmaleimide (NEM) was used to determine whether these 5-HT1D autoreceptors are coupled to G proteins. The inhibitory effect of sumatriptan on electrically evoked release of [3H]-5-HT was attenuated in NEM-pretreated slices from mesencephalic raphe, hippocampus and frontal cortex, indicating that the 5-HT1D autoreceptors activated by sumatriptan are coupled to G proteins in these three structures. Taken together with our previous results, this suggests that, in addition to the 5

  18. A history of atmospheric tritium gas (HT) 1950 2002

    NASA Astrophysics Data System (ADS)

    Happell, James D.; Östlund, Göte; Mason, Allen S.

    2004-07-01

    Data collected as a part of this study from 1968 2002 and data from other studies from 1950 1967 show that the maximum atmospheric concentration of tritium gas (HT) occurred in the early to mid 1970s, which corresponds to the era of frequent, large underground nuclear tests. These data clearly show that the major source of HT to the atmosphere between 1962 and the early 1990s was the underground testing of nuclear weapons. Samples collected at both our Alaska and Miami stations clearly show marked increases in the autumn of each year between 1970 and 1975 that were associated with large underground explosions conducted by the former Soviet Union at the Novaya Zemlya test site. Other significant sources of HT include accidental releases of HT used in the manufacture and maintenance of nuclear weapons stockpiles, the reprocessing of spent nuclear fuel rods and emissions from nuclear power plants. Since the early 1990s, when underground testing largely ceased, emission estimates from our data agree very well with United Nations estimates of worldwide releases from fuel reprocessing and nuclear power plants, suggesting that the nuclear power industry is now the major source of HT to the atmosphere.

  19. Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT(1A) or 5-HT(1B) receptor knockout mice.

    PubMed

    Ase, A R; Reader, T A; Hen, R; Riad, M; Descarries, L

    2000-12-01

    Measurements of serotonin (5-HT), dopamine (DA), and noradrenaline, and of 5-HT and DA metabolites, were obtained by HPLC from 16 brain regions and the spinal cord of 5-HT(1A) or 5-HT(1B) knockout and wild-type mice of the 129/Sv strain. In 5-HT(1A) knockouts, 5-HT concentrations were unchanged throughout, but levels of 5-HT metabolites were higher than those of the wild type in dorsal/medial raphe nuclei, olfactory bulb, substantia nigra, and locus coeruleus. This was taken as an indication of increased 5-HT turnover, reflecting an augmented basal activity of midbrain raphe neurons and consequent increase in their somatodendritic and axon terminal release of 5-HT. It provided a likely explanation for the increased anxious-like behavior observed in 5-HT(1A) knockout mice. Concomitant increases in DA content and/or DA turnover were interpreted as the result of a disinhibition of DA, whereas increases in noradrenaline concentration in some territories of projection of the locus coeruleus could reflect a diminished activity of its neurons. In 5-HT(1B) knockouts, 5-HT concentrations were lower than those of the wild type in nucleus accumbens, locus coeruleus, spinal cord, and probably also several other territories of 5-HT innervation. A decrease in DA, associated with increased DA turnover, was measured in nucleus accumbens. These changes in 5-HT and DA metabolism were consistent with the increased aggressiveness and the supersensitivity to cocaine reported in 5-HT(1B) knockout mice. Thus, markedly different alterations in CNS monoamine metabolism may contribute to the opposite behavioral phenotypes of these two knockouts. PMID:11080193

  20. The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants.

    PubMed Central

    Gerald, C; Adham, N; Kao, H T; Olsen, M A; Laz, T M; Schechter, L E; Bard, J A; Vaysse, P J; Hartig, P R; Branchek, T A

    1995-01-01

    Molecular cloning efforts have provided primary amino acid sequence and signal transduction data for a large collection of serotonin receptor subtypes. These include five 5-HT1-like receptors, three 5-HT2 receptors, one 5-HT3 receptor, two 5-HT5 receptors, one 5-HT6 receptor and one 5-HT7 receptor. Molecular biological information on the 5-HT4 receptor is notably absent from this list. We now report the cloning of the pharmacologically defined 5-HT4 receptor. Using degenerate oligonucleotide primers, we identified a rat brain PCR fragment which encoded a '5-HT receptor-like' amino acid sequence. The corresponding full length cDNA was isolated from a rat brain cDNA library. Transiently expressed in COS-7 cells, this receptor stimulates adenylyl cyclase activity and is sensitive to the benzamide derivative cisapride. The response is also blocked by ICS-205930. Interestingly, we isolated two splice variants of the receptor, 5-HT4L and 5-HT4S, differing in the length and sequence of their C-termini. In rat brain, the 5-HT4S transcripts are restricted to the striatum, but the 5-HT4L transcripts are expressed throughout the brain, except in the cerebellum where it was barely detectable. In peripheral tissues, differential expression was also observed in the atrium of the heart where only the 5-HT4S isoform was detectable. Images PMID:7796807

  1. Well completion and operations for MHF of Fenton Hill HDR Well EE-2

    SciTech Connect

    Dreesen, D.S.; Nicholson, R.W.

    1985-01-01

    Previous attempts to connect Fenton Hill Hot Dry Rock Geothermal Site Wells EE-2 and EE-3 by pumping 150 thousand to 1.3 million gallons of water had not achieved a detectable hydraulic fracture connection. Therefore, preparations were made to conduct, in December 1983, a 4 to 6 million gallon, 50 BPM water injection in EE-2. The objective was to enlarge the previously created reservoir in EE-2 using massive hydraulic facturing (MHF). The planning, preparations, operations and results of the MHF are presented here. 4 refs., 7 figs.

  2. The new holism: P4 systems medicine and the medicalization of health and life itself.

    PubMed

    Vogt, Henrik; Hofmann, Bjørn; Getz, Linn

    2016-06-01

    The emerging concept of systems medicine (or 'P4 medicine'-predictive, preventive, personalized and participatory) is at the vanguard of the post-genomic movement towards 'precision medicine'. It is the medical application of systems biology, the biological study of wholes. Of particular interest, P4 systems medicine is currently promised as a revolutionary new biomedical approach that is holistic rather than reductionist. This article analyzes its concept of holism, both with regard to methods and conceptualization of health and disease. Rather than representing a medical holism associated with basic humanistic ideas, we find a technoscientific holism resulting from altered technological and theoretical circumstances in biology. We argue that this holism, which is aimed at disease prevention and health optimization, points towards an expanded form of medicalization, which we call 'holistic medicalization': Each person's whole life process is defined in biomedical, technoscientific terms as quantifiable and controllable and underlain a regime of medical control that is holistic in that it is all-encompassing. It is directed at all levels of functioning, from the molecular to the social, continual throughout life and aimed at managing the whole continuum from cure of disease to optimization of health. We argue that this medicalization is a very concrete materialization of a broader trend in medicine and society, which we call 'the medicalization of health and life itself'. We explicate this holistic medicalization, discuss potential harms and conclude by calling for preventive measures aimed at avoiding eventual harmful effects of overmedicalization in systems medicine (quaternary prevention). PMID:26821201

  3. Postmodification of PS-b-P4VP diblock copolymer membranes by ARGET ATRP.

    PubMed

    Keskin, Damla; Clodt, Juliana I; Hahn, Janina; Abetz, Volker; Filiz, Volkan

    2014-07-29

    The surfaces of polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) diblock copolymer membranes were modified in order to obtain polymer brushes by using surface-initiated activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). Isoporous membranes were prepared by the combination of self-assembly of PS-b-P4VP diblock copolymers and the nonsolvent induced phase separation process, also known as "phase inversion". In order to allow further functionalization, the membranes were modified with an ATRP initiator, 2-bromoisobutyryl bromide (BIBB). Therefore, the mussel-inspired poly(dopamine) coating was used to attach BIBB on the membranes surface. In the next step the coated membranes were postmodified by using surface-initiated ARGET ATRP with the hydrophilic monomer 2-hydroxyethyl methacrylate (HEMA). HEMA as a hydrophilic methacrylate was chosen for the modification in order to enhance the membrane characteristics and to obtain a surface with antifouling properties. The surface-initiated ARGET ATRP reaction was carried out using different reaction times and environments. PHEMA could successfully incorporate on the membrane surface as confirmed by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), (1)H nuclear magnetic resonance spectroscopy ((1)H NMR), scanning electron microscopy (SEM), and contact angle measurements. Furthermore, stability tests against heat and solvents were performed, and water flux was measured for the raw and modified membranes. Stability against heat and hydrophilicity could be increased with this type of modification for diblock copolymer membranes. PMID:24948370

  4. Mineralization of dentin induced by treatment with bioactive glass S53P4 in vitro.

    PubMed

    Forsback, Ari-Pekka; Areva, Sami; Salonen, Jukka I

    2004-02-01

    Dentin hypersensitivity can be managed to occlude dentin tubules, but none of the agents used are components of natural dentin. Using a calcium phosphate precipitation (CPP) method, dentin tubules can be occluded with a calcium phosphate (CaP) layer similar to the major inorganic component of dentin. The CPP method utilizes acidic pH conditions, such as etching of dentin, over the course of several dental treatments. A gentler method can be used to produce a CaP layer on the surface of dentin. By treating with bioactive glass S53P4 (BAG), or regular commercial glass (CG), mineralization occurs in physiologically neutral solutions such as simulated body fluid (SBF) and remineralization solution (RMS). After a short period of immersion, silica is dissolved from both types of glass, but the amount of silica released is much greater from BAG than from CG. The dissolved silica is adsorbed on the surface of dentin during the pretreatment procedure and enhances the mineralization of dentin in SBF. After 14 days' mineralization the dentin is fully covered by the CaP layer, but after 14 days' immersion in RMS decalcification of the dentin occurs. Pretreatment with BAG decreases the degree of decalcification of dentin during the mineralization process. These findings suggest that bioactive glass S53P4 can be used as a therapeutic material for mineralization of dentin and its tubules in a physiological environment. PMID:15124778

  5. Recent Progress of HT-7U Superconducting Tokamak

    NASA Astrophysics Data System (ADS)

    Weng, Pei-de

    2002-12-01

    HT-7U is a superconducting tokamak, which is being constructed in Institute of Plasma Physics, Chinese Academy of Sciences. The mission of the HT-7U project is to develop a scientific and engineering basis of the steady state operation of advanced tokamak. The engineering design of the device has been optimized. The R&D program is going on. Short samples of the conductor and a CS model coil were tested. All the TF and PF coils will be manufactured and tested in Institute of Plasma Physics. Therefore, a 600-meter long jacketing line for cable-in-conduit conductors along with two winding machines, a set of VPI equipment and a test facility for the TF and PF coils are ready in ASIPP now. In this paper, the recent progress of the HT-7U is described.

  6. Dorsal Raphe Neurons Signal Reward through 5-HT and Glutamate

    PubMed Central

    Liu, Zhixiang; Zhou, Jingfeng; Li, Yi; Hu, Fei; Lu, Yao; Ma, Ming; Feng, Qiru; Zhang, Ju-en; Wang, Daqing; Zeng, Jiawei; Bao, Junhong; Kim, Ji-Young; Chen, Zhou-Feng; Mestikawy, Salah El; Luo, Minmin

    2015-01-01

    Summary The dorsal raphe nucleus (DRN) in the midbrain is a key center for serotonin (5-hydroxytryptamine; 5-HT) expressing neurons. Serotonergic neurons in the DRN have been theorized to encode punishment by opposing the reward signaling of dopamine neurons. Here, we show that DRN neurons encode reward, but not punishment, through 5-HT and glutamate. Optogenetic stimulation of DRN Pet-1 neurons reinforces mice to explore the stimulation-coupled spatial region, shifts sucrose preference, drives optical self-stimulation, and directs sensory discrimination learning. DRN Pet-1 neurons increase their firing activity during reward tasks and this activation can be used to rapidly change neuronal activity patterns in the cortnassociated with 5-HT, they also release glutamate, and both neurotransmitters contribute to reward signaling. These experiments demonstrate the ability of DRN neurons to organize reward behaviors and might provide insights into the underlying mechanisms of learning facilitation and anhedonia treatment. PMID:24656254

  7. A SEARCH FOR POINT SOURCES OF EeV NEUTRONS

    SciTech Connect

    Abreu, P.; Andringa, S.; Aglietta, M.; Ahlers, M.; Ahn, E. J.; Albuquerque, I. F. M.; Allard, D.; Allekotte, I.; Allen, J.; Allison, P.; Almela, A.; Alvarez Castillo, J.; Alvarez-Muniz, J.; Alves Batista, R.; Ambrosio, M.; Aramo, C.; Aminaei, A.; Anchordoqui, L.; Antici'c, T.; Arganda, E.; Collaboration: Pierre Auger Collaboration; and others

    2012-12-01

    A thorough search of the sky exposed at the Pierre Auger Cosmic Ray Observatory reveals no statistically significant excess of events in any small solid angle that would be indicative of a flux of neutral particles from a discrete source. The search covers from -90 Degree-Sign to +15 Degree-Sign in declination using four different energy ranges above 1 EeV (10{sup 18} eV). The method used in this search is more sensitive to neutrons than to photons. The upper limit on a neutron flux is derived for a dense grid of directions for each of the four energy ranges. These results constrain scenarios for the production of ultrahigh energy cosmic rays in the Galaxy.

  8. Collins Effect from Polarized SIDIS and e+e- Data

    SciTech Connect

    Prokudin, A.; Tuerk, C.

    2007-06-13

    The recent data on the transverse single spin asymmetry A{sub UT}{sup sin({phi}{sub h}+{phi}{sub S})} from HERMES and COMPASS Collaborations are analysed within LO parton model with unintegrated parton distribution and fragmentation functions. A fit of SIDIS data from HERMES Collaboration is performed leading to the extraction of favoured and unfavoured Collins fragmentation functions. A very good description of COMPASS data is obtained. BELLE e+e- data are shown to be compatible with our estimates based on the extracted Collins fragmentation functions. Predictions for A{sub UT}{sup sin({phi}{sub h}+{phi}{sub S})} asymmetries at JLab and COMPASS operating on a proton target are given.

  9. TMPyP4 promotes cancer cell migration at low doses, but induces cell death at high doses

    PubMed Central

    Zheng, Xiao-Hui; Nie, Xin; Liu, Hai-Ying; Fang, Yi-Ming; Zhao, Yong; Xia, Li-Xin

    2016-01-01

    TMPyP4 is widely considered as a potential photosensitizer in photodynamic therapy and a G-quadruplex stabilizer for telomerase-based cancer therapeutics. However, its biological effects including a possible adverse-effect are poorly understood. In this study, whole genome RNA-seq analysis was used to explore the alteration in gene expression induced by TMPyP4. Unexpectedly, we find that 27.67% of changed genes were functionally related to cell adhesion. Experimental evidences from cell adhesion assay, scratch-wound and transwell assay indicate that TMPyP4 at conventional doses (≤0.5 μM) increases cell-matrix adhesion and promotes the migration of tumor cells. In contrast, a high dose of TMPyP4 (≥2 μM) inhibits cell proliferation and induces cell death. The unintended “side-effect” of TMPyP4 on promoting cell migration suggests that a relative high dose of TMPyP4 is preferred for therapeutic purpose. These findings contribute to better understanding of biological effects induced by TMPyP4 and provide a new insight into the complexity and implication for TMPyP4 based cancer therapy. PMID:27221067

  10. TMPyP4 promotes cancer cell migration at low doses, but induces cell death at high doses.

    PubMed

    Zheng, Xiao-Hui; Nie, Xin; Liu, Hai-Ying; Fang, Yi-Ming; Zhao, Yong; Xia, Li-Xin

    2016-01-01

    TMPyP4 is widely considered as a potential photosensitizer in photodynamic therapy and a G-quadruplex stabilizer for telomerase-based cancer therapeutics. However, its biological effects including a possible adverse-effect are poorly understood. In this study, whole genome RNA-seq analysis was used to explore the alteration in gene expression induced by TMPyP4. Unexpectedly, we find that 27.67% of changed genes were functionally related to cell adhesion. Experimental evidences from cell adhesion assay, scratch-wound and transwell assay indicate that TMPyP4 at conventional doses (≤0.5 μM) increases cell-matrix adhesion and promotes the migration of tumor cells. In contrast, a high dose of TMPyP4 (≥2 μM) inhibits cell proliferation and induces cell death. The unintended "side-effect" of TMPyP4 on promoting cell migration suggests that a relative high dose of TMPyP4 is preferred for therapeutic purpose. These findings contribute to better understanding of biological effects induced by TMPyP4 and provide a new insight into the complexity and implication for TMPyP4 based cancer therapy. PMID:27221067

  11. Comment on "Collinear Segment Detection Using HT Neighborhoods".

    PubMed

    Rahmdel, Payam S; Shi, Daming; Comley, Richard

    2014-02-01

    A novel application of the Hough transform (HT) neighborhood approach to collinear segment detection was proposed in [1]. It, however, suffered from one major weakness in that it could not provide an effective solution to the case of segment intersection. This paper analyzes a vital prerequisite step, disturbance elimination in the Hough space, and shows why, this method alone, is incapable of distinguishing the true segment endpoints. To address the problem, a unique HT butterfly separation method is proposed in this correspondence, as an essential complement to the above publication. PMID:26270930

  12. Models for the positive latitude e{-}e{+} annihilation feature

    NASA Astrophysics Data System (ADS)

    von Ballmoos, P.; Guessoum, N.; Jean, P.; Knödlseder, J.

    2003-01-01

    Galactic maps of e-e+ annihilation radiation based on CGRO-OSSE, SMM and TGRS data have indicated the existence of an extended component at positive Galactic latitudes (l~ -2 deg, b~ 7 deg), in addition to the emission from the galactic bulge and disk (Purcell et al. \\cite{Purcell97}; Cheng et al. \\cite{Cheng97}; Milne et al. \\cite{Milne00}; Milne et al. \\cite{Milne01}). This Positive Latitude Enhancement (PLE) was first attributed to an ``annihilation fountain" in the Galactic center (Dermer & Skibo \\cite{Dermer97}) but has since been the object of several models. After discussing the observational evidence for the PLE, we investigate various models for the PLE: besides the scenarios proposed in the literature, we have introduced a number of models requiring relatively modest positron rates due to a local origin of the e-e+ emission (local galactic-, solar system-, earth- and spacecraft-environment origins). The various scenarios for the PLE are constrained in the light of the latest OSSE-SMM-TGRS data analysis results: we have looked at the possible positron production mechanisms as well as the annihilation conditions in the different physical environments (temperature and dust grain content) proposed for the positive-latitude region. By constraining those parameters, based on the recent limits for the line width and the positronium fraction, we found that some of the models can essentially be discarded. A number of other scenarios will have to await further measurements and maps, such as will be possible with INTEGRAL's SPI and IBIS instruments. We present a table/checklist of model-falsification criteria.

  13. GR-127935-sensitive mechanism mediating hypotension in anesthetized rats: are 5-HT5B receptors involved?

    PubMed

    Sánchez-Maldonado, Carolina; López-Sánchez, Pedro; Anguiano-Robledo, Liliana; Leopoldo, Marcello; Lacivita, Enza; Terrón, José A

    2015-04-01

    The 5-HT1B/1D receptor antagonist, GR-127935, inhibits hypotensive responses produced by the 5-HT1A, 5-HT1B/1D and 5-HT7 receptor agonist, and 5-HT5A/5B receptor ligand, 5-carboxamidotryptamine (5-CT), in rats. This work further characterized the above mechanism using more selective 5-HT1B and 5-HT1D receptor antagonists. Also, expression of 5-HT5A and 5-HT5B receptor mRNAs in blood vessels was searched by reverse transcription polymerase chain reaction. Decreases in diastolic blood pressure induced by 5-CT (0.001-10 μg/kg, intravenously) were analyzed in anesthetized rats that had received intravenous vehicle (1 mL/kg), SB-224289 (5-HT1B antagonist; 0.3 and 1.0 mg/kg), BRL15572 (5-HT1D antagonist; 0.3 and 1.0 mg/kg), SB-224289 + BRL15572 (0.3 mg/kg, each), or SB-224289 + BRL15572 (0.3 mg/kg, each) + GR-127935 (1 mg/kg). Because only the latter treatment inhibited 5-CT-induced hypotension, suggestive of a mechanism unrelated to 5-HT1B/1D receptors, the effects of antagonists/ligands at 5-HT5A (SB-699551, 1 mg/kg), 5-HT6 (SB-399885, 1 mg/kg), and 5-HT1B/1D/5A/5B/7 receptors (ergotamine, 0.1 mg/kg) on 5-CT-induced hypotension were tested. Interestingly, only ergotamine blocked 5-CT-induced responses; this effect closely paralleled that of SB-224289 + BRL-15572 + GR-127935. Neither did ergotamine nor GR-127935 inhibit hypotensive responses induced by the 5-HT7 receptor agonist, LP-44. Faint but clear bands corresponding to 5-HT5A and 5-HT5B receptor mRNAs in aorta and mesenteric arteries were detected. Results suggest that the GR-127935-sensitive mechanism mediating hypotension in rats is unrelated to 5-HT1B, 5-HT1D, 5-HT5A, 5-HT6, and 5-HT7 receptors. This mechanism, however, resembles putative 5-HT5B receptors. PMID:25502305

  14. Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity

    PubMed Central

    Anastasio, N C; Liu, S; Maili, L; Swinford, S E; Lane, S D; Fox, R G; Hamon, S C; Nielsen, D A; Cunningham, K A; Moeller, F G

    2014-01-01

    Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses (‘cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence. PMID:24618688

  15. 5-HT2A receptor activation is necessary for CO2-induced arousal.

    PubMed

    Buchanan, Gordon F; Smith, Haleigh R; MacAskill, Amanda; Richerson, George B

    2015-07-01

    Hypercapnia-induced arousal from sleep is an important protective mechanism pertinent to a number of diseases. Most notably among these are the sudden infant death syndrome, obstructive sleep apnea and sudden unexpected death in epilepsy. Serotonin (5-HT) plays a significant role in hypercapnia-induced arousal. The mechanism of 5-HT's role in this protective response is unknown. Here we sought to identify the specific 5-HT receptor subtype(s) involved in this response. Wild-type mice were pretreated with antagonists against 5-HT receptor subtypes, as well as antagonists against adrenergic, cholinergic, histaminergic, dopaminergic, and orexinergic receptors before challenge with inspired CO2 or hypoxia. Antagonists of 5-HT(2A) receptors dose-dependently blocked CO2-induced arousal. The 5-HT(2C) receptor antagonist, RS-102221, and the 5-HT1A receptor agonist, 8-OH-DPAT, attenuated but did not completely block CO2-induced arousal. Blockade of non-5-HT receptors did not affect CO2-induced arousal. None of these drugs had any effect on hypoxia-induced arousal. 5-HT2 receptor agonists were given to mice in which 5-HT neurons had been genetically eliminated during embryonic life (Lmx1b(f/f/p)) and which are known to lack CO2-induced arousal. Application of agonists to 5-HT(2A), but not 5-HT(2C), receptors, dose-dependently restored CO2-induced arousal in these mice. These data identify the 5-HT(2A) receptor as an important mediator of CO2-induced arousal and suggest that, while 5-HT neurons can be independently activated to drive CO2-induced arousal, in the absence of 5-HT neurons and endogenous 5-HT, 5-HT receptor activation can act in a permissive fashion to facilitate CO2-induced arousal via another as yet unidentified chemosensor system. PMID:25925320

  16. 5-HT2A receptor activation is necessary for CO2-induced arousal

    PubMed Central

    Smith, Haleigh R.; MacAskill, Amanda; Richerson, George B.

    2015-01-01

    Hypercapnia-induced arousal from sleep is an important protective mechanism pertinent to a number of diseases. Most notably among these are the sudden infant death syndrome, obstructive sleep apnea and sudden unexpected death in epilepsy. Serotonin (5-HT) plays a significant role in hypercapnia-induced arousal. The mechanism of 5-HT's role in this protective response is unknown. Here we sought to identify the specific 5-HT receptor subtype(s) involved in this response. Wild-type mice were pretreated with antagonists against 5-HT receptor subtypes, as well as antagonists against adrenergic, cholinergic, histaminergic, dopaminergic, and orexinergic receptors before challenge with inspired CO2 or hypoxia. Antagonists of 5-HT2A receptors dose-dependently blocked CO2-induced arousal. The 5-HT2C receptor antagonist, RS-102221, and the 5-HT1A receptor agonist, 8-OH-DPAT, attenuated but did not completely block CO2-induced arousal. Blockade of non-5-HT receptors did not affect CO2-induced arousal. None of these drugs had any effect on hypoxia-induced arousal. 5-HT2 receptor agonists were given to mice in which 5-HT neurons had been genetically eliminated during embryonic life (Lmx1bf/f/p) and which are known to lack CO2-induced arousal. Application of agonists to 5-HT2A, but not 5-HT2C, receptors, dose-dependently restored CO2-induced arousal in these mice. These data identify the 5-HT2A receptor as an important mediator of CO2-induced arousal and suggest that, while 5-HT neurons can be independently activated to drive CO2-induced arousal, in the absence of 5-HT neurons and endogenous 5-HT, 5-HT receptor activation can act in a permissive fashion to facilitate CO2-induced arousal via another as yet unidentified chemosensor system. PMID:25925320

  17. Asymmetry in the triplet 3p-4s Mg lines in cool DZ white dwarfs

    NASA Astrophysics Data System (ADS)

    Allard, N. F.; Leininger, T.; Gadéa, F. X.; Brousseau-Couture, V.; Dufour, P.

    2016-04-01

    The purpose of the present work is to make an exhaustive study of the line shape of the triplet 3p-4s Mg line (Mgb triplet), which is perturbed by He in the extreme physical conditions found in the cool atmosphere of DZ white dwarfs. This study is undertaken by inferring both a unified theory of spectral line broadening and ab initio potential energies. Cool white dwarfs require a specific treatment for line broadening owing to the high helium densities that are involved. Beyond the conventional symmetrical Lorentzian core at low density, we show that the line profiles are asymmetrical and have significant additional contributions on the short wavelength side. This blue asymmetry is a consequence of low maxima in the corresponding Mg-He potential energy difference curves at short and intermediate internuclear distances. The new profiles are shown to provide a good fit to an SDSS (Sloan Digital Sky Survey) observation.

  18. Hippocampal 5-HT1A Receptor and Spatial Learning and Memory

    PubMed Central

    Glikmann-Johnston, Yifat; Saling, Michael M.; Reutens, David C.; Stout, Julie C.

    2015-01-01

    Spatial cognition is fundamental for survival in the topographically complex environments inhabited by humans and other animals. The hippocampus, which has a central role in spatial cognition, is characterized by high concentration of serotonin (5-hydroxytryptamine; 5-HT) receptor binding sites, particularly of the 1A receptor (5-HT1A) subtype. This review highlights converging evidence for the role of hippocampal 5-HT1A receptors in spatial learning and memory. We consider studies showing that activation or blockade of the 5-HT1A receptors using agonists or antagonists, respectively, lead to changes in spatial learning and memory. For example, pharmacological manipulation to induce 5-HT release, or to block 5-HT uptake, have indicated that increased extracellular 5-HT concentrations maintain or improve memory performance. In contrast, reduced levels of 5-HT have been shown to impair spatial memory. Furthermore, the lack of 5-HT1A receptor subtype in single gene knockout mice is specifically associated with spatial memory impairments. These findings, along with evidence from recent cognitive imaging studies using positron emission tomography (PET) with 5-HT1A receptor ligands, and studies of individual genetic variance in 5-HT1A receptor availability, strongly suggests that 5-HT, mediated by the 5-HT1A receptor subtype, plays a key role in spatial learning and memory. PMID:26696889

  19. Physiologically identified 5-HT2-like receptors at the crayfish neuromuscular junction.

    PubMed

    Tabor, Jami N; Cooper, Robin L

    2002-04-01

    The model synaptic preparation of the crayfish opener neuromuscular junction is known to be responsive to exogenous application of 5-HT. The primary effect of 5-HT is an enhancement of vesicular release from the presynaptic motor nerve terminal. 5-HT is known to act through an IP(3) cascade which suggests the presence of a 5-HT(2) receptor subtype; however, this is based on vertebrate 5-HT receptor classification. We examined this possibility by using a selective agonist and two antagonists of the vertebrate 5-HT(2) receptor subtypes. The antagonist ketanserin and spiperone reduce the responsiveness of 5-HT in a dose-dependent manner. The broad 5-HT(2) receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT) enhances synaptic transmission, in a concentration-dependent manner, but it is not as potent as 5-HT. These results support the notion that a 5-HT(2) receptor subtype is present presynaptically on the crayfish motor nerve terminals. By knowing the types of 5-HT receptors present on the presynaptic motor nerve terminals in this model synaptic preparation, a better understanding of the mechanisms of action of 5-HT on vesicular release will be forthcoming. PMID:11911865

  20. 5-HT1B receptor modulation of the serotonin transporter in vivo: studies using KO mice.

    PubMed

    Montañez, Sylvia; Munn, Jaclyn L; Owens, W Anthony; Horton, Rebecca E; Daws, Lynette C

    2014-07-01

    The serotonin transporter (SERT) controls the strength and duration of serotonergic neurotransmission by the high-affinity uptake of serotonin (5-HT) from extracellular fluid. SERT is a key target for many psychotherapeutic and abused drugs, therefore understanding how SERT activity and expression are regulated is of fundamental importance. A growing literature suggests that SERT activity is under regulatory control of the 5-HT1B autoreceptor. The present studies made use of mice with a constitutive reduction (5-HT1B+/-) or knockout of 5-HT1B receptors (5-HT1B-/-), as well as mice with a constitutive knockout of SERT (SERT-/-) to further explore the relationship between SERT activity and 5-HT1B receptor expression. High-speed chronoamperometry was used to measure clearance of 5-HT from CA3 region of hippocampus in vivo. Serotonin clearance rate, over a range of 5-HT concentrations, did not differ among 5-HT1B receptor genotypes, nor did [(3)H]cyanoimipramine binding to SERT in this brain region, suggesting that SERT activity is not affected by constitutive reduction or loss of 5-HT1B receptors; alternatively, it might be that other transport mechanisms for 5-HT compensate for loss of 5-HT1B receptors. Consistent with previous reports, we found that the 5-HT1B receptor antagonist, cyanopindolol, inhibited 5-HT clearance in wild-type mice. However, this effect of cyanopindolol was lost in 5-HT1B-/- mice and diminished in 5-HT1B+/- mice, indicating that the 5-HT1B receptor is necessary for cyanopindolol to inhibit 5-HT clearance. Likewise, cyanopindolol was without effect on 5-HT clearance in SERT-/- mice, demonstrating a requirement for the presence of both SERT and 5-HT1B receptors in order for cyanopindolol to inhibit 5-HT clearance in CA3 region of hippocampus. Our findings are consistent with SERT being under the regulatory control of 5-HT1B autoreceptors. Future studies to identify signaling pathways involved may help elucidate novel therapeutic targets for the

  1. Immobilization of metalloporphyrins on P(4VP-co-St)/SiO 2 by the quaternarization reaction

    NASA Astrophysics Data System (ADS)

    Wang, Ruixin; Jiao, Weizhou; Gao, Baojiao

    2010-08-01

    Poly(4vinylpyridine-co-styrene) (P(4VP-co-St)) was grafted on silica gel particles in the manner of "grafting from", and the grafting particle P(4VP-co-St)/SiO 2 was gained. The chloromethylation reaction for the tetraphenylporphyrin (TPP) was performed using a chloromethylation reagent, 1,4-bis(chloromethyoxy)butane which was uncarcinogenic, and the tetra-chloromethylphenyl-porphyrin (TMCPP) was prepared. Then, the quaternization reaction between the benzyl chloride groups on TMCPP and pyridine groups of the grafted P(4VP-co-St) macromolecules occurred and the bonding of TMCPP on the particles P(4VP-co-St)/SiO 2 was realized, resulting in the functional composite-type particles TMCPP-P(4VP-co-St)/SiO 2. Subsequently, the metallation of the bonded particles TMCPP-P(4VP-co-St)/SiO 2 was carried out via the coordination reaction between TMCPP-P(4VP-co-St)/SiO 2 and metal salt, resulting in the supported metalloporphyrin (MP) catalysts MP-P(4VP-co-St)/SiO 2. The supported catalysts were characterized by UV-Vis spectra. The effects of various factors on the bonding process of TMCPP on P(4VP-co-St)/SiO 2 were studied in detail. In addition, the catalytic activity of the supported catalysts MP-P(4VP-co-St)/SiO 2 have been studied in oxidation process of ethyl benzene with molecular oxygen to acetophenone without the use of sacrificial co-reductant. The experimental results showed that the tetra-chloromethylphenyl-porphyrin (TMCPP) could be successfully bonded onto the P(4VP-co-St)/SiO 2 surfaces by means of the quaternization reaction between TMCPP and the pyridine groups on grafted P(4VP-co-St) macromolecules. The supported catalysts MP-P(4VP-co-St)/SiO 2 exhibited the fine catalytic activity. Moreover, the supported cobalt porphyrin was more active than the supported iron and manganese porphyrins.

  2. Improvements to an Electrical Engineering Skill Audit Exam to Improve Student Mastery of Core EE Concepts

    ERIC Educational Resources Information Center

    Parent, D. W.

    2011-01-01

    The San Jose State University Electrical Engineering (EE) Department implemented a skill audit exam for graduating seniors in 1999 with the purpose of assessing the teaching and the students' mastery of core concepts in EE. However, consistent low scores for the first years in which the test was administered suggested that students had little…

  3. Reschooling Society and the Promise of ee-Learning: An Interview with Steve Eskow

    ERIC Educational Resources Information Center

    Trevitte, Chad; Eskow, Steve

    2007-01-01

    In this article, Chad Trevitte interviews "Innovate" guest editor Steve Eskow about the concept of ee-learning and the promise it holds for revitalizing higher education. Eskow defines ee-learning as a combination of the electronic technologies employed in online learning ("e-learning 1") and a pedagogy of experiential learning rooted in real-life…

  4. Participation of 5-HT1-like and 5-HT2A receptors in the contraction of human temporal artery by 5-hydroxytryptamine and related drugs.

    PubMed Central

    Verheggen, R.; Freudenthaler, S.; Meyer-Dulheuer, F.; Kaumann, A. J.

    1996-01-01

    1. We investigated the hypothesis that, as in some other large human arteries, 5-HT-induced contraction of the temporal artery is mediated through two co-existing receptor populations, 5-HT1-like- and 5-HT2A. Temporal arterial segments were obtained from patients undergoing brain surgery and rings prepared set up to contract with 5-HT and related agents. Fractions of maximal 5-HT responses mediated through 5-HT1-like and 5-HT2A receptors, f1 and f2 = 1-f1, were estimated by use of the 5-HT2A-selective antagonist ketanserin. 2. In rings with intact endothelium 5-HT evoked contractions with a -log EC50, M of 7.0. Ketanserin (10-1000 nM) antagonized part of the 5-HT-induced contractions. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M of 6.9 and f1 of 0.17 (100 nM ketanserin) and -log EC50, M of 6.4 and f1 of 0.20 (1000 nM ketanserin). 3. In rings with endothelial function attenuated by enzymatic treatment, 5-HT caused contractions with a -log EC50, M of 7.2 that were partially blocked by ketanserin. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M 7.4 and f1 of 0.16 (100 nM ketanserin) and -log EC50, M of 7.5 and f1 of 0.14 (1000 nM ketanserin). 4. The ketanserin-resistant component of 5-HT-evoked contraction was blocked by methiothepin (100-1000 nM) consistent with mediation through 5-HT1-like receptors. 5. In rings with intact endothelium the 5-HT1-like-selective agonist, sumatriptan, caused small contractions with a -log EC50, M of 6.5 and intrinsic activity of 0.21 with respect to 5-HT that were resistant to blockade by 1000 nM ketanserin but antagonized by 100 nM methiothepin. 6. In rings with intact endothelium the 5-HT2A receptor partial agonist SK&F 103829 (2,3,4,5-tetrahydro-8[methyl sulphonyl]-1H3-benzazepin-7-ol methensulphonate) contracted rings with a -log EC50, M of 5.0 and an intrinsic activity of 0.49 with respect to 5-HT; the effects were antagonized by ketanserin 1000

  5. Serotonin (5-HT) 2C Receptor (5-HT2CR) Protein Expression is Enriched in Synaptosomal and Postsynaptic Compartments of Rat Cortex

    PubMed Central

    Anastasio, Noelle C.; Lanfranco, Maria Fe; Bubar, Marcy J.; Seitz, Patricia K.; Stutz, Sonja J.; McGinnis, Andrew G.; Watson, Cheryl S.; Cunningham, Kathryn A.

    2010-01-01

    The action of serotonin (5-HT) at the 5-HT2C receptor (5-HT2CR) in cerebral cortex is emerging as a candidate modulator of neural processes that mediate core phenotypic facets of several psychiatric and neurological disorders. However, our understanding of the neurobiology of the cortical 5-HT2CR protein complex is currently limited. The goal of the present study was to explore the subcellular localization of the 5-HT2CR in synaptosomes and the postsynaptic density, an electron-dense thickening specialized for postsynaptic signaling and neuronal plasticity. Utilizing multiples tissues (brain, peripheral tissues), protein fractions (synaptosomal, postsynaptic density), and controls (peptide neutralization, 5-HT2CR stable-expressing cells), we established the selectivity of two commercially available 5-HT2CR antibodies and employed the antibodies in Western blot and immunoprecipitation studies of PFC and motor cortex, two regions implicated in cognitive, emotional and motor dysfunction. For the first time, we demonstrated the expression of the 5-HT2CR in postsynaptic density-enriched fractions from both PFC and motor cortex. Co-immunoprecipitation studies revealed the presence of PSD-95 within the 5-HT2CR protein complex expressed in PFC and motor cortex. Taken together, these data support the hypothesis that the 5-HT2CR is localized within the postsynaptic thickening of synapses and is therefore positioned to directly modulate synaptic plasticity in cortical neurons. PMID:20345755

  6. Highly Ordered Structure Formation in RAFT-Synthesized PtBOS-b-P4VP Diblock Copolymers.

    PubMed

    Faber, Martin; Hofman, Anton H; Loos, Katja; Brinke, Gerrit Ten

    2016-06-01

    Linear poly(4-tert-butoxystyrene)-b-poly(4-vinylpyridine) (PtBOS-b-P4VP) diblock copolymers are synthesized using reversible addition-fragmentation chain transfer polymerization. The self-assembly of four different PtBOS-b-P4VP diblock copolymers is studied using small-angle X-ray scattering and transmission electron microscopy and a number of interesting observations are made. A tBOS62 -b-4VP28 diblock copolymer with a weight fraction P4VP of 0.21 shows a disordered morphology of P4VP spheres with liquid-like short-range order despite an estimated value of χN of the order of 50. Increasing the length of the 4VP block to tBOS62 -b-4VP199 results in a diblock copolymer with a weight fraction P4VP of 0.66. It forms a remarkably well-ordered lamellar structure. Likewise, a tBOS146 -b-4VP120 diblock copolymer with a weight fraction P4VP of 0.33 forms an extremely well-ordered hexagonal structure of P4VP cylinders. Increasing the P4VP block of this block copolymer to tBOS146 -b-4VP190 with a weight fraction P4VP of 0.44 results in a bicontinuous gyroid morphology despite the estimated strong segregation of χN≅150. These results are discussed in terms of the architectural dissimilarity of the two monomers, characterized by the presence of the large side group of PtBOS, and the previously reported value of the interaction parameter, χ≅0.39, for this polymer pair. PMID:27079547

  7. Genotype-Dependent Difference in 5-HT2C Receptor-Induced Hypolocomotion: Comparison with 5-HT2A Receptor Functional Activity

    PubMed Central

    Bazovkina, Darya V.; Kondaurova, Elena M.; Naumenko, Vladimir S.; Ponimaskin, Evgeni

    2015-01-01

    In the present study behavioral effects of the 5-HT2C serotonin receptor were investigated in different mouse strains. The 5-HT2C receptor agonist MK-212 applied intraperitoneally induced significant dose-dependent reduction of distance traveled in the open field test in CBA/Lac mice. This effect was receptor-specific because it was inhibited by the 5-HT2C receptor antagonist RS102221. To study the role of genotype in 5-HT2C receptor-induced hypolocomotion, locomotor activity of seven inbred mouse strains was measured after MK-212 acute treatment. We found that the 5-HT2C receptor stimulation by MK-212 decreased distance traveled in the open field test in CBA/Lac, C57Bl/6, C3H/He, and ICR mice, whereas it failed to affect locomotor activity in DBA/2J, Asn, and Balb/c mice. We also compared the interstrain differences in functional response to 5-HT2C and 5-HT2A receptors activation measured by the quantification of receptor-mediated head-twitches. These experiments revealed significant positive correlation between 5-HT2C and 5-HT2A receptors functional responses for all investigated mouse strains. Moreover, we found that 5-HT2A receptor activation with DOI did not change locomotor activity in CBA/Lac mice. Taken together, our data indicate the implication of 5-HT2C receptors in regulation of locomotor activity and suggest the shared mechanism for functional responses mediated by 5-HT2C and 5-HT2A receptors. PMID:26380122

  8. Effects of ginger constituents on the gastrointestinal tract: role of cholinergic M3 and serotonergic 5-HT3 and 5-HT4 receptors.

    PubMed

    Pertz, Heinz H; Lehmann, Jochen; Roth-Ehrang, René; Elz, Sigurd

    2011-07-01

    The herbal drug ginger (Zingiber officinale Roscoe) may be effective for treating nausea, vomiting, and gastric hypomotility. In these conditions, cholinergic M (3) receptors and serotonergic 5-HT (3) and 5-HT (4) receptors are involved. The major chemical constituents of ginger are [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol. We studied the interaction of [6]-gingerol, [8]-gingerol, [10]-gingerol (racemates), and [6]-shogaol with guinea pig M (3) receptors, guinea pig 5-HT (3) receptors, and rat 5-HT (4) receptors. In whole segments of guinea pig ileum (bioassay for contractile M (3) receptors), [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol slightly but significantly depressed the maximal carbachol response at an antagonist concentration of 10 µM. In the guinea pig myenteric plexus preparation (bioassay for contractile 5-HT (3) receptors), 5-HT maximal responses were depressed by [10]-gingerol from 93 ± 3 % to 65 ± 6 % at an antagonist concentration of 3 µM and to 48 ± 3 % at an antagonist concentration of 5 µM following desensitization of 5-HT (4) receptors and blockade of 5-HT (1) and 5-HT (2) receptors. [6]-Shogaol (3 µM) induced depression to 61 ± 3 %. In rat esophageal tunica muscularis mucosae (bioassay for relaxant 5-HT (4) receptors), [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol (2-6.3 µM) showed no agonist effects. The maximal 5-HT response remained unaffected in the presence of the compounds. It is concluded that the efficiency of ginger in reducing nausea and vomiting may be based on a weak inhibitory effect of gingerols and shogaols at M (3) and 5-HT (3) receptors. 5-HT (4) receptors, which play a role in gastroduodenal motility, appear not to be involved in the action of these compounds. PMID:21305447

  9. Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures.

    PubMed

    Venzi, Marcello; David, François; Bellet, Joachim; Cavaccini, Anna; Bombardi, Cristiano; Crunelli, Vincenzo; Di Giovanni, Giuseppe

    2016-09-01

    Absence seizures (ASs) are the hallmark of childhood/juvenile absence epilepsy. Monotherapy with first-line anti-absence drugs only controls ASs in 50% of patients, indicating the need for novel therapeutic targets. Since serotonin family-2 receptors (5-HT2Rs) are known to modulate neuronal activity in the cortico-thalamo-cortical loop, the main network involved in AS generation, we investigated the effect of selective 5-HT2AR and 5-HT2CR ligands on ASs in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well established polygenic rat model of these non-convulsive seizures. GAERS rats were implanted with fronto-parietal EEG electrodes under general anesthesia, and their ASs were later recorded under freely moving conditions before and after intraperitoneal administration of various 5-HT2AR and 5-HT2CR ligands. The 5-HT2A agonist TCB-2 dose-dependently decreased the total time spent in ASs, an effect that was blocked by the selective 5-HT2A antagonist MDL11,939. Both MDL11,939 and another selective 5-HT2A antagonist (M100,907) increased the length of individual seizures when injected alone. The 5-HT2C agonists lorcaserin and CP-809,101 dose-dependently suppressed ASs, an effect blocked by the selective 5-HT2C antagonist SB 242984. In summary, 5-HT2ARs and 5-HT2CRs negatively control the expression of experimental ASs, indicating that selective agonists at these 5-HT2R subtypes might be potential novel anti-absence drugs. PMID:27085605

  10. Genotype-Dependent Difference in 5-HT2C Receptor-Induced Hypolocomotion: Comparison with 5-HT2A Receptor Functional Activity.

    PubMed

    Bazovkina, Darya V; Kondaurova, Elena M; Naumenko, Vladimir S; Ponimaskin, Evgeni

    2015-01-01

    In the present study behavioral effects of the 5-HT2C serotonin receptor were investigated in different mouse strains. The 5-HT2C receptor agonist MK-212 applied intraperitoneally induced significant dose-dependent reduction of distance traveled in the open field test in CBA/Lac mice. This effect was receptor-specific because it was inhibited by the 5-HT2C receptor antagonist RS102221. To study the role of genotype in 5-HT2C receptor-induced hypolocomotion, locomotor activity of seven inbred mouse strains was measured after MK-212 acute treatment. We found that the 5-HT2C receptor stimulation by MK-212 decreased distance traveled in the open field test in CBA/Lac, C57Bl/6, C3H/He, and ICR mice, whereas it failed to affect locomotor activity in DBA/2J, Asn, and Balb/c mice. We also compared the interstrain differences in functional response to 5-HT2C and 5-HT2A receptors activation measured by the quantification of receptor-mediated head-twitches. These experiments revealed significant positive correlation between 5-HT2C and 5-HT2A receptors functional responses for all investigated mouse strains. Moreover, we found that 5-HT2A receptor activation with DOI did not change locomotor activity in CBA/Lac mice. Taken together, our data indicate the implication of 5-HT2C receptors in regulation of locomotor activity and suggest the shared mechanism for functional responses mediated by 5-HT2C and 5-HT2A receptors. PMID:26380122

  11. The opposite effect of a 5-HT1B receptor agonist on 5-HT synthesis, as well as its resistant counterpart, in an animal model of depression

    PubMed Central

    Skelin, Ivan; Kovačević, Tomislav; Sato, Hiroki; Diksic, Mirko

    2013-01-01

    Flinders Sensitive Line (FSL) rat is as an animal model of depression with altered parameters of the serotonergic (5-HT) system function (5-HT synthesis rates, tissue concentrations, release, receptor density and affinity), as well as an altered sensitivity of these parameters to different 5-HT based antidepressants. The effects of acute and chronic treatments with the 5-HT1B agonist, CP-94253 on 5-HT synthesis, in the FSL rats and the Flinders Resistant Line (FRL) controls were measured using α-[14C]methyl-L-tryptophan (α-MTrp) autoradiography. CP-94253 (5 mg/kg), or an adequate volume of saline, was injected i.p. as a single dose in the acute experiment or delivered via the subcutaneously implanted osmotic minipump (5 mg/kg/day for 14 days) in the chronic experiment. The acute treatment with CP-94253 significantly decreased the 5-HT synthesis in both the FRL and FSL rats, with a more widespread effect in the FRL rats. Chronic treatment with CP-94253 significantly decreased 5-HT synthesis in the FRL rats, while 5-HT synthesis in the FSL rats was significantly increased throughout the brain. In both the acute and chronic experiment, the FRL rats had higher brain 5-HT synthesis rates, relative to the FSL rats. The shift in the direction of the treatment effect from acute to chronic, using the 5-HT1B agonist, CP-94253, on 5-HT synthesis in the FSL model of depression, with an opposite effect on the control FRL rats, suggests the differential adaptation of the 5-HT system in the FSL and FRL rats to chronic stimulation of 5-HT1B receptors. PMID:22542420

  12. Redrilling of well EE-3 at the Los Alamos National Laboratory HDR (Hot Dry Rock) project

    SciTech Connect

    Schillo, J.C.; Nicholson, R.W.; Hendron, R.H.; Thomson, J.C.

    1987-01-01

    The successful sidetracking of well EE-3 and the drilling of well EE-3A proved that with detailed planning and by adjusting techniques based on previous experience at Fenton Hill, drilling can be accomplished with reduced risk. The primary drilling problems associated with drilling of hot, crystalline basement rock, are (a) abrasiveness between the downhole tools and the formations and (b) a crooked wellbore path. These were essentially eliminated by a specially designed drilling fluid and careful pre-planning of the directional drilling operations. These improvements have taken much of the risk out of drilling at the Fenton Hill Hot Dry Rock (HDR) Geothermal Test Site. The sidetracking of EE-3 and drilling of EE-3A were undertaken to complete the hydraulic connection between boreholes. Drilling through fractured regions indicated by the dense zones of microseismic activity increased the probability of success. EE-3 was sidetracked at 9373' and redrilled to a depth of 13,182'.

  13. The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects

    PubMed Central

    Krobert, Kurt A; Levy, Finn Olav

    2002-01-01

    Using membranes from stably or transiently transfected HEK293 cells cultured in 5-HT-free medium and expressing the recombinant human 5-HT7 receptor splice variants (h5-HT7(a), h5-HT7(b) and h5-HT7(d)), we compared their abilities to constitutively activate adenylyl cyclase (AC).All h5-HT7 splice variants elevated basal and forskolin-stimulated AC. The basal AC activity was reduced by the 5-HT7 antagonist methiothepin and this effect was blocked by mesulergine (neutral 5-HT7 antagonist) indicating that the inhibitory effect of methiothepin is inverse agonism at the 5-HT7 receptor.Receptor density correlated poorly with constitutive AC activity in stable clonal cell lines and transiently transfected cells. Mean constitutive AC activity as a percentage of forskolin-stimulated AC was significantly higher for the h5-HT7(b) splice variant compared to the h5-HT7(a) and h5-HT7(d) splice variants but only in stable cell lines.All eight 5-HT antagonists tested inhibited constitutive AC activity of all splice variants in a concentration-dependent manner. No differences in inverse agonist potencies (pIC50) were observed between the splice variants. The rank order of potencies was in agreement and highly correlated with antagonist potencies (pKb) determined by antagonism of 5-HT-stimulated AC activity (methiothepin>metergoline>mesulergine⩾clozapine⩾spiperone⩾ritanserin>methysergide>ketanserin).The efficacy of inverse agonism was not receptor level dependent and varied for several 5-HT antagonists between membrane preparations of transiently and stably transfected cells.It is concluded that the h5-HT7 splice variants display similar constitutive activity and inverse agonist properties. PMID:11906971

  14. Agonist actions of dihydroergotamine at 5-HT2B and 5-HT2C receptors and their possible relevance to antimigraine efficacy

    PubMed Central

    Schaerlinger, B; Hickel, P; Etienne, N; Guesnier, L; Maroteaux, L

    2003-01-01

    The pharmaceutical compound, dihydroergotamine (DHE) is dispensed to prevent and reduce the occurrence of migraine attacks. Although still controversial, the prophylactic effect of this drug is believed to be caused through blockade and/or activation of numerous receptors including serotonin (5-HT) receptors of the 5-HT2 subtype. To elucidate if 5-HT2 receptors (5-HT2Rs) may be involved in DHE prophylactic effect, we performed investigations aimed to determine the respective pharmacological profile of DHE and of its major metabolite 8′-hydroxy-DHE (8′-OH-DHE) at the 5-HT2B and 5-HT2CRs by binding, inositol triphosphate (IP3) or cyclic GMP (cGMP) coupling studies in transfected fibroblasts. DHE and 8′-OH-DHE are competitive compounds at 5-HT2B and 5-HT2CRs. 8′-OH-DHE interaction at (5-HT2BRs) was best fitted by a biphasic competition curve and displayed the highest affinity with a Ki of 5 nM. These two compounds acted as agonists for both receptors in respect to cGMP production with pEC50 of 8.32±0.09 for 8′-OH-DHE at 5-HT2B and 7.83±0.06 at 5-HT2CRs. Knowing that the antimigraine prophylactic effect of DHE is only observed after long-term treatment, we chronically exposed the recombinant cells to DHE and 8′-OH-DHE. The number of 5-HT2BR-binding sites was always more affected than 5-HT2CRs. At 5-HT2BRs, 8′-OH-DHE was more effective than DHE, with an uncoupling that persisted for more than 40 h for IP3 or cGMP. By contrast, the 5-HT2CR coupling was reversible after either treatment. Chronic exposure to 8′-OH-DHE caused a persistent agonist-mediated desensitisation of 5-HT2B, but not 5-HT2CRs. This may be of relevance to therapeutic actions of the compound. PMID:12970106

  15. 49 CFR 178.44 - Specification 3HT seamless steel cylinders for aircraft use.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Specification 3HT seamless steel cylinders for...) SPECIFICATIONS FOR PACKAGINGS Specifications for Cylinders § 178.44 Specification 3HT seamless steel cylinders for aircraft use. (a) Type, size and service pressure. A DOT 3HT cylinder is a seamless steel...

  16. 49 CFR 178.44 - Specification 3HT seamless steel cylinders for aircraft use.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 3 2012-10-01 2012-10-01 false Specification 3HT seamless steel cylinders for...) SPECIFICATIONS FOR PACKAGINGS Specifications for Cylinders § 178.44 Specification 3HT seamless steel cylinders for aircraft use. (a) Type, size and service pressure. A DOT 3HT cylinder is a seamless steel...

  17. 49 CFR 178.44 - Specification 3HT seamless steel cylinders for aircraft use.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Specification 3HT seamless steel cylinders for...) SPECIFICATIONS FOR PACKAGINGS Specifications for Cylinders § 178.44 Specification 3HT seamless steel cylinders for aircraft use. (a) Type, size and service pressure. A DOT 3HT cylinder is a seamless steel...

  18. 49 CFR 178.44 - Specification 3HT seamless steel cylinders for aircraft use.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 3 2014-10-01 2014-10-01 false Specification 3HT seamless steel cylinders for...) SPECIFICATIONS FOR PACKAGINGS Specifications for Cylinders § 178.44 Specification 3HT seamless steel cylinders for aircraft use. (a) Type, size and service pressure. A DOT 3HT cylinder is a seamless steel...

  19. Localization and Function of a 5-HT Transporter in Crypt Epithelia of the Gastrointestinal Tract

    PubMed Central

    Wade, P. R.; Chen, J.; Jaffe, B.; Kassem, I. S.; Blakely, R. D.; Gershon, M. D.

    2012-01-01

    The peristaltic reflex can be evoked in the absence of input from the CNS because the responsible neural pathways are intrinsic to the intestine. Mucosal enterochromaffin cells have been postulated to be pressure transducers, which activate the intrinsic sensory neurons that initiate the reflex by secreting 5-HT. All of the criteria necessary to establish 5-HT as this transmitter have been fulfilled previously, except that no mucosal mechanism for 5-HT inactivation was known. In the current investigation, desensitization of 5-HT receptors was demonstrated to inhibit the peristaltic reflex in the guinea pig large intestine in vitro. At low concentration (1.0 nM), the 5-HT uptake inhibitor fluoxetine potentiated the reflex, but higher concentrations blocked it, suggesting that the peristaltic reflex depends on the 5-HT transporter-mediated inactivation of 5-HT. Specific (Na+-dependent, fluoxetine-sensitive) uptake of 3H- 5-HT by intestinal crypt epithelial cells was found by radioautography. mRNA encoding the neuronal 5-HT transporter was demonstrated in the intestinal mucosa by Northern analysis and located in crypt epithelial cells as well as in myenteric neurons by in situ hybridization. cDNA encoding the 5-HT transporter was cloned from the mucosa and completely sequenced. 5-HT transporter immunoreactivity was detected in crypt epithelial cells and enteric neurons. Mucosal epithelial cells thus express a plasmalemmal 5-HT transporter identical to that of serotonergic neurons. This molecule seems to play a critical role in the peristaltic reflex. PMID:8601815

  20. Immunohistological localization of 5-HT in the CNS and feeding system of the Stable Fly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    5-HT immunoreactive neurons were detected in the CNS of the stable fly. The finding of strong innervations of the cibarial pump muscles and the foregut by 5-HT IR neurons in the feeding-related systems suggests that 5-HT may play a crucial role in the control of the feeding behavior in both the larv...

  1. The role of serotonin 5-HT2A receptors in memory and cognition

    PubMed Central

    Zhang, Gongliang; Stackman, Robert W.

    2015-01-01

    Serotonin 5-HT2A receptors (5-HT2ARs) are widely distributed in the central nervous system, especially in brain region essential for learning and cognition. In addition to endogenous 5-HT, several hallucinogens, antipsychotics, and antidepressants function by targeting 5-HT2ARs. Preclinical studies show that 5-HT2AR antagonists have antipsychotic and antidepressant properties, whereas agonist ligands possess cognition-enhancing and hallucinogenic properties. Abnormal 5-HT2AR activity is associated with a number of psychiatric disorders and conditions, including depression, schizophrenia, and drug addiction. In addition to its traditional activity as a G protein-coupled receptor (GPCR), recent studies have defined novel operations of 5-HT2ARs. Here we review progress in the (1) receptor anatomy and biology: distribution, signaling, polymerization and allosteric modulation; and (2) receptor functions: learning and memory, hallucination and spatial cognition, and mental disorders. Based on the recent progress in basic research on the 5-HT2AR, it appears that post-training 5-HT2AR activation enhances non-spatial memory consolidation, while pre-training 5-HT2AR activation facilitates fear extinction. Further, the potential influence that 5-HT2AR-elicited visual hallucinations may have on visual cue (i.e., landmark) guided spatial cognition is discussed. We conclude that the development of selective 5-HT2AR modulators to target distinct signaling pathways and neural circuits represents a new possibility for treating emotional, neuropsychiatric, and neurodegenerative disorders. PMID:26500553

  2. HT.sub.m4 methods of treatment and assays, agonists and antagonists

    DOEpatents

    Lim, Bing; Adra, Chaker N.; Lelias, Jean-Michel

    1999-01-01

    The invention relates to a recombinant DNA molecule which encodes a HT.sub.m4 protein, a transformed host cell which has been stably transfected with a DNA molecule which encodes a HT.sub.m4 protein and a recombinant HT.sub.m4 protein. The invention also relates to a method for detecting the presence of a hereditary atopy.

  3. Directed evolution of a sphingomyelin flippase reveals mechanism of substrate backbone discrimination by a P4-ATPase.

    PubMed

    Roland, Bartholomew P; Graham, Todd R

    2016-08-01

    Phospholipid flippases in the type IV P-type ATPase (P4-ATPases) family establish membrane asymmetry and play critical roles in vesicular transport, cell polarity, signal transduction, and neurologic development. All characterized P4-ATPases flip glycerophospholipids across the bilayer to the cytosolic leaflet of the membrane, but how these enzymes distinguish glycerophospholipids from sphingolipids is not known. We used a directed evolution approach to examine the molecular mechanisms through which P4-ATPases discriminate substrate backbone. A mutagenesis screen in the yeast Saccharomyces cerevisiae has identified several gain-of-function mutations in the P4-ATPase Dnf1 that facilitate the transport of a novel lipid substrate, sphingomyelin. We found that a highly conserved asparagine (N220) in the first transmembrane segment is a key enforcer of glycerophospholipid selection, and specific substitutions at this site allow transport of sphingomyelin. PMID:27432949

  4. Towards novel 5-HT7versus 5-HT1A receptor ligands among LCAPs with cyclic amino acid amide fragments: design, synthesis, and antidepressant properties. Part II.

    PubMed

    Canale, Vittorio; Kurczab, Rafał; Partyka, Anna; Satała, Grzegorz; Witek, Jagna; Jastrzębska-Więsek, Magdalena; Pawłowski, Maciej; Bojarski, Andrzej J; Wesołowska, Anna; Zajdel, Paweł

    2015-03-01

    A 26-membered library of novel long-chain arylpiperazines, which contained primary and tertiary amides of cyclic amino acids (proline and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide) in the terminal fragment was synthesized and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Docking studies confirmed advantages of Tic-amide over Pro-amide fragment for interaction with 5-HT7 receptors. Selected compounds 32 and 28, which behaved as 5-HT7Rs antagonist and 5-HT1A partial agonist, respectively, produced antidepressant-like effects in the forced swim test in mice after acute treatment in doses of 10 mg/kg (32) and 1.25 mg/kg (28). Compound 32 reduced immobility in a manner similar to the selective 5-HT7 antagonist SB-269970. PMID:25555143

  5. Lower bound on e+e- decay of massive neutrinos

    NASA Technical Reports Server (NTRS)

    Cowsik, R.; Schramm, D. N.; Hoflicn, P

    1988-01-01

    Astronomical observations of SN1987A, such as the light curve, spectral intensities of lines, the X-ray emissions, etc., constrain the lifetime for the decay of a heavy neutrino 1 MeV less than or equivalent to m sub nu H less than or equal to 50 MeV through nu sub H yields nu sub 1+e(+)+e(-) exceeds 4 x 10 to the 15th exp(-m sub nuH/5MeV) seconds. Otherwise. resulting ionization energy deposits and stronger X-ray emission would have been observed. This coupled with traditional cosmological considerations argues that the lifetime of tau-neutrinos probably exceeds the age of the universe. This in turn would imply the standard cosmological mass bound does apply to nu sub tau, namely m sub nu sub tau less than or equivalent to 100 h squared eV (where h is the Hubble constant in units of 100 km/sec/mpc). The only significant loophole for these latter arguments would be if nu sub tau primarily decays rapidly into particles having very weak interactions.

  6. Critical role of 5-HT1A, 5-HT3, and 5-HT7 receptor subtypes in the initiation, generation, and propagation of the murine colonic migrating motor complex.

    PubMed

    Dickson, Eamonn J; Heredia, Dante J; Smith, Terence K

    2010-07-01

    The colonic migrating motor complex (CMMC) is necessary for fecal pellet propulsion in the murine colon. We have previously shown that 5-hydroxytryptamine (5-HT) released from enterochromaffin cells activates 5-HT(3) receptors on the mucosal processes of myenteric Dogiel type II neurons to initiate the events underlying the CMMC. Our aims were to further investigate the roles of 5-HT(1A), 5-HT(3), and 5-HT(7) receptor subtypes in generating and propagating the CMMC using intracellular microelectrodes or tension recordings from the circular muscle (CM) in preparations with and without the mucosa. Spontaneous CMMCs were recorded from the CM in isolated murine colons but not in preparations without the mucosa. In mucosaless preparations, ondansetron (3 microM; 5-HT(3) antagonist) plus hexamethonium (100 microM) completely blocked spontaneous inhibitory junction potentials, depolarized the CM. Ondansetron blocked the preceding hyperpolarization associated with a CMMC. Spontaneous CMMCs and CMMCs evoked by spritzing 5-HT (10 and 100 microM) or nerve stimulation in preparations without the mucosa were blocked by SB 258719 or SB 269970 (1-5 microM; 5-HT(7) antagonists). Both NAN-190 and (S)-WAY100135 (1-5 microM; 5-HT(1A) antagonists) blocked spontaneous CMMCs and neurally evoked CMMCs in preparations without the mucosa. Both NAN-190 and (S)-WAY100135 caused an atropine-sensitive depolarization of the CM. The precursor of 5-HT, 5-hydroxytryptophan (5-HTP) (10 microM), and 5-carboxamidotryptamine (5-CT) (5 microM; 5-HT(1/5/7) agonist) increased the frequency of spontaneous CMMCs. 5-HTP and 5-CT also induced CMMCs in preparations with and without the mucosa, which were blocked by SB 258719. 5-HT(1A), 5-HT(3), and 5-HT(7) receptors, most likely on Dogiel Type II/AH neurons, are important in initiating, generating, and propagating the CMMC. Tonic inhibition of the CM appears to be driven by ongoing activity in descending serotonergic interneurons; by activating 5-HT(7

  7. FPIN2 posttest analysis of cylindrical canisters in SLSF Experiment P4

    SciTech Connect

    Hughes, T H; Kramer, J M

    1984-12-01

    Results demonstrate that the clad deformation is dominated by the expansion of the fuel when it melts. In our analysis we moved the end space volume and some of the fuel-clad radial gap volume to an artificial central hole. This approximation may affect the details in the early parts of the transient, but clearly did not affect the major cladding deformation. It is also clear that the accuracy of the value of the fuel expansion upon melting is significant as is the dimensional accuracy of the fuel and canisters. The major conclusions from the FPIN2 posttest analysis of the cylindrical canisters in SLSF Experiment P4 are: The maximum melt fractions in the two canisters were about 75%. Both canisters experienced about the same diametral strains of 12% prior to failure. These strains were almost entirely due to the additional volume that must be created inside the canisters to accommodate the expansion of fuel on melting. The mode of cladding failure was plastic instability by necking of the canister walls. The failure time of the 20% CW canister and the nonmechanical failure of the 10% CW canister are consistent with the FPIN2 calculations using the plastic instability failure criteria.

  8. n-ZnO/p-4H-SiC diode: Structural, electrical, and photoresponse characteristics

    SciTech Connect

    Guziewicz, M. Jung, W.

    2015-09-07

    Epitaxial n-type ZnO film has been grown, on a commercial 5 μm thick p-type 4H-SiC(00.1) Al doped epilayer, by atomic layer deposition. A full width at half maximum of the ZnO 00.2 diffraction peak rocking curve of 0.34°{sup  }± 0.02° has been measured. Diodes formed on the n-ZnO/p-4H-SiC heterostructure show rectifying behavior with a forward to reverse current ratio at the level of 10{sup 9} at ±4 V, a leakage current density of ∼6 × 10{sup −8} A/cm{sup 2}, and a low ideality factor equal to 1.17 ± 0.04. In addition, the diodes exhibit selective photoresponse with a maximum at 367 nm, and with a current increase of ∼10{sup 3} under illuminations with respect to the dark value, which makes such devices prospective candidates for ultraviolet light sensors.

  9. Functional Status of the Serotonin 5-HT2C Receptor (5-HT2CR) Drives Interlocked Phenotypes that Precipitate Relapse-Like Behaviors in Cocaine Dependence

    PubMed Central

    Anastasio, Noelle C; Stutz, Sonja J; Fox, Robert G; Sears, Robert M; Emeson, Ronald B; DiLeone, Ralph J; O'Neil, Richard T; Fink, Latham H; Li, Dingge; Green, Thomas A; Gerard Moeller, F; Cunningham, Kathryn A

    2014-01-01

    Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues (‘cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors. PMID:23939424

  10. The Lipid Kinase PI5P4Kβ Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis.

    PubMed

    Sumita, Kazutaka; Lo, Yu-Hua; Takeuchi, Koh; Senda, Miki; Kofuji, Satoshi; Ikeda, Yoshiki; Terakawa, Jumpei; Sasaki, Mika; Yoshino, Hirofumi; Majd, Nazanin; Zheng, Yuxiang; Kahoud, Emily Rose; Yokota, Takehiro; Emerling, Brooke M; Asara, John M; Ishida, Tetsuo; Locasale, Jason W; Daikoku, Takiko; Anastasiou, Dimitrios; Senda, Toshiya; Sasaki, Atsuo T

    2016-01-21

    While cellular GTP concentration dramatically changes in response to an organism's cellular status, whether it serves as a metabolic cue for biological signaling remains elusive due to the lack of molecular identification of GTP sensors. Here we report that PI5P4Kβ, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4Kβ preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4Kβ is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4Kβ is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4Kβ. The critical role of the GTP-sensing activity of PI5P4Kβ in cancer signifies this lipid kinase as a cancer therapeutic target. PMID:26774281

  11. The Role of 5-HT3 Receptors in Signaling from Taste Buds to Nerves.

    PubMed

    Larson, Eric D; Vandenbeuch, Aurelie; Voigt, Anja; Meyerhof, Wolfgang; Kinnamon, Sue C; Finger, Thomas E

    2015-12-01

    Activation of taste buds triggers the release of several neurotransmitters, including ATP and serotonin (5-hydroxytryptamine; 5-HT). Type III taste cells release 5-HT directly in response to acidic (sour) stimuli and indirectly in response to bitter and sweet tasting stimuli. Although ATP is necessary for activation of nerve fibers for all taste stimuli, the role of 5-HT is unclear. We investigated whether gustatory afferents express functional 5-HT3 receptors and, if so, whether these receptors play a role in transmission of taste information from taste buds to nerves. In mice expressing GFP under the control of the 5-HT(3A) promoter, a subset of cells in the geniculate ganglion and nerve fibers in taste buds are GFP-positive. RT-PCR and in situ hybridization confirmed the presence of 5-HT(3A) mRNA in the geniculate ganglion. Functional studies show that only those geniculate ganglion cells expressing 5-HT3A-driven GFP respond to 10 μM 5-HT and this response is blocked by 1 μM ondansetron, a 5-HT3 antagonist, and mimicked by application of 10 μM m-chlorophenylbiguanide, a 5-HT3 agonist. Pharmacological blockade of 5-HT3 receptors in vivo or genetic deletion of the 5-HT3 receptors reduces taste nerve responses to acids and other taste stimuli compared with controls, but only when urethane was used as the anesthetic. We find that anesthetic levels of pentobarbital reduce taste nerve responses apparently by blocking the 5-HT3 receptors. Our results suggest that 5-HT released from type III cells activates gustatory nerve fibers via 5-HT3 receptors, accounting for a significant proportion of the neural taste response. PMID:26631478

  12. 31 CFR 351.64 - What is the issue date of a book-entry Series EE savings bond?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 2 2011-07-01 2011-07-01 false What is the issue date of a book-entry... OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.64 What is the issue date of a book-entry Series EE savings bond? The issue date of a book-entry Series EE savings...

  13. 31 CFR 351.69 - When is a book-entry Series EE savings bond validly issued?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 2 2011-07-01 2011-07-01 false When is a book-entry Series EE savings... OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.69 When is a book-entry Series EE savings bond validly issued? A book-entry bond is validly issued when it is posted...

  14. 31 CFR 351.64 - What is the issue date of a book-entry Series EE savings bond?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false What is the issue date of a book... OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.64 What is the issue date of a book-entry Series EE savings bond? The issue date of a book-entry Series EE savings...

  15. Interaction of 5-HT1B/D ligands with recombinant h 5-HT1A receptors: intrinsic activity and modulation by G-protein activation state.

    PubMed

    Pauwels, P J; Palmier, C; Dupuis, D S; Colpaert, F C

    1998-05-01

    Many 5-HT1B/D receptor ligands have affinity for 5-HT1A receptors. In the present study, the intrinsic activity of a series of 5-HT1B/D ligands was investigated at human 5-HT1A (h 5-HT1A) receptors by measuring G-protein activation in recombinant C6-glial and HeLa membranes, using agonist-stimulated [35S]GTPgammaS binding. In these two membrane preparations, the density of h 5-HT1A receptors (i.e., 246 to 320 fmol mg(-1) protein) and of their G-proteins, and the receptor: G-protein density ratio (0.08 to 0.18) appeared to be similar. It was found that: (i) the maximal [35S]GTPgammaS binding responses induced by the 5-HT1B/D receptor ligands in the HeLa preparation at 30 microM GDP were comparable to that of the native agonist 5-HT; (ii) as compared to 5-HT (1.00), similar potencies but lower maximal responses were observed in the C6-glial preparation at 0.3 microM GDP for zolmitriptan (0.89), dihydroergotamine (0.81), rizatriptan (0.71), CP122638 (0.69), naratriptan (0.60) and sumatriptan (0.53); and that (iii) maximal [35S]GTPgammaS binding responses induced by 5-HT1B/D ligands in the C6-glial preparation were either unaffected or significantly enhanced by increasing the GDP concentration from 0.3 to 30 microM and higher concentrations. These features differ from those observed with 5-HT1A receptor agonists; the latter display the same rank order of potency and efficacy in both membrane preparations, and increasing the amount of GDP with C6-glial membranes results in an attenuation of both the agonist's maximal effect and the apparent potency of partial agonists. The differential regulation of 5-HT1A and 5-HT1B/D agonist responses by GDP suggests that different G-protein subtypes are involved upon 5-HT1A receptor activation by 5-HT1A and 5-HT1B/D agonists. PMID:9650800

  16. Evaluation of gene expression changes of serotonin receptors, 5-HT3AR and 5-HT2AR as main stress factors in breast cancer patients.

    PubMed

    Hejazi, Seyed Hesam; Ahangari, Ghasem; Pornour, Majid; Deezagi, Abdolkhaleagh; Aminzadeh, Saeed; Ahmadkhaniha, Hamid Reza; Akbari, Mohamad Esmail

    2014-01-01

    Breast cancer is a serious and potentially lethal multi-factor disease among 40-50 aged women in both developed and developing countries. Also, various studies have pointed to roles of neurotransmitters like serotonin in development of cancers, through action on various types of receptors. This study was conducted to evaluate serotonin receptor (5HT2AR and 5HT3AR) genes expression in peripheral blood mononuclear cells (PBMCs) of breast cancer patients in comparison with the healthy people and in the MCF7 cell line. Peripheral blood samples were obtained from 30 patients and 30 healthy individuals. Total RNA was extracted from PBMCs and MCF-7 cells. and 5HT2AR and 5HT3AR were detected by RT-PCR techniques. Finally, serotonin receptor gene expression variation in breast cancer patients and MCF-7 cells were determined by real time-PCR. This latter indicated significant promotion in expression of 5HT3AR and 5HT2AR in PBMCs in breast cancer patients but expression of 5HT2AR in the MCF-7 cell line was significantly decreased. In conclusion, after performing complimentary tests, determine of gene expression changes in serotonin receptors (5HT2AR and 5HT3AR) may be useful as a new approach in treatment of breast cancer based on use of antagonists. PMID:24969868

  17. Human colon cancer HT-29 cell death responses to doxorubicin and Morus Alba leaves flavonoid extract.

    PubMed

    Fallah, S; Karimi, A; Panahi, G; Gerayesh Nejad, S; Fadaei, R; Seifi, M

    2016-01-01

    The mechanistic basis for the biological properties of Morus alba flavonoid extract (MFE) and chemotherapy drug of doxorubicin on human colon cancer HT-29 cell line death are unknown. The effect of doxorubicin and flavonoid extract on colon cancer HT-29 cell line death and identification of APC gene expression and PARP concentration of HT-29 cell line were investigated. The results showed that flavonoid extract and doxorubicin induce a dose dependent cell death in HT-29 cell line. MFE and doxorubicin exert a cytotoxic effect on human colon cancer HT-29 cell line by probably promoting or induction of apoptosis. PMID:27064876

  18. New halogenated tris-(phenylalkyl)amines as h5-HT2B receptor ligands.

    PubMed

    Kapadia, Nirav; Ahmed, Shahrear; Harding, Wayne W

    2016-07-15

    A series of compounds in which various halogen substituents were incorporated into a phenyl ring of a tris-(phenylalkyl)amine scaffold, was synthesized and evaluated for affinity to h5-HT2 receptors. In general, all compounds were found to have good affinity for the 5-HT2B receptor and were selective over 5-HT2A and 5-HT2C receptors. Compound 9i was the most selective compound in this study and is the highest affinity 5-HT2B receptor ligand bearing a tris-(phenylalkyl)amine scaffold to date. PMID:27261181

  19. 31 CFR 351.68 - Are taxpayer identification numbers (TINs) required for registration of book-entry Series EE...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (TINs) required for registration of book-entry Series EE savings bonds? 351.68 Section 351.68 Money and... TREASURY BUREAU OF THE PUBLIC DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.68 Are taxpayer identification numbers (TINs) required for registration of...

  20. 31 CFR 351.68 - Are taxpayer identification numbers (TINs) required for registration of book-entry Series EE...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (TINs) required for registration of book-entry Series EE savings bonds? 351.68 Section 351.68 Money and... TREASURY BUREAU OF THE PUBLIC DEBT OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.68 Are taxpayer identification numbers (TINs) required for registration of...

  1. 31 CFR 351.69 - When is a book-entry Series EE savings bond validly issued?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false When is a book-entry Series EE savings bond validly issued? 351.69 Section 351.69 Money and Finance: Treasury Regulations Relating to... OFFERING OF UNITED STATES SAVINGS BONDS, SERIES EE Book-Entry Series EE Savings Bonds § 351.69 When is...

  2. NASA Rotor 37 CFD Code Validation: Glenn-HT Code

    NASA Technical Reports Server (NTRS)

    Ameri, Ali A.

    2010-01-01

    In order to advance the goals of NASA aeronautics programs, it is necessary to continuously evaluate and improve the computational tools used for research and design at NASA. One such code is the Glenn-HT code which is used at NASA Glenn Research Center (GRC) for turbomachinery computations. Although the code has been thoroughly validated for turbine heat transfer computations, it has not been utilized for compressors. In this work, Glenn-HT was used to compute the flow in a transonic compressor and comparisons were made to experimental data. The results presented here are in good agreement with this data. Most of the measures of performance are well within the measurement uncertainties and the exit profiles of interest agree with the experimental measurements.

  3. The 5-HT1A receptor in Major Depressive Disorder.

    PubMed

    Kaufman, Joshua; DeLorenzo, Christine; Choudhury, Sunia; Parsey, Ramin V

    2016-03-01

    Major Depressive Disorder (MDD) is a highly prevalent psychiatric diagnosis that is associated with a high degree of morbidity and mortality. This debilitating disorder is currently one of the leading causes of disability nationwide and is predicted to be the leading cause of disease burden by the year 2030. A large body of previous research has theorized that serotonergic dysfunction, specifically of the serotonin (5-HT) 1A receptor, plays a key role in the development of MDD. The purpose of this review is to describe the evolution of our current understanding of the serotonin 1A (5-HT1A) receptor and its role in the pathophysiology MDD through the discussion of animal, post-mortem, positron emission tomography (PET), pharmacologic and genetic studies. PMID:26851834

  4. SLSF in-reactor local fault safety experiment P4. Final report

    SciTech Connect

    Thompson, D. H.; Holland, J. W.; Braid, T. H.; Ragland, W. A.

    1985-09-01

    The Sodium Loop Safety Facility (SLSF), a major facility in the US fast-reactor safety program, has been used to simulate a variety of sodium-cooled fast reactor accidents. SLSF experiment P4 was conducted to investigate the behavior of a "worse-than-case" local fault configuration. Objectives of this experiment were to eject molten fuel into a 37-pin bundle of full-length Fast-Test-Reactor-type fuel pins form heat-generating fuel canisters, to characterize the severity of any molten fuel-coolant interaction, and to demonstrate that any resulting blockage could either be tolerated during continued power operation or detected by global monitors to prevent fuel failure propagation. The design goal for molten fuel release was 10 to 30 g. Explusion of molten fuel from fuel canisters caused failure of adjacent pins and a partial flow channel blockage in the fuel bundle during full-power operation. Molten fuel and fuel debris also lodged against the inner surface of the test subassembly hex-can wall. The total fuel disruption of 310 g evaluated from posttest examination data was in excellent agreement with results from the SLSF delayed neutron detection system, but exceeded the target molten fuel release by an order of magnitude. This report contains a summary description of the SLSF in-reactor loop and support systems and the experiment operations. results of the detailed macro- and microexamination of disrupted fuel and metal and results from the analysis of the on-line experimental data are described, as are the interpretations and conclusions drawn from the posttest evaluations. 60 refs., 74 figs.

  5. Deletion of the 5-HT3A-receptor subunit blunts the induction of cocaine sensitization

    PubMed Central

    Hodge, C. W.; Bratt, A. M.; Kelley, S. P.

    2008-01-01

    Serotonin (5-HT) receptors are classified into seven groups (5-HT1–7), comprising at least 14 structurally and pharmacologically distinct receptor subtypes. Pharma-cological antagonism of ionotropic 5-HT3 receptors has been shown to modulate both behavioral and neuro-chemical aspects of the induction of sensitization to cocaine. It is not known, however, if specific molecular subunits of the 5-HT3 receptor influence the development of cocaine sensitization. To address this question, we studied the effects of acute and chronic intermittent cocaine administration in mice with a targeted deletion of the gene for the 5-HT3A-receptor subunit (5-HT3A −/−). 5-HT3A (−/−) mice showed blunted induction of cocaine-induced locomotor sensitization as compared with wild-type littermate controls. 5-HT3A (−/−) mice did not differ from wild-type littermate controls on measures of basal motor activity or response to acute cocaine treatment. Enhanced locomotor response to saline injection following cocaine sensitization was observed equally in 5-HT3A (−/−) and wild-type mice suggesting similar conditioned effects associated with chronic cocaine treatment. These data show a role for the 5-HT3A-receptor subunit in the induction of behavioral sensitization to cocaine and suggest that the 5-HT3A molecular subunit modulates neurobehavioral adaptations to cocaine, which may underlie aspects of addiction. PMID:17559417

  6. A Subpopulation of Serotonergic Neurons That Do Not Express the 5-HT1A Autoreceptor

    PubMed Central

    2012-01-01

    5-HT neurons are topographically organized in the hindbrain, and have been implicated in the etiology and treatment of psychiatric diseases such as depression and anxiety. Early studies suggested that the raphe 5-HT neurons were a homogeneous population showing similar electrical properties, and feedback inhibition mediated by 5-HT1A autoreceptors. We utilized histochemistry techniques in ePet1-eGFP and 5-HT1A-iCre/R26R mice to show that a subpopulation of 5-HT neurons do not express the somatodendritic 5-HT1A autoreceptor mRNA. In addition, we performed patch-clamp recordings followed by single-cell PCR in ePet1-eGFP mice. From 134 recorded 5-HT neurons located in the dorsal, lateral, and median raphe, we found lack of 5-HT1A mRNA expression in 22 cells, evenly distributed across raphe subfields. We compared the cellular characteristics of these neuronal types and found no difference in passive membrane properties and general excitability. However, when injected with large depolarizing current, 5-HT1A-negative neurons fired more action potentials, suggesting a lack of autoinhibitory action of local 5-HT release. Our results support the hypothesis that the 5-HT system is composed of subpopulations of serotonergic neurons with different capacity for adaptation. PMID:23336048

  7. Distribution of cells responsive to 5-HT6 receptor antagonist-induced hypophagia

    PubMed Central

    Garfield, Alastair S.; Burke, Luke K.; Shaw, Jill; Evans, Mark L.; Heisler, Lora K.

    2014-01-01

    The central 5-hydroxytryptamine (5-HT; serotonin) system is well established as an important regulator of appetite and continues to remain a focus of obesity research. While much emphasis has focussed on the 5-HT2C receptor (5-HT2CR) in 5-HT's anorectic effect, pharmacological manipulation of the 5-HT6 receptor (5-HT6R) also reduces appetite and body weight and may be amenable to obesity treatment. However, the neurological circuits that underlie 5-HT6R-induced hypophagia remain to be identified. Using c-fos immunoreactivity (FOS-IR) as a marker of neuronal activation, here we mapped the neuroanatomical targets activated by an anorectic dose of the 5-HT6R antagonist SB-399885 throughout the brain. Furthermore, we quantified SB-399855 activated cells within brain appetitive nuclei, the hypothalamus, dorsal raphe nucleus (DRN) and nucleus of the solitary tract (NTS). Our results reveal that 5-HT6R antagonist-induced hypophagia is associated with significantly increased neuronal activation in two nuclei with an established role in the central control of appetite, the paraventricular nucleus of the hypothalamus (PVH) and the NTS. In contrast, no changes in FOS-IR were observed between treatment groups within other hypothalamic nuclei or DRN. The data presented here provide a first insight into the neural circuitry underlying 5-HT6R antagonist-induced appetite suppression and highlight the PVH and NTS in the coordination of 5-HT6R hypophagia. PMID:24566060

  8. Surface complex of ZnTMPyP4 metalloporphyrin with double-stranded Poly(A)-Poly(U).

    PubMed

    Tolstykh, G; Sizov, V; Kudrev, A

    2016-08-01

    This communication presents synthesis and spectral characterization of metalloporphyrin [Zn(X)TMPyP4] (TMPyP4 is 5,10,15,20-tetrakis (N-methylpyridinium-4-yl)porphyrin), and studies its binding onto anionic surface sites of synthetic double stranded polynucleotide Poly(A)-Poly(U). [Zn(X)TMPyP4] binding with Poly(A)-Poly(U) was monitored by UV-Vis absorbance spectroscopy, two fluorescence spectroscopies and 1H NMR in a working aqueous medium of 0.15M ionic strength, pH7.0 and at 25°C. The evidence provided by spectroscopic measurements and multivariate data analysis suggests the use of this metalloporphyrin as a probe for investigation of the polynucleotide surface. In contrast to TMPyP4 intercalation, an outside adsorption of [Zn(X)TMPyP4] induces an attenuation of luminescence intensity and has little influence on the shape of luminescence band. Special attention was paid to the quantitative description of the interaction between neighboring ligands on the Poly(A)-Poly(U) surface. The intrinsic binding constant to an isolated binding site lgKin 5.8±0.1, the cooperativity parameter ω 1.8±0.2, and number of monomers occupied by a ligand n=2 (25°C; pH7.0) were calculated based upon the recently proposed non-linear least-squares fitting procedure. The discovered cooperativity of binding of [Zn(X)TMPyP4] metalloporphyrin to Poly(A)-Poly(U) is significantly lower as compared to free porphyrin TMPyP4, reflecting minimal mutual influence between the nearest neighboring ligands bound with functional PO4(-) groups of the polynucleotide surface. PMID:27216450

  9. The serotonin 5-HT7 receptors: two decades of research.

    PubMed

    Gellynck, Evelien; Heyninck, Karen; Andressen, Kjetil W; Haegeman, Guy; Levy, Finn Olav; Vanhoenacker, Peter; Van Craenenbroeck, Kathleen

    2013-10-01

    Like most neurotransmitters, serotonin possesses a simple structure. However, the pharmacological consequences are more complex and diverse. Serotonin is involved in numerous functions in the human body including the control of appetite, sleep, memory and learning, temperature regulation, mood, behavior, cardiovascular function, muscle contraction, endocrine regulation, and depression. Low levels of serotonin may be associated with several disorders, namely increase in aggressive and angry behaviors, clinical depression, Parkinson's disease, obsessive-compulsive disorder, eating disorders, migraine, irritable bowel syndrome, tinnitus, and bipolar disease. These effects are mediated via different serotonin (5-HT) receptors. In this review, we will focus on the last discovered member of this serotonin receptor family, the 5-HT7 receptor. This receptor belongs to the G protein-coupled receptor superfamily and was cloned two decades ago. Later, different splice variants were described but no major functional differences have been described so far. All 5-HT7 receptor variants are coupled to Gαs proteins and stimulate cAMP formation. Recently, several interacting proteins have been reported, which can influence receptor signaling and trafficking. PMID:24042216

  10. The influence of 5-HT2 and 5-HT4 receptor antagonists to modify drug induced disinhibitory effects in the mouse light/dark test

    PubMed Central

    Costall, Brenda; Naylor, Robert J

    1997-01-01

    The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box. The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box. Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(−)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril. The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone. GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists

  11. Density and Function of Central Serotonin (5-HT) Transporters, 5-HT1A and 5-HT2A Receptors, and Effects of their Targeting on BTBR T+tf/J Mouse Social Behavior

    PubMed Central

    Gould, Georgianna G.; Hensler, Julie G.; Burke, Teresa F.; Benno, Robert H.; Onaivi, Emmanuel S.; Daws, Lynette C.

    2010-01-01

    BTBR mice are potentially useful tools for autism research because their behavior parallels core social interaction impairments and restricted-repetitive behaviors. Altered regulation of central serotonin (5-HT) neurotransmission may underlie such behavioral deficits. To test this, we compared 5-HT transporter (SERT), 5-HT1A and 5-HT2A receptor densities among BTBR and C57 strains. Autoradiographic [3H] cyanoimipramine (1nM) binding to SERT was 20–30% lower throughout the adult BTBR brain as compared to C57BL/10J mice. In hippocampal membrane homogenates [3H] citalopram maximal binding (Bmax) to SERT was 95 ± 13 fmol/mg protein in BTBR and 171 ± 20 fmol/mg protein in C57BL/6J mice, and the BTBR dissociation constant (KD) was 2 ± 0.3 nM vs. 1.1 ± 0.2 in C57BL/6J mice. Hippocampal 5-HT1A and 5-HT2A receptor binding was similar among strains. However, 8-OH-DPAT-stimulated [35S] GTPγS binding in the BTBR hippocampal CA1 region was 28% higher, indicating elevated 5-HT1A capacity to activate G-proteins. In BTBR mice, the SERT blocker, fluoxetine (10 mg/kg) and the 5-HT1A receptor partial-agonist, buspirone (2 mg/kg) enhanced social interactions. The D2/5-HT2 receptor antagonist, risperidone (0.1 mg/kg) reduced marble burying but failed to improve sociability. Overall, altered SERT and/or 5-HT1A functionality in hippocampus could contribute to the relatively low sociability of BTBR mice. PMID:21070242

  12. Evaluation of the ocular hypotensive response of serotonin 5-HT1A and 5-HT2 receptor ligands in conscious ocular hypertensive cynomolgus monkeys.

    PubMed

    May, Jesse A; McLaughlin, Marsha A; Sharif, Najam A; Hellberg, Mark R; Dean, Thomas R

    2003-07-01

    Published investigations of serotonin-1A (5-hydroxytryptamine1A; 5-HT1A) receptor agonists and serotonin-2A (5-hydroxytryptamine2A; 5-HT2A) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressure-lowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT1A agonists and 5-HT2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT2 receptor antagonists [e.g., R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M-100907) and 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxamide (SB-242084)] lowered intraocular pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT1A and 5-HT2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-alpha-methyltryptamine, 5-methoxy-alpha-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT2 receptor agonist R-(-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans. PMID:12676887

  13. Effects of chronic citalopram treatment on 5-HT1A and 5-HT2A receptors in group- and isolation-housed mice.

    PubMed

    Günther, Lydia; Liebscher, Sabine; Jähkel, Monika; Oehler, Jochen

    2008-09-28

    Selective serotonin reuptake inhibitors (SSRI) are characterized by high clinical effectiveness and good tolerability. A 2-3 week delay in the onset of effects is caused by adaptive mechanisms, probably at the serotonergic (5-HT) receptor level. To analyze this in detail, we measured 5-HT(1A) and 5-HT(2A) receptor bindings in vitro after 3 weeks of citalopram treatment (20 mg/kg i.p. daily) in group-housed as well as isolation-housed mice, reflecting neurobiological aspects seen in psychiatric patients. Isolation housing increased somatodendritic (+52%) and postsynaptic (+30-95%) 5-HT(1A) as well as postsynaptic 5-HT(2A) receptor binding (+25-34%), which confirms previous findings. Chronic citalopram treatment did not induce alterations in raphe 5-HT(1A) autoreceptor binding, independent of housing conditions. Housing-dependent citalopram effects on postsynaptic 5-HT(1A) receptor binding were found with increases in group- (+11-42%) but decreases in isolation-housed (-11 to 35%) mice. Forebrain 5-HT(2A) receptor binding decreased between 11 and 38% after chronic citalopram administration, independent of housing conditions. Citalopram's long-term action comprises alterations at the postsynaptic 5-HT(1A) and 5-HT(2A) receptor binding levels. Housing conditions interact with citalopram effects, especially on 5-HT(1A) receptor binding, and should be more strongly considered in pharmacological studies. In general, SSRI-induced alterations were more pronounced and affected more brain regions in isolates, supporting the concept of a higher responsiveness in "stressed" animals. Isolation-induced receptor binding changes were partly normalized by chronic citalopram treatment, suggesting the isolation housing model for further analyses of SSRI effects, especially at the behavioral level. PMID:18657534

  14. Role of 5-HT5A and 5-HT1B/1D receptors in the antinociception produced by ergotamine and valerenic acid in the rat formalin test.

    PubMed

    Vidal-Cantú, Guadalupe C; Jiménez-Hernández, Mildred; Rocha-González, Héctor I; Villalón, Carlos M; Granados-Soto, Vinicio; Muñoz-Islas, Enriqueta

    2016-06-15

    Sumatriptan, dihydroergotamine and methysergide inhibit 1% formalin-induced nociception by activation of peripheral 5-HT1B/1D receptors. This study set out to investigate the pharmacological profile of the antinociception produced by intrathecal and intraplantar administration of ergotamine (a 5-HT1B/1D and 5-HT5A/5B receptor agonist) and valerenic acid (a partial agonist at 5-HT5A receptors). Intraplantar injection of 1% formalin in the right hind paw resulted in spontaneous flinching behavior of the injected hindpaw of female Wistar rats. Intrathecal ergotamine (15nmol) or valerenic acid (1 nmol) blocked in a dose dependent manner formalin-induced nociception. The antinociception by intrathecal ergotamine (15nmol) or valerenic acid (1nmol) was partly or completely blocked by intrathecal administration of the antagonists: (i) methiothepin (non-selective 5-HT5A/5B; 0.01-0.1nmol); (ii) SB-699551 (selective 5-HT5A; up to 10nmol); (iii) anti-5-HT5A antibody; (iv) SB-224289 (selective 5-HT1B; 0.1-1nmol); or (v) BRL-15572 (selective 5-HT1D; 0.1-1nmol). Likewise, antinociception by intraplantar ergotamine (15nmol) and valerenic acid (10nmol) was: (i) partially blocked by methiothepin (1nmol), SB-699551 (10nmol) or SB-224289 (1nmol); and (ii) abolished by BRL-15572 (1nmol). The above doses of antagonists (which did not affect per se the formalin-induced nociception) were high enough to completely block their respective receptors. Our results suggest that ergotamine and valerenic acid produce antinociception via 5-HT5A and 5-HT1B/1D receptors located at both spinal and peripheral sites. This provides new evidence for understanding the modulation of nociceptive pathways in inflammatory pain. PMID:27068146

  15. Increased expression of 5-HT(2A) and 5-HT(2B) receptors in detrusor muscle after partial bladder outlet obstruction in rats.

    PubMed

    Michishita, Mai; Yano, Kazuo; Kasahara, Ken-ichi; Tomita, Ken-ichi; Matsuzaki, Osamu

    2015-01-01

    Serotonin (5-hydroxytryptamine; 5-HT)-induced bladder contraction is enhanced after partial bladder outlet obstruction (pBOO) in rats. We investigated time-dependent changes in bladder contraction and expression of 5-HT(2A) and 5-HT(2B) receptor mRNA in bladder tissue to elucidate the mechanism of this enhancement. On day 3 and 7 after pBOO, contractile responses of isolated rat bladder strips to 5-HT were increased compared with that in sham-operated rats; on day 14, the response had decreased to the same level as that in sham rat bladders. In contrast, carbacholinduced contraction was not enhanced by pBOO at any time point. In sham rats, 5-HT(2A) receptor mRNA was expressed in the urothelium, and 5-HT(2B) receptor mRNA was expressed in the detrusor muscle layer. In pBOO rats, both receptor mRNAs were increased in the detrusor muscle and subserosal layers, but not in the urothelium. The increase of 5-HT(2A) receptor mRNA was maintained from day 3 to day 14 after pBOO, and 5-HT(2B) receptor mRNA was increased on day 7 after pBOO. These results suggested that pBOO induced up-regulation of the 5-HT(2A) and 5-HT(2B) receptors in the detrusor muscle and subserosal layers of the bladder, and such up-regulation may be related to the enhanced bladder contractile response to 5-HT. PMID:26106048

  16. 5-HT1D receptor inhibits renal sympathetic neurotransmission by nitric oxide pathway in anesthetized rats.

    PubMed

    García-Pedraza, José-Ángel; García, Mónica; Martín, María-Luisa; Morán, Asunción

    2015-09-01

    Although serotonin has been shown to inhibit peripheral sympathetic outflow, serotonin regulation on renal sympathetic outflow has not yet been elucidated. This study investigated which 5-HT receptor subtypes are involved. Wistar rats were anesthetized (sodium pentobarbital; 60mg/kg, i.p.), and prepared for in situ autoperfused rat kidney, which allows continuous measurement of systemic blood pressure (SBP), heart rate (HR) and renal perfusion pressure (PP). Electrical stimulation of renal sympathetic nerves resulted in frequency-dependent increases in PP (18.3±1.0, 43.7±2.7 and 66.7±4.0 for 2, 4 and 6Hz, respectively), without altering SBP or HR. 5-HT, 5-carboxamidotryptamine (5-HT1/7 agonist) (0.00000125-0.1μg/kg each) or l-694,247 (5-HT1D agonist; 0.0125μg/kg) i.a. bolus inhibited vasopressor responses by renal nerve electrical stimulation, unlike i.a. bolus of agonists α-methyl-5-HT (5-HT2), 1-PBG (5-HT3), cisapride (5-HT4), AS-19 (5-HT7), CGS-12066B (5-HT1B) or 8-OH-DPAT (5-HT1A) (0.0125μg/kg each). The effect of l-694,247 did not affect the exogenous norepinephrine-induced vasoconstrictions, whereas was abolished by antagonist LY310762 (5-HT1D; 1mg/kg) or l-NAME (nitric oxide; 10mg/kg), but not by indomethacin (COX1/2; 2mg/kg) or glibenclamide (ATP-dependent K(+) channel; 20mg/kg). These results suggest that 5-HT mechanism-induced inhibition of rat vasopressor renal sympathetic outflow is mainly mediated by prejunctional 5-HT1D receptors via nitric oxide release. PMID:26003124

  17. New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders.

    PubMed

    Di Giovanni, Giuseppe; De Deurwaerdère, Philippe

    2016-01-01

    The 5-HT2C receptor (R) displays a widespread distribution in the CNS and is involved in the action of 5-HT in all brain areas. Knowledge of its functional role in the CNS pathophysiology has been impaired for many years due to the lack of drugs capable of discriminating among 5-HT2R subtypes, and to a lesser extent to the 5-HT1B, 5-HT5, 5-HT6 and 5-HT7Rs. The situation has changed since the mid-90s due to the increased availability of new and selective synthesized compounds, the creation of 5-HT2C knock out mice, and the progress made in molecular biology. Many pharmacological classes of drugs including antipsychotics, antidepressants and anxiolytics display affinities toward 5-HT2CRs and new 5-HT2C ligands have been developed for various neuropsychiatric disorders. The 5-HT2CR is presumed to mediate tonic/constitutive and phasic controls on the activity of different central neurobiological networks. Preclinical data illustrate this complexity to a point that pharmaceutical companies developed either agonists or antagonists for the same disease. In order to better comprehend this complexity, this review will briefly describe the molecular pharmacology of 5-HT2CRs, as well as their cellular impacts in general, before addressing its central distribution in the mammalian brain. Thereafter, we review the preclinical efficacy of 5-HT2C ligands in numerous behavioral tests modeling human diseases, highlighting the multiple and competing actions of the 5-HT2CRs in neurobiological networks and monoaminergic systems. Notably, we will focus this evidence in the context of the physiopathology of psychiatric and neurological disorders including Parkinson's disease, levodopa-induced dyskinesia, and epilepsy. PMID:26617215

  18. The Role of 5-HT3 Receptors in Signaling from Taste Buds to Nerves

    PubMed Central

    Vandenbeuch, Aurelie; Voigt, Anja; Meyerhof, Wolfgang; Kinnamon, Sue C.; Finger, Thomas E.

    2015-01-01

    Activation of taste buds triggers the release of several neurotransmitters, including ATP and serotonin (5-hydroxytryptamine; 5-HT). Type III taste cells release 5-HT directly in response to acidic (sour) stimuli and indirectly in response to bitter and sweet tasting stimuli. Although ATP is necessary for activation of nerve fibers for all taste stimuli, the role of 5-HT is unclear. We investigated whether gustatory afferents express functional 5-HT3 receptors and, if so, whether these receptors play a role in transmission of taste information from taste buds to nerves. In mice expressing GFP under the control of the 5-HT3A promoter, a subset of cells in the geniculate ganglion and nerve fibers in taste buds are GFP-positive. RT-PCR and in situ hybridization confirmed the presence of 5-HT3A mRNA in the geniculate ganglion. Functional studies show that only those geniculate ganglion cells expressing 5-HT3A-driven GFP respond to 10 μm 5-HT and this response is blocked by 1 μm ondansetron, a 5-HT3 antagonist, and mimicked by application of 10 μm m-chlorophenylbiguanide, a 5-HT3 agonist. Pharmacological blockade of 5-HT3 receptors in vivo or genetic deletion of the 5-HT3 receptors reduces taste nerve responses to acids and other taste stimuli compared with controls, but only when urethane was used as the anesthetic. We find that anesthetic levels of pentobarbital reduce taste nerve responses apparently by blocking the 5-HT3 receptors. Our results suggest that 5-HT released from type III cells activates gustatory nerve fibers via 5-HT3 receptors, accounting for a significant proportion of the neural taste response. SIGNIFICANCE STATEMENT Historically, serotonin (5-hydroxytryptamine; 5-HT) has been described as a candidate neurotransmitter in the gustatory system and recent studies show that type III taste receptor cells release 5-HT in response to various taste stimuli. In the present study, we demonstrate that a subset of gustatory sensory neurons express functional

  19. EE-drospirenone-levomefolate calcium versus EE-drospirenone + folic acid: folate status during 24 weeks of treatment and over 20 weeks following treatment cessation

    PubMed Central

    Diefenbach, Konstanze; Trummer, Dietmar; Ebert, Frank; Lissy, Michael; Koch, Manuela; Rohde, Beate; Blode, Hartmut

    2013-01-01

    Background Adequate folate supplementation in the periconceptional phase is recommended to reduce the risk of neural tube defects. Oral contraceptives may provide a reasonable delivery vehicle for folate supplementation before conception in women of childbearing potential. This study aimed to demonstrate that a fixed-dose combination of an oral contraceptive and levomefolate calcium leads to sustainable improvements in folate status compared with an oral contraceptive + folic acid. Methods This was a double-blind, randomized, parallel-group study in which 172 healthy women aged 18–40 years received ethinylestradiol (EE)-drospirenone-levomefolate calcium or EE-drospirenone + folic acid for 24 weeks (invasion phase), and EE-drospirenone for an additional 20 weeks (folate elimination phase). The main objective of the invasion phase was to examine the area under the folate concentration time-curve for plasma and red blood cell (RBC) folate, while the main objective of the elimination phase was to determine the duration of time for which RBC folate concentration remained ≥ 906 nmol/L after cessation of EE-drospirenone-levomefolate calcium. Results Mean concentration-time curves for plasma folate, RBC folate, and homocysteine were comparable between treatment groups during both study phases. During the invasion phase, plasma and RBC folate concentrations increased and approached steady-state after about 8 weeks (plasma) or 24 weeks (RBC). After cessation of treatment with levomefolate calcium, folate concentrations decreased slowly. The median time to RBC folate concentrations falling below 906 nmol/L was 10 weeks (95% confidence interval 8–12 weeks) after cessation of EE-drospirenone-levomefolate calcium treatment. Plasma and RBC folate levels remained above baseline values in 41.3% and 89.3% of women, respectively, at the end of the 20-week elimination phase. Conclusion Improvements in folate status were comparable between EE-drospirenone-levomefolate calcium and

  20. Growth, Structure, Thermal Properties and Spectroscopic Characteristics of Nd3+-Doped KGdP4O12 Crystal

    PubMed Central

    Sun, Tongqing; Zhang, Yu; Shan, Pai; Zhang, Zichang; Chen, Shaolin; Kong, Yongfa; Xu, Jingjun

    2014-01-01

    A single crystal of Nd3+-doped KGdP4O12 was successfully grown with the top-seeded solution growth and slow cooling (TSSG−SC) technique. It crystallizes in space group C2/c with cell parameters a = 7.812(2) Å, b = 12.307(3) Å, c = 10.474(2) Å, β = 110.84(3)° and Z = 4. The IR and Raman spectra also indicated that the phosphoric polyhedra of Nd:KGdP4O12 has a cyclic symmetry. The chemical composition of the crystal was analyzed and the distribution coefficient of Nd3+ was calculated. The crystal morphology of KGdP4O12 was identified using X-ray diffraction. The compound has good thermal stability to 920°C. Its specific heat and thermal conductivity were determined for potential applications. The spectral properties of Nd:KGdP4O12 indicates that it exhibits broad absorption and emission bands, which are attributed to low symmetry of the crystal. The broad absorption band around 798 nm has a full-width at half-maximum (FWHM) of 14.8 nm and is suitable for AlGaAs laser diode pumping. Moreover, 5 at% Nd3+-doped KGdP4O12 crystal has a long luminescence lifetime of 300 μs and a high quantum efficiency of 96%. PMID:24968165

  1. Serum levels of acute phase proteins: SAA, Hp and progesterone (P4) in mares with early embryonic death.

    PubMed

    Krakowski, L; Krawczyk, C H; Kostro, K; Stefaniak, T; Novotny, F; Obara, J

    2011-08-01

    The study involved 46 healthy purebred Arabian mares exhibiting regular oestrous cycles that underwent artificial insemination (AI). Pregnancy was detected ultrasonographically (US) in 40 mares. In 15 mares in foal, early embryonic death (EED) was observed during the pregnancy days 14-21. Blood for determinations of serum acute phase proteins (SAA and Hp) and progesterone (P4) was sampled 12-24 h before ovulation and the first insemination, at 12, 24, 72, 96 h and on day 7, 10, 14, 21, 35 and 55 after ovulation. The results revealed that in 25 mares without EED, the serum levels of P4, SAA and Hp were within physiological limits; in 15 mares with EED, the levels of SAA and Hp were significantly increased. In seven mares with EED, high levels of SAA and Hp were already found before ovulation and at 12, 24, 72, 96 h as well as on day 7 and 10 post-ovulation, whereas the level of P4 was normal for early pregnancy. In the remaining eight mares with EED, increased levels of SAA and Hp were found at 72 h after ovulation and maintained until day 55. In this group, the level of P4 decreased since 96 h after ovulation. Determinations of SAA, Hp and P4 in mares in early pregnancy (EP) are useful for monitoring normal development of pregnancy and for diagnosis of subclinical genital inflammations, which may lead to EED. PMID:21241377

  2. Mechanism and significance of P4 ATPase-catalyzed lipid transport: lessons from a Na+/K+-pump.

    PubMed

    Puts, Catheleyne F; Holthuis, Joost C M

    2009-07-01

    Members of the P(4) subfamily of P-type ATPases are believed to catalyze phospholipid transport across membrane bilayers, a process influencing a host of cellular functions. Atomic structures and functional analysis of P-type ATPases that pump small cations and metal ions revealed a transport mechanism that appears to be conserved throughout the family. A challenging problem is to understand how this mechanism is adapted in P(4) ATPases to flip phospholipids. P(4) ATPases form oligomeric complexes with members of the CDC50 protein family. While formation of these complexes is required for P(4) ATPase export from the endoplasmic reticulum, little is known about the functional role of the CDC50 subunits. The Na(+)/K(+)-ATPase and closely-related H(+)/K(+)-ATPase are the only other P-type pumps that are oligomeric, comprising mandatory beta-subunits that are strikingly reminiscent of CDC50 proteins. Besides serving a role in the functional maturation of the catalytic alpha-subunit, the beta-subunit also contributes specifically to intrinsic transport properties of the Na(+)/K(+) pump. As beta-subunits and CDC50 proteins likely adopted similar structures to accomplish analogous tasks, current knowledge of the Na(+)/K(+)-ATPase provides a useful guide for understanding the inner workings of the P(4) ATPase class of lipid pumps. PMID:19233312

  3. Regulation of Ins(3,4,5,6)P(4) signaling by a reversible kinase/phosphatase.

    PubMed

    Ho, Melisa W Y; Yang, Xiaonian; Carew, Mark A; Zhang, Tong; Hua, Len; Kwon, Yong-Uk; Chung, Sung-Kee; Adelt, Stephan; Vogel, Günter; Riley, Andrew M; Potter, Barry V L; Shears, Stephen B

    2002-03-19

    Regulation of Cl(-) channel conductance by Ins(3,4,5,6)P(4) provides receptor-dependent control over salt and fluid secretion, cell volume homeostasis, and electrical excitability of neurones and smooth muscle. Ignorance of how Ins(3,4,5,6)P(4) is synthesized has long hindered our understanding of this signaling pathway. We now show Ins(3,4,5,6)P(4) synthesis by Ins(1,3,4,5,6)P(5) 1-phosphatase activity by an enzyme previously characterized as an Ins(3,4,5,6)P(4) 1-kinase. Rationalization of these phenomena with a ligand binding model unveils Ins(1,3,4)P(3) as not simply an alternative kinase substrate, but also an activator of Ins(1,3,4,5,6)P(5) 1-phosphatase. Stable overexpression of the enzyme in epithelial monolayers verifies its physiological role in elevating Ins(3,4,5,6)P(4) levels and inhibiting secretion. It is exceptional for a single enzyme to catalyze two opposing signaling reactions (1-kinase/1-phosphatase) under physiological conditions. Reciprocal coordination of these opposing reactions offers an alternative to general doctrine that intracellular signals are regulated by integrating multiple, distinct phosphatases and kinases. PMID:11909533

  4. 5-HT1A and 5-HT1B receptors control the firing of serotoninergic neurons in the dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice.

    PubMed

    Evrard, A; Laporte, A M; Chastanet, M; Hen, R; Hamon, M; Adrien, J

    1999-11-01

    The characteristics of the spontaneous firing of serotoninergic neurons in the dorsal raphe nucleus and its control by serotonin (5-hydroxytryptamine, 5-HT) receptors were investigated in wild-type and 5-HT1B knock-out (5-HT1B-/-) mice of the 129/Sv strain, anaesthetized with chloral hydrate. In both groups of mice, 5-HT neurons exhibited a regular activity with an identical firing rate of 0.5-4.5 spikes/s. Intravenous administration of the 5-HT reuptake inhibitor citalopram or the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced a dose-dependent inhibition of 5-HT neuronal firing which could be reversed by the selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xane carboxamide (WAY 100635). Both strains were equally sensitive to 8-OH-DPAT (ED50 approximately 6.3 microgram/kg i.v.), but the mutants were less sensitive than wild-type animals to citalopram (ED50 = 0.49 +/- 0.02 and 0.28 +/- 0.01 mg/kg i.v., respectively, P < 0.05). This difference could be reduced by pre-treatment of wild-type mice with the 5-HT1B/1D antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4-methoxy-3-(4-methyl-piperazine-1-yl)-phenyl]amide (GR 127935), and might be accounted for by the lack of 5-HT1B receptors and a higher density of 5-HT reuptake sites (specifically labelled by [3H]citalopram) in 5-HT1B-/- mice. In wild-type but not 5-HT1B-/- mice, the 5-HT1B agonists 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253, 3 mg/kg i.v.) and 5-methoxy-3-(1,2,3, 6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 0.6 mg/kg i.v.) increased the firing rate of 5-HT neurons (+22.4 +/- 2.8% and +13.7 +/- 6.0%, respectively, P < 0.05), and this effect could be prevented by the 5-HT1B antagonist GR 127935 (1 mg/kg i.v.). Altogether, these data indicate that in the mouse, the firing of 5-HT neurons in the dorsal raphe nucleus is under both an inhibitory control through 5-HT1A

  5. Characterisation of the 5-HT receptor binding profile of eletriptan and kinetics of [3H]eletriptan binding at human 5-HT1B and 5-HT1D receptors.

    PubMed

    Napier, C; Stewart, M; Melrose, H; Hopkins, B; McHarg, A; Wallis, R

    1999-03-01

    The affinity of eletriptan ((R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl )ethyl]-1H-indole) for a range of 5-HT receptors was compared to values obtained for other 5-HT1B/1D receptor agonists known to be effective in the treatment of migraine. Eletriptan, like sumatriptan, zolmitriptan, naratriptan and rizatriptan had highest affinity for the human 5-HT1B, 5-HT1D and putative 5-ht1f receptor. Kinetic studies comparing the binding of [3H]eletriptan and [3H]sumatriptan to the human recombinant 5-HT1B and 5-HT1D receptors expressed in HeLa cells revealed that both radioligands bound with high specificity (>90%) and reached equilibrium within 10-15 min. However, [3H]eletriptan had over 6-fold higher affinity than [3H]sumatriptan at the 5-HT1D receptor (K(D)): 0.92 and 6.58 nM, respectively) and over 3-fold higher affinity than [3H]sumatriptan at the 5-HT1B receptor (K(D): 3.14 and 11.07 nM, respectively). Association and dissociation rates for both radioligands could only be accurately determined at the 5-HT1D receptor and then only at 4 degrees C. At this temperature, [3H]eletriptan had a significantly (P<0.05) faster association rate (K(on) 0.249 min(-1) nM(-1)) than [3H]sumatriptan (K(on) 0.024 min(-1) nM(-1)) and a significantly (P<0.05) slower off-rate (K(off) 0.027 min(-1) compared to 0.037 min(-1) for [3H]sumatriptan). These data indicate that eletriptan is a potent ligand at the human 5-HT1B, 5-HT1D, and 5-ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache. PMID:10193663

  6. Morphologic differentiation of colon carcinoma cell lines HT-29 and HT-29KM in rotating-wall vessels

    NASA Technical Reports Server (NTRS)

    Goodwin, T. J.; Jessup, J. M.; Wolf, D. A.

    1992-01-01

    A new low shear stress microcarrier culture system has been developed at NASA's Johnson Space Center that permits three-dimensional tissue culture. Two established human colon adenocarcinoma cell lines, HT-29, an undifferentiated, and HT-29KM, a stable, moderately differentiated subline of HT-29, were grown in new tissue culture bioreactors called Rotating-Wall Vessels (RWVs). RWVs are used in conjunction with multicellular cocultivation to develop a unique in vitro tissue modeling system. Cells were cultivated on Cytodex-3 microcarrier beads, with and without mixed normal human colonic fibroblasts, which served as the mesenchymal layer. Culture of the tumor lines in the absence of fibroblasts produced spheroidlike growth and minimal differentiation. In contrast, when tumor lines were co-cultivated with normal colonic fibroblasts, initial growth was confined to the fibroblast population until the microcarriers were covered. The tumor cells then commenced proliferation at an accelerated rate, organizing themselves into three-dimensional tissue masses that achieved 1.0- to 1.5-cm diameters. The masses displayed glandular structures, apical and internal glandular microvilli, tight intercellular junctions, desmosomes, cellular polarity, sinusoid development, internalized mucin, and structural organization akin to normal colon crypt development. Differentiated samples were subjected to transmission and scanning electron microscopy and histologic analysis, revealing embryoniclike mesenchymal cells lining the areas around the growth matrices. Necrosis was minimal throughout the tissue masses. These data suggest that the RWV affords a new model for investigation and isolation of growth, regulatory, and structural processes within neoplastic and normal tissue.

  7. Increased hypothalamic 5-HT2A receptor gene expression and effects of pharmacologic 5-HT2A receptor inactivation in obese A{sup y} mice

    SciTech Connect

    Nonogaki, Katsunori . E-mail: knonogaki-tky@umin.ac.jp; Nozue, Kana; Oka, Yoshitomo

    2006-12-29

    Serotonin (5-hydroxytryptamine; 5-HT) 2A receptors contribute to the effects of 5-HT on platelet aggregation and vascular smooth muscle cell proliferation, and are reportedly involved in decreases in plasma levels of adiponectin, an adipokine, in diabetic subjects. Here, we report that systemic administration of sarpogrelate, a 5-HT2A receptor antagonist, suppressed appetite and increased hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, 5-HT2C, and 5-HT1B receptor gene expression. A{sup y} mice, which have ectopic expression of the agouti protein, significantly increased hypothalamic 5-HT2A receptor gene expression in association with obesity compared with wild-type mice matched for age. Systemic administration of sarpogrelate suppressed overfeeding, body weight gain, and hyperglycemia in obese A{sup y} mice, whereas it did not increase plasma adiponectin levels. These results suggest that obesity increases hypothalamic 5-HT2A receptor gene expression, and pharmacologic inactivation of 5-HT2A receptors inhibits overfeeding and obesity in A{sup y} mice, but did not increase plasma adiponectin levels.

  8. Conformational state of human cardiac 5-HT(4(g)) receptors influences the functional effects of polyclonal anti-5-HT(4) receptor antibodies.

    PubMed

    Di Scala, Emmanuella; Rose, Stéphanie; Hérault, Olivier; Argibay, Jorge; Cosnay, Pierre; Bozon, Véronique

    2007-04-01

    The functional effects of the anti-G21V antibody directed against the second extracellular loop of human heart 5-HT(4) receptors can differ when the receptors are expressed in different cell lines. Here, we extend these studies to show variation in the responses of 5-HT(4(g)) receptors to the antibody within the same expression system. In a previous report no effect of the anti-G21V antibodies had been shown upon 5-HT(4(g)) receptors expressed in CHO cells. Here the same antibodies alone or when added before 5-HT had a functional "inverse-agonist like" effect upon 5-HT(4(g)) receptors expressed in a separate line of CHO cells. Although these CHO cells showed a lower efficacy of cAMP production evoked by 5-HT than the previous report they express a similar h5-HT(4(g)) receptor density. Inhibition of either phosphodiesterases or Gi proteins had no effect upon the action of the antibody. Conformational states of the 5-HT(4) receptor and/or equilibrium between different states of receptors may then determine the functional effect of antibodies against this receptor. PMID:17222392

  9. The impact of P3HT molecular weight and solvent composition on P3HT films processed from binary solvent mixtures

    NASA Astrophysics Data System (ADS)

    Lloyd, Lawson; Gordon, Madeleine; Boucher, David

    2015-03-01

    Recent experimental endeavors have shown that well-ordered P3HT assemblies formed in solution can improve the crystallinity and morphological uniformity of thin films and composites, thereby providing a promising new route to more efficient polymeric optoelectronic materials. We have studied the assembly and crystallinity of two regioregular poly(3-hexylthiophene) (P3HT) samples, Mn ~ 28 kDa and Mn ~ 65 kDa, in several different binary mixtures of organic solvents. We use an excitonic coupling analysis of the UV/Vis absorbance spectra to assess the impact that the solvent and the molecular weight of P3HT have on the relative structural order of the polymer assemblies. In addition, we investigate the influence that the solvent composition and the structural order of P3HT aggregates have on the assembly and organization of P3HT films. We use optical and atomic force microscopy techniques to study thin films of P3HT processed from different solvent mixtures. Our results show that relatively small variations to the P3HT solutions can produce significant changes in the morphology and macromolecular structures of the P3HT films.

  10. Arrival directions of cosmic rays of E .4 EeV

    NASA Technical Reports Server (NTRS)

    Cady, R.; Cooper, R.; Baltrusaitis, R. M.; Cassiday, G. I.; Elbert, J. W.; Gerhardy, P. R.; Ko, S.; Loh, E. C.; Mizumoto, Y.; Salamon, M. H.

    1985-01-01

    The anisotropy of cosmic rays observed by the Utah Fly's Eye detector has been studied. Emphasis has been placed on examining distributions of events in galactic coordinates. No statistically significant departure from isotropy has been observed for energies greater than 0.4 EeV (1 EeV = 10 to the 18th power eV). Results of the standard harmonic analysis in right ascension are also presented.

  11. Cloning, expression and pharmacology of a truncated splice variant of the human 5-HT7 receptor (h5-HT7(b))

    PubMed Central

    Jasper, J R; Kosaka, A; To, Z P; Chang, D J; Eglen, R M

    1997-01-01

    The rat 5-hydroxytryptamine (5-HT)7 receptor displays two splice variations, a long form, and a truncated splice isoform, arising from the introduction of a stop codon near the carboxy-terminus. The human 5-HT7 receptor gene contains at least two introns and encodes a 445 amino acid 5-HT receptor. A truncated splice variation in the human 5-HT7 receptor was isolated from a human placental cDNA library. In accordance with current NC-IUPHAR nomenclature guidelines, it is suggested that this receptor be denoted as the h5-HT7(b) receptor and the long form of the receptor as h5-HT7(a). The h5-HT7(b) receptor was stably expressed in HEK 293 cells and ligand affinities were determined by displacement of [3H]-5-carboxyamidotryptamine (5-CT; Kd=0.28±0.06 nM, Bmax=7.3±1.7 pmol mg−1 protein). The rank order of affinities (pKi) for a series of ligands was: 5-carboxamidotryptamine (5-CT, 9.65)>5-hydroxytryptamine (5-HT, 9.41)>methiothepin (8.87)>mesulergine (7.87)>8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT, 6.85)>ketanserin (6.44). The h5-HT7(b) receptor coupled positively to adenylyl cyclase in HEK 293 cells. This response was elicited by a number of agonists with the following order of potency (pEC50): 5-CT (8.7±0.11)>5-MeOT (5-methoxytryptamine; 8.1±0.20)>5-HT (7.5±0.13)>tryptamine (5.6±0.36)>8-OH-DPAT (5.3±0.28)>5-methoxytryptamine (5.0±0.06). This rank order was comparable to that observed in the radioligand binding studies. In a similar fashion to that described for the 5-HT7(a) receptor, PCR studies suggested that the 5-HT7(b) receptor mRNA is found in great abundance throughout the brain, in the small intestine and aorta. It is concluded that the h5-HT7 receptor, like the rat receptor, exists as splice variants exhibiting similar pharmacology, signal transduction and distribution. It is thus likely that there exists a complex physiological role for alternate splicing products of the 5-HT7 receptor gene. PMID:9298538

  12. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells.

    PubMed

    Gurbuz, Nilgun; Ashour, Ahmed A; Alpay, S Neslihan; Ozpolat, Bulent

    2014-01-01

    Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D- mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new

  13. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells.

    PubMed

    Gurbuz, Nilgun; Ashour, Ahmed A; Alpay, S Neslihan; Ozpolat, Bulent

    2014-01-01

    Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D-mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new

  14. Luteal P4 synthesis in early pregnant gilts after induction of estrus with PMSG/hCG.

    PubMed

    Blitek, Agnieszka; Szymanska, Magdalena; Pieczywek, Marta; Morawska-Pucinska, Ewa

    2016-03-01

    The present study was designed to examine whether an estrus induction with gonadotropins could affect luteal P4 synthesis in early pregnant gilts. Sixteen prepubertal gilts received 750IU of PMSG and 500IU of hCG 72h later. Prepubertal gilts in the control group (n=17) were observed daily for estrus behavior. All gilts were inseminated in their first estrus. Corpora lutea (CLs) were collected on days 10, 12 and 15 of pregnancy and analyzed for (1) the mRNA and protein expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 family 11 subfamily A polypeptide 1 (CYP11A1), and 3β-hydroxysteroid dehydrogenase (3βHSD); (2) the tissue concentration of P4; and (3) the mRNA expression of luteinizing hormone receptor (LHR) and estrogen receptors (ESR1 and ESR2). Additionally, P4 concentration was analyzed in blood serum of all animals. PMSG/hCG injections to induce estrus decreased mRNA expression of StAR, CYP11A1 and 3βHSD on day 10 and CYP11A1 on day 12 of pregnancy compared with the control group, while CYP11A1 and 3βHSD proteins were down-regulated on day 10 in the hormonally-treated gilts. Concentrations of P4 in luteal tissue and blood serum were also lower in animals after gonadotropin-induced estrus. In contrast, LHR and ESR1 mRNA expression was greater in PMSG/hCG-treated than control gilts on day 15 of gestation. In conclusion, induction of estrus with a PMSG/hCG protocol in prepubertal gilts impaired expression of the luteal P4 synthesis system. Low P4 content may, in turn, induce local mechanisms involving LHR and ESR1 expression to support CL function. PMID:26781360

  15. Evidence that 5-HT1D receptors mediate inhibition of sympathetic ganglionic transmission in anaesthetized cats.

    PubMed Central

    Jones, J. F.; Martin, G. R.; Ramage, A. G.

    1995-01-01

    In anaesthetized cats, 5-carboxamidotryptamine (5-CT) or 5-hydroxytryptamine (5-HT) (0.3-300 micrograms kg-1,i.v.) inhibited the postganglionic compound action potential evoked by preganglionic electrical stimulation (0.5 Hz) with a similar potency in the stellate and splanchnic ganglia. In the 5-HT experiments transmission thorough the inferior mesenteric ganglia was also recorded. The maximal inhibitory effect of 5-HT was greater on the stellate and splanchnic ganglia (60 +/- 4 and 52 +/- 5%) than on the inferior mesenteric (15 +/- 2%). The effects of 5-HT were unaffected by pretreatment with antagonists (1 mg kg-1;i.v.) for 5-HT2 (BW501C67), 5-HT1A (WAY-100635) and 5-HT3 receptors (ondansetron). However, responses to both 5-HT and 5-CT were attenuated significantly by GR127935 (1 mg kg-1) except the responses to 5-HT at the inferior mesenteric ganglia. These results are consistent with the involvement of 5-HT1D receptors mediating inhibition of sympathetic ganglionic transmission in vivo. PMID:8528548

  16. Analysis of the agonist activity of fenoldopam (SKF 82526) at the vascular 5-HT2 receptor.

    PubMed Central

    Christie, M. I.; Harper, D.; Smith, G. W.

    1992-01-01

    1. The 5-HT2 receptor agonist activity of fenoldopam (SKF 82526) was characterized in the rabbit isolated aorta preparation. 2. Fenoldopam was an agonist at the vascular 5-HT2 receptor with lower affinity and efficacy than the naturally occurring agonist 5-hydroxytryptamine (5-HT). Fenoldopam had an affinity (pKA) of 5.84 +/- 0.04 and efficacy (tau) of 0.57 +/- 0.04, whereas 5-HT had a pKA of 6.65 +/- 0.12 and tau of 2.66 +/- 0.41. 3. The constrictor effects of fenoldopam and 5-HT were competitively antagonized by the 5-HT2 antagonist, ketanserin, with pKB values of 8.81 +/- 0.11 and 8.83 +/- 0.10 respectively. 4. Prior incubation with fenoldopam produced a concentration-related rightward shift of a subsequent 5-HT concentration-response curve. This inhibition was specific for 5-HT since constrictor responses to angiotensin II were unaffected. 5. This study indicates that the D1 receptor agonist, fenoldopam, acts as an agonist at the vascular 5-HT2 receptor, but with an affinity and efficacy less than that of the naturally occurring agonist, 5-HT. PMID:1361397

  17. Organization of the mouse 5-HT3 receptor gene and functional expression of two splice variants.

    PubMed

    Werner, P; Kawashima, E; Reid, J; Hussy, N; Lundström, K; Buell, G; Humbert, Y; Jones, K A

    1994-10-01

    The structure of the mouse 5-HT3 receptor gene, 5-HT3R-A, is most similar to nicotinic acetylcholine receptor (nAChR) genes, in particular to the gene encoding the neuronal nAChR subunit alpha 7. These genes share among other things the location of three adjacent introns, suggesting that 5-HT3R-A and nAChR genes arose from a common precursor gene. The alternative use of two adjacent splice acceptor sites in intron 8 creates, in addition to the original 5-HT3R-A cDNA (5-HT3R-AL), a shorter isoform (5-HT3R-AS) which lacks six codons in the segment that translates into the major intracellular domain. This splice consensus sequence is not found in human genomic DNA. In mouse, we demonstrate by RNAse protection assay that 5-HT3R-AS mRNA is approximately 5 times more abundant than 5-HT3R-AL mRNA in both neuroblastoma cell lines and neuronal tissues. We used the Semliki Forest virus expression system for electrophysiological characterization of 5-HT3R-AS and 5-HT3R-AL in mammalian cells. No differences in electrophysiological characteristics, such as voltage dependence, desensitization kinetics, or unitary conductance were found between homomeric 5-HT3R-AS and 5-HT3R-AL receptors. Their properties are very similar to those of 5-HT3 receptors in mouse neuroblastoma cell lines. PMID:7854052

  18. 5-HT2A receptors are involved in cognitive but not antidepressant effects of fluoxetine.

    PubMed

    Castañé, Anna; Kargieman, Lucila; Celada, Pau; Bortolozzi, Analía; Artigas, Francesc

    2015-08-01

    The prefrontal cortex (PFC) plays a crucial role in cognitive and affective functions. It contains a rich serotonergic (serotonin, 5-HT) innervation and a high density of 5-HT receptors. Endogenous 5-HT exerts robust actions on the activity of pyramidal neurons in medial PFC (mPFC) via excitatory 5-HT2A and inhibitory 5-HT1A receptors, suggesting the involvement of 5-HT neurotransmission in cortical functions. However, the underlying mechanisms must be elucidated. Here we examine the role of 5-HT2A receptors in the processing of emotional and cognitive signals evoked by increasing the 5-HT tone after acute blockade of the 5-HT transporter. Fluoxetine (5-20mg/kg i.p.) dose-dependently reduced the immobility time in the tail-suspension test in wild-type (WT) and 5-HT2Aknockout (KO2A) mice, with non-significant differences between genotypes. Fluoxetine (10mg/kg i.p.) significantly impaired mice performance in the novel object recognition test 24h post-administration in WT, but not in KO2A mice. The comparable effect of fluoxetine on extracellular 5-HT in the mPFC of both genotypes suggests that presynaptic differences are not accountable. In contrast, single unit recordings of mPFC putative pyramidal neurons showed that fluoxetine (1.8-7.2mg/kg i.v.) significantly increased neuronal discharge in KO2A but not in WT mice. This effect is possibly mediated by an altered excitatory/inhibitory balance in the PFC in KO2A mice. Overall, the present results suggest that 5-HT2A receptors play a detrimental role in long-term memory deficits mediated by an excess 5-HT in PFC. PMID:25914158

  19. 5-HT potentiation of the GABAA response in the rat sacral dorsal commissural neurones

    PubMed Central

    Xu, Tian-Le; Pang, Zhi-Ping; Li, Ji-Shuo; Akaike, Norio

    1998-01-01

    The modulatory effect of 5-hydroxytryptamine (5-HT) on the γ-aminobutyric acidA (GABAA) response was investigated in the neurones freshly dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin perforated patch recording configuration under the voltage-clamp conditions.5-HT potentiated GABA-induced Cl− current (IGABA) without affecting the reversal potential of IGABA and the apparent affinity of GABA to its receptor.α-Methyl-5-HT mimicked the potentiation effect of 5-HT on IGABA while ketanserine blocked it. 1-Oleoyl-2-acetyl-glycerol (OAG) potentiated IGABA, and the effect of 5-HT on IGABA was occluded by OAG pretreatment. In the presence of chelerythrine, 5-HT failed to potentiate IGABA, suggesting that protein kinase C (PKC) is involved in the pathway through which the activation of the 5-HT2 receptor potentiates the IGABA.The facilitatory effect of 5-HT on IGABA remained in the presence of BAPTA-AM. LiCl also had no effect on 5-HT-induced potentiation of IGABA.H-89, genistein, okadaic acid and pervanadate all had no effects on 5-HT potentiation of IGABA. Pertussis toxin treatment for 6–8 h did not block the facilitatory effect of 5-HT on IGABA.The present results show that GABAA receptor in the rat SDCN could be modulated in situ by 5-HT, one of the major transmitters involved in the supraspinal control of nociception, and that the phosphorylation of GABAA receptor by PKC may be sufficient to support such modulation. The results also strongly support the hypothesis that the cotransmission by 5-HT and GABA has an important role in the spinal cord. PMID:9690871

  20. 5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking.

    PubMed

    You, In-Jee; Wright, Sherie R; Garcia-Garcia, Alvaro L; Tapper, Andrew R; Gardner, Paul D; Koob, George F; David Leonardo, E; Bohn, Laura M; Wee, Sunmee

    2016-04-01

    Cocaine addiction and depression are comorbid disorders. Although it is well recognized that 5-hydroxytryptamine (5-HT; serotonin) plays a central role in depression, our understanding of its role in addiction is notably lacking. The 5-HT system in the brain is carefully controlled by a combined process of regulating 5-HT neuron firing through 5-HT autoreceptors, neurotransmitter release, enzymatic degradation, and reuptake by transporters. This study tests the hypothesis that activation of 5-HT1A autoreceptors, which would lessen 5-HT neuron firing, contributes to cocaine-seeking behaviors. Using 5-HT neuron-specific reduction of 5-HT1A autoreceptor gene expression in mice, we demonstrate that 5-HT1A autoreceptors are necessary for cocaine conditioned place preference. In addition, using designer receptors exclusively activated by designer drugs (DREADDs) technology, we found that stimulation of the serotonergic dorsal raphe nucleus (DRN) afferents to the nucleus accumbens (NAc) abolishes cocaine reward and promotes antidepressive-like behaviors. Finally, using a rat model of compulsive-like cocaine self-administration, we found that inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with 6 h extended access, but not 1 h access to the drug. Therefore, our findings suggest an important role for 5-HT1A autoreceptors, and thus DRNNAc 5-HT neuronal activity, in the etiology and vulnerability to cocaine reward and addiction. Moreover, our findings support a strategy for antagonizing 5-HT1A autoreceptors for treating cocaine addiction. PMID:26324408

  1. Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats.

    PubMed

    Wallace, Ashley; Pehrson, Alan L; Sánchez, Connie; Morilak, David A

    2014-10-01

    Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade. PMID:24852131

  2. Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences.

    PubMed

    Li, Qian; Holmes, Andrew; Ma, Li; Van de Kar, Louis D; Garcia, Francisca; Murphy, Dennis L

    2004-12-01

    Our previous studies found that serotonin transporter (SERT) knock-out mice showed increased sensitivity to minor stress and increased anxiety-like behavior but reduced locomotor activity. These mice also showed decreased density of 5-hydroxytryptamine (5-HT1A) receptors in the hypothalamus, amygdala, and dorsal raphe. To evaluate the contribution of hypothalamic 5-HT1A receptors to these phenotypes of SERT knock-out mice, two studies were conducted. Recombinant adenoviruses containing 5-HT1A sense and antisense sequences (Ad-1AP-sense and Ad-1AP-antisense) were used to manipulate 5-HT1A receptors in the hypothalamus. The expression of the 5-HT1A genes is controlled by the 5-HT1A promoter, so that they are only expressed in 5-HT1A receptor-containing cells. (1) Injection of Ad-1AP-sense into the hypothalamus of SERT knock-out mice restored 5-HT1A receptors in the medial hypothalamus; this effect was accompanied by elimination of the exaggerated adrenocorticotropin responses to a saline injection (minor stress) and reduced locomotor activity but not by a change in increased exploratory anxiety-like behavior. (2) To further confirm the observation in SERT-/- mice, Ad-1AP-antisense was injected into the hypothalamus of normal mice. The density and the function of 5-HT1A receptors in the medial hypothalamus were significantly reduced in Ad-1AP-antisense-treated mice. Compared with the control group (injected with Ad-track), Ad-1A-antisense-treated mice showed a significant reduction in locomotor activity, but again no changes in exploratory anxiety-like behaviors, tested by elevated plus-maze and open-field tests. Thus, the present results demonstrate that medial hypothalamic 5-HT1A receptors regulate stress responses and locomotor activity but may not regulate exploratory anxiety-like behaviors. PMID:15574737

  3. Pharmacological Characterization of a 5-HT1-Type Serotonin Receptor in the Red Flour Beetle, Tribolium castaneum

    PubMed Central

    Vleugels, Rut; Lenaerts, Cynthia; Baumann, Arnd; Vanden Broeck, Jozef; Verlinden, Heleen

    2013-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is known for its key role in modulating diverse physiological processes and behaviors by binding various 5-HT receptors. However, a lack of pharmacological knowledge impedes studies on invertebrate 5-HT receptors. Moreover, pharmacological information is urgently needed in order to establish a reliable classification system for invertebrate 5-HT receptors. In this study we report on the molecular cloning and pharmacological characterization of a 5-HT1 receptor from the red flour beetle, Tribolium castaneum (Trica5-HT1). The Trica5-HT1 receptor encoding cDNA shows considerable sequence similarity with members of the 5-HT1 receptor class. Real time PCR showed high expression in the brain (without optic lobes) and the optic lobes, consistent with the role of 5-HT as neurotransmitter. Activation of Trica5-HT1 in mammalian cells decreased NKH-477-stimulated cyclic AMP levels in a dose-dependent manner, but did not influence intracellular Ca2+ signaling. We studied the pharmacological profile of the 5-HT1 receptor and demonstrated that α-methylserotonin, 5-methoxytryptamine and 5-carboxamidotryptamine acted as agonists. Prazosin, methiothepin and methysergide were the most potent antagonists and showed competitive inhibition in presence of 5-HT. This study offers important information on a 5-HT1 receptor from T. castaneum facilitating functional research of 5-HT receptors in insects and other invertebrates. The pharmacological profiles may contribute to establish a reliable classification scheme for invertebrate 5-HT receptors. PMID:23741451

  4. 5-Hydroxytryptamine-induced bladder hyperactivity via the 5-HT2A receptor in partial bladder outlet obstruction in rats.

    PubMed

    Sakai, Takumi; Kasahara, Ken-ichi; Tomita, Ken-ichi; Ikegaki, Ichiro; Kuriyama, Hiroshi

    2013-04-01

    We investigated the effects of partial bladder outlet obstruction (BOO) on the function and gene expression of 5-hydroxytryptamine (5-HT) receptor subtypes in rat bladder. Isometric contractions of the isolated bladders from sham-operated control and BOO rats were examined. The contractile responses to 5-HT were significantly increased in BOO rat bladder strips, while the responses to KCl, carbachol, or phenylephrine were not different from the control. The 5-HT-induced hypercontraction in BOO rat bladder strips was inhibited by ketanserin, a 5-HT(2A) receptor antagonist. The contractile responses to 5-HT in bladder strips were not affected by urothelium removal from the intact bladder. The gene expression of 5-HT receptor subtypes in the bladders was analyzed by RT-PCR. The mRNA expression of the 5-HT(2A), 5-HT(2B), 5-HT(2C), 5-HT(4), and 5-HT(7) receptors was detected in both the control and BOO rat bladders. Quantitative RT-PCR analysis showed there was a significant increase of 5-HT(2A) receptor mRNA in the BOO rat bladder compared with the control bladder. On the other hand, the gene expression of the 5-HT(4) receptor was not changed in the BOO rat bladder. These results suggest that the increased contractile responses to 5-HT in BOO rat bladder may be partly caused by 5-HT(2A) receptor upregulation in the detrusor smooth muscles. PMID:23344575

  5. Serotonin 5-HT3 receptors in rat CA1 hippocampal interneurons: functional and molecular characterization

    PubMed Central

    Sudweeks, Sterling N; van Hooft, Johannes A; Yakel, Jerrel L

    2002-01-01

    The molecular makeup of the serotonin 5-HT3 receptor (5-HT3R) channel was investigated in rat hippocampal CA1 interneurons in slices using single-cell RT-PCR and patch-clamp recording techniques. We tested for the expression of the 5-HT3A (both short and long splice variants) and 5-HT3B subunits, as well as the expression of the α4 subunit of the neuronal nicotinic ACh receptors (nAChRs), the latter of which has been shown to co-assemble with the 5-HT3A subunit in heterologous expression systems. Both the 5-HT3A-short and α4-nAChR subunits were expressed in these interneurons, but we could not detect any expression of either the 5-HT3B or the 5-HT3A-long subunits. Furthermore, there was a strong tendency for the 5-HT3A-short and α4-nAChR subunits to be co-expressed in individual interneurons. To assess whether there was any functional evidence for co-assembly between the 5-HT3A-short and α4-nAChR subunits, we used the sulphydryl agent 2-aminoethyl methanethiosulphonate (MTSEA), which has previously been shown to modulate expressed 5-HT3Rs that contain the α4-nAChR subunit. In half of the interneurons examined, MTSEA significantly enhanced the amplitude of the 5-HT3R-mediated responses, which is consistent with the notion that the α4-nAChR subunit co-assembles with the 5-HT3A subunit to form a native heteromeric 5-HT3R channel in rat CA1 hippocampal interneurons in vivo. In addition, the single-channel properties of the 5-HT3R were investigated in outside-out patches. No resolvable single-channel currents were observed. Using non-stationary fluctuation analysis, we obtained an estimate of the single-channel conductance of 4 pS, which is well below that expected for channels containing both the 5-HT3A and 5-HT3B subunits. PMID:12411518

  6. Phosphotidylinositol turnover in vascular, uterine, fundal, and tracheal smooth muscle: effect of serotonin (5HT)

    SciTech Connect

    Cohen, M.L.; Wittenauer, L.A.

    1986-03-01

    In brain, platelets, and aorta, 5HT has been reported to increase phosphotidylinositol turnover, an effect linked to 5HT/sub 2/ receptors. The authors examined the effect of 5HT on /sup 3/H-inositol-1-phosphate (/sup 3/H-I-P) in tissues possessing 5HT/sub 2/ receptors that mediate contraction to 5HT (rat jugular vein, aorta, uterus and guinea pig trachea) and in a tissue in which contraction to 5HT is not mediated by 5HT/sub 2/ receptors (rat stomach fundus). Tissues were incubated (37/sup 0/C, 95% O/sub 2/, 5% CO/sub 2/) with /sup 3/H-inositol (90 min), washed, LiCl/sub 2/ (10 mM) and 5HT added for 90 min, extracted, and /sup 3/H-I-P eluted from a Dowex-1 column. Basal /sup 3/H-I-P was 10-fold higher in the uterus than in the other tissues. 5HT (10/sup -6/-10/sup -4/M) increased /sup 3/H-I-P in the jugular vein, aorta, and uterus but not in the trachea or fundus. Maximum increase was greatest in the jugular vein (8-fold) with an ED/sub 50/ of 0.4 ..mu..M 5HT. The selective 5HT/sub 2/ receptor blocker, LY53857 (10/sup -8/M) antagonized the increase in /sup 3/H-I-P by 5HT in the jugular vein, aorta and uterus. Pargyline (10/sup -5/M) added to the trachea and fundus did not unmask an effect of 5HT (10/sup -4/M). These data suggest that (1) the jugular vein produced the most sensitive response to 5HT-induced increases in /sup 3/H-I-P, (2) increases in /sup 3/H-I-P by 5HT in smooth muscle may be linked to 5HT/sub 2/ receptors and (3) activation of 5HT/sub 2/ receptors as occurred in the trachea will not always increase /sup 3/H-I-P.

  7. Graphene nanoribbon blends with P3HT for organic electronics

    NASA Astrophysics Data System (ADS)

    El Gemayel, Mirella; Narita, Akimitsu; Dössel, Lukas F.; Sundaram, Ravi S.; Kiersnowski, Adam; Pisula, Wojciech; Hansen, Michael Ryan; Ferrari, Andrea C.; Orgiu, Emanuele; Feng, Xinliang; Müllen, Klaus; Samorì, Paolo

    2014-05-01

    In organic field-effect transistors (OFETs) the electrical characteristics of polymeric semiconducting materials suffer from the presence of structural/morphological defects and grain boundaries as well as amorphous domains within the film, hindering an efficient transport of charges. To improve the percolation of charges we blend a regioregular poly(3-hexylthiophene) (P3HT) with newly designed N = 18 armchair graphene nanoribbons (GNRs). The latter, prepared by a bottom-up solution synthesis, are expected to form solid aggregates which cannot be easily interfaced with metallic electrodes, limiting charge injection at metal-semiconductor interfaces, and are characterized by a finite size, thus by grain boundaries, which negatively affect the charge transport within the film. Both P3HT and GNRs are soluble/dispersible in organic solvents, enabling the use of a single step co-deposition process. The resulting OFETs show a three-fold increase in the charge carrier mobilities in blend films, when compared to pure P3HT devices. This behavior can be ascribed to GNRs, and aggregates thereof, facilitating the transport of the charges within the conduction channel by connecting the domains of the semiconductor film. The electronic characteristics of the devices such as the Ion/Ioff ratio are not affected by the addition of GNRs at different loads. Studies of the electrical characteristics under illumination for potential use of our blend films as organic phototransistors (OPTs) reveal a tunable photoresponse. Therefore, our strategy offers a new method towards the enhancement of the performance of OFETs, and holds potential for technological applications in (opto)electronics.In organic field-effect transistors (OFETs) the electrical characteristics of polymeric semiconducting materials suffer from the presence of structural/morphological defects and grain boundaries as well as amorphous domains within the film, hindering an efficient transport of charges. To improve the

  8. Recent experiments in the EAST and HT-7 superconducting tokamaks

    NASA Astrophysics Data System (ADS)

    Wan, Baonian; International EAST Collaborators; HT-7 Teams

    2009-10-01

    First divertor plasma configuration in Experimental Advanced Superconducting Tokamak (EAST) was obtained in the second campaign after the last IAEA meeting. To achieve long pulse diverted plasma discharges, new capabilities including the fully actively water cooled in-vessel components, current drive and heating systems, diagnostics and real-time plasma control algorithm were developed. Pre-programmed shape and feedback control of plasma position and current (RZIP) produced a variety of shaped plasma configurations, covering most of the configurations foreseen at the design stage of the machine. Control algorithm based on real-time equilibrium reconstruction and iso-flux control for the last closed magnetic flux surface (RTEFIT/ISOFLUX) has also been realized. A number of operational issues, such as plasma initiation and ramp up under constraints of superconducting coils were successfully investigated. First LHCD experiments demonstrated long pulse discharges longer than 20 s and nearly full non-inductive current drive. The physical engineering capability on the superconducting magnetic system was assessed by simulating discharges. Since the last IAEA meeting, experiments in HT-7 have been focusing on long pulse operation to support the EAST experiments on both physics and technical aspects. Long pulse discharges up to 400 s have now been achieved in HT-7. Investigation of sawtooth activities in ohmic and LHCD plasmas supports the turbulence model instead of the fast reconnection of the m = 1 magnetic island. Coexistence of electron mode and ion mode in high density ohmic plasmas has been observed by 2D ECE imaging (ECEI) in HT-7. The spectral characteristics of geodesic acoustic mode at the plasma boundary have been investigated by Langmuir probe arrays.

  9. INSIGHTS INTO THE REGULATION OF 5-HT2A RECEPTORS BY SCAFFOLDING PROTEINS AND KINASES

    PubMed Central

    Allen, John A.; Yadav, Prem N.

    2008-01-01

    SUMMARY 5-HT2A serotonin receptors are essential molecular targets for the actions of LSD-like hallucinogens and atypical antipsychotic drugs. 5-HT2A serotonin receptors also mediate a variety of physiological processes in peripheral and central nervous systems including platelet aggregation, smooth muscle contraction, and the modulation of mood and perception. Scaffolding proteins have emerged as important regulators of 5-HT2A receptors and our recent studies suggest multiple scaffolds exist for 5-HT2A receptors including PSD95, arrestin, and caveolin. In addition, a novel interaction has emerged between p90 ribosomal S6 kinase and 5-HT2A receptors which attenuates receptor signaling. This article reviews our recent studies and emphasizes the role of scaffolding proteins and kinases in the regulation of 5-HT2A trafficking, targeting and signaling. PMID:18640136

  10. PEO-b-P4VP/Yttrium Hydroxide Hybrid Nanotubes as Supporter for Catalyst Gold Nanoparticles

    NASA Astrophysics Data System (ADS)

    Yang, Qian; Chen, Dao-yong

    2012-06-01

    The adsorption of poly (ethylene oxide)-b-poly(4-vinylpyridine)(PEO-b-P4VP) micelles onto the surface of yttrium hydroxide nanotubes (YNTs) resulted in the hybrid nanotubes with a dense P4VP inner layer and a stretched PEO outer layer surrounding YNTs. The dense P4VP layer was further stabilized by the crosslinking using 1,4-dibromobutane as the crosslinker. Then, the crosslinked hybrid nanotubes (CHNTs) were used as a novel nano supporter for loading the catalyst gold nanoparticles (GNPs) within the crosslinked P4VP layer. The resultant GNPs/CHNTs (GNTs loaded on CHNTs) were applied to catalyze the reduction reaction of p-nitrophenol. The results indicate that this novel nano supporter has advantages such as good dispersity in the suspension, high capacity in loading GNPs (0.87 mmol/g), high catalytic activity of the loaded GNPs (12.9 μmol-1min-1), and good reusability of GNTs/CHNTs.

  11. Structure-activity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties.

    PubMed

    Corte, James R; Fang, Tianan; Pinto, Donald J P; Han, Wei; Hu, Zilun; Jiang, Xiang-Jun; Li, Yun-Long; Gauuan, Jolicia F; Hadden, Mark; Orton, Darren; Rendina, Alan R; Luettgen, Joseph M; Wong, Pancras C; He, Kan; Morin, Paul E; Chang, Chong-Hwan; Cheney, Daniel L; Knabb, Robert M; Wexler, Ruth R; Lam, Patrick Y S

    2008-05-01

    Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model. PMID:18424044

  12. On the relationship between radiation-stimulated photoluminescence and nitrogen atoms in p-4 H-SiC

    NASA Astrophysics Data System (ADS)

    Lebedev, A. A.; Ber, B. Ya.; Bogdanova, E. V.; Seredova, N. V.; Kazantsev, D. Yu.; Kozlovski, V. V.

    2015-12-01

    Photoluminescence (PL) appearing in p-4 H-SiC upon its electron irradiation has been studied. A model that accounts for the dependence of the PL intensity on the irradiation dose is suggested. The conclusion is drawn that nitrogen-radiation defect donor-acceptor pairs are PL activators.

  13. 5-HT6 receptor agonism facilitates emotional learning

    PubMed Central

    Pereira, Marcela; Martynhak, Bruno J.; Andreatini, Roberto; Svenningsson, Per

    2015-01-01

    Serotonin (5-HT) and its receptors play crucial roles in various aspects of mood and cognitive functions. However, the role of specific 5-HT receptors in these processes remains to be better understood. Here, we examined the effects of the selective and potent 5-HT6 agonist (WAY208466) on mood, anxiety and emotional learning in mice. Male C57Bl/6J mice were therefore tested in the forced swim test (FST), elevated plus-maze (EPM), and passive avoidance tests (PA), respectively. In a dose-response experiment, mice were treated intraperitoneally with WAY208466 at 3, 9, or 27 mg/kg and examined in an open field arena open field test (OFT) followed by the FST. 9 mg/kg of WAY208466 reduced immobility in the FST, without impairing the locomotion. Thus, the dose of 9 mg/kg was subsequently used for tests of anxiety and emotional learning. There was no significant effect of WAY208466 in the EPM. In the PA, mice were trained 30 min before the treatment with saline or WAY208466. Two separate sets of animals were used for short term memory (tested 1 h post-training) or long term memory (tested 24 h post-training). WAY208466 improved both short and long term memories, evaluated by the latency to enter the dark compartment, in the PA. The WAY208466-treated animals also showed more grooming and rearing in the light compartment. To better understand the molecular mechanisms and brain regions involved in the facilitation of emotional learning by WAY208466, we studied its effects on signal transduction and immediate early gene expression. WAY208466 increased the levels of phospho-Ser845-GluA1 and phospho-Ser217/221-MEK in the caudate-putamen. Levels of phospho-Thr202/204-Erk1/2 and the ratio mature BDNF/proBDNF were increased in the hippocampus. Moreover, WAY208466 increased c-fos in the hippocampus and Arc expression in both hippocampus and prefrontal cortex (PFC). The results indicate antidepressant efficacy and facilitation of emotional learning by 5-HT6 receptor agonism via

  14. Mechanism for the acute effects of organophosphate pesticides on the adult 5-HT system.

    PubMed

    Judge, Sarah J; Savy, Claire Y; Campbell, Matthew; Dodds, Rebecca; Gomes, Larissa Kruger; Laws, Grace; Watson, Anna; Blain, Peter G; Morris, Christopher M; Gartside, Sarah E

    2016-02-01

    The neurotransmitter serotonin (5-HT) is involved in mood disorder aetiology and it has been reported that (organophosphate) OP exposure affects 5-HT turnover. The aim of this study was to elucidate the mechanism underlying OP effects on the adult 5-HT system. First, acute in vivo administration of the OP diazinon (0, 1.3, 13 or 39 mg/kg i.p.) to male Hooded Lister rats inhibited the activity of the cholinergic enzyme acetylcholinesterase in blood and in the hippocampus, dorsal raphe nucleus (DRN), striatum and prefrontal cortex. Diazinon-induced cholinesterase inhibition was greatest in the DRN, the brain's major source of 5-HT neurones. Second, acute in vivo diazinon exposure (0 or 39 mg/kg i.p.) increased the basal firing rate of DRN neurones measured ex vivo in brain slices. The excitatory responses of DRN neurones to α1-adrenoceptor or AMPA/kainate receptor activation were not affected by in vivo diazinon exposure but the inhibitory response to 5-HT was attenuated, indicating 5-HT1A autoreceptor down-regulation. Finally, direct application of the diazinon metabolite diazinon oxon to naive rat brain slices increased the firing rate of DRN 5-HT neurones, as did chlorpyrifos-oxon, indicating the effect was not unique to diazinon. The oxon-induced augmentation of firing was blocked by the nicotinic acetylcholine receptor antagonist mecamylamine and the AMPA/kainate glutamate receptor antagonist DNQX. Together these data indicate that 1) acute OP exposure inhibits DRN cholinesterase, leading to acetylcholine accumulation, 2) the acetylcholine activates nicotinic receptors on 5-HT neurones and also on glutamatergic neurones, thus releasing glutamate and activating 5-HT neuronal AMPA/kainate receptors 3) the increase in 5-HT neuronal activity, and resulting 5-HT release, may lead to 5-HT1A autoreceptor down-regulation. This mechanism may be involved in the reported increase in risk of developing anxiety and depression following occupational OP exposure. PMID

  15. Sulfonyl-containing modulators of serotonin 5-HT6 receptors and their pharmacophore models

    NASA Astrophysics Data System (ADS)

    Ivachtchenko, A. V.

    2014-05-01

    Data published in recent years on the synthesis of serotonin 5-HT6 receptor modulators are summarized. Modulators with high affinity for 5-HT6 receptors exhibiting different degrees of selectivity — from highly selective to semiselective and multimodal — are described. Clinical trial results are reported for the most promising serotonin 5-HT6 receptor modulators attracting special attention of medicinal chemists. The bibliography includes 128 references.

  16. Sphingosine 1-phosphate analogue recognition and selectivity at S1P4 within the endothelial differentiation gene family of receptors

    PubMed Central

    Inagaki, Yuichi; Pham, TrucChi T.; Fujiwara, Yuko; Kohno, Takayuki; Osborne, Daniel A.; Igarashi, Yasuyuki; Tigyi, Gabor; Parrill, Abby L.

    2005-01-01

    Synergistic computational and experimental studies provided previously unforeseen details concerning the structural basis of S1P (sphingosine 1-phosphate) recognition by the S1P4 G-protein-coupled receptor. Similarly to reports on the S1P1 receptor, cationic and anionic residues in the third transmembrane domain (R3.28 and E3.29 at positions 124 and 125) form ion pairs with the phosphate and ammonium of S1P, and alanine mutations at these positions abolished specific S1P binding, S1P-induced receptor activation and cell migration. Unlike findings on the S1P1 receptor, no cationic residue in the seventh transmembrane domain interacts with the phosphate. Additionally, two previously undiscovered interactions with the S1P polar headgroup have been identified. Trp186 at position 4.64 in the fourth transmembrane domain interacts by a cation-π interaction with the ammonium group of S1P. Lys204 at position 5.38 forms an ion pair with the S1P. The S1P4 and S1P1 receptors show differences in binding-pocket shape and electrostatic distributions that correlate with the published structure–activity relationships. In particular, the binding pocket of mS1P4 (mouse S1P4) has recognition sites for the anionic phosphate and cationic ammonium groups that are equidistant from the end of the non-polar tail. In contrast, the binding pocket of hS1P1 (human S1P4) places the ammonium recognition site 2 Å (1 Å=0.1 nm) closer to the end of the non-polar tail than the phosphate recognition site. PMID:15733055

  17. Yokukansan Increases 5-HT1A Receptors in the Prefrontal Cortex and Enhances 5-HT1A Receptor Agonist-Induced Behavioral Responses in Socially Isolated Mice

    PubMed Central

    Ueki, Toshiyuki; Mizoguchi, Kazushige; Yamaguchi, Takuji; Nishi, Akinori; Ikarashi, Yasushi; Hattori, Tomohisa; Kase, Yoshio

    2015-01-01

    The traditional Japanese medicine yokukansan has an anxiolytic effect, which occurs after repeated administration. In this study, to investigate the underlying mechanisms, we examined the effects of repeated yokukansan administration on serotonin 1A (5-HT1A) receptor density and affinity and its expression at both mRNA and protein levels in the prefrontal cortex (PFC) of socially isolated mice. Moreover, we examined the effects of yokukansan on a 5-HT1A receptor-mediated behavioral response. Male mice were subjected to social isolation stress for 6 weeks and simultaneously treated with yokukansan. Thereafter, the density and affinity of 5-HT1A receptors were analyzed by a receptor-binding assay. Levels of 5-HT1A receptor protein and mRNA were also measured. Furthermore, (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT; a 5-HT1A receptor agonist) was injected intraperitoneally, and rearing behavior was examined. Social isolation stress alone did not affect 5-HT1A receptor density or affinity. However, yokukansan significantly increased receptor density and decreased affinity concomitant with unchanged protein and mRNA levels. Yokukansan also enhanced the 8-OH-DPAT-induced decrease in rearing behavior. These results suggest that yokukansan increases 5-HT1A receptors in the PFC of socially isolated mice and enhances their function, which might underlie its anxiolytic effects. PMID:26681968

  18. Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors.

    PubMed

    Moya, Pablo R; Berg, Kelly A; Gutiérrez-Hernandez, Manuel A; Sáez-Briones, Patricio; Reyes-Parada, Miguel; Cassels, Bruce K; Clarke, William P

    2007-06-01

    2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT)(2A/2C) agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A(2) (PLA(2))] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA(2) and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT(2A) or 5-HT(2C) receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT(2C) receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT(2A) receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT(2C) receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT(2C) receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA(2)-specific at the 5-HT(2A) receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT(2A) receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile. PMID:17337633

  19. 5-HT(2A) receptor blockade and 5-HT(2C) receptor activation interact to reduce cocaine hyperlocomotion and Fos protein expression in the caudate-putamen.

    PubMed

    Pockros, Lara A; Pentkowski, Nathan S; Conway, Sineadh M; Ullman, Teresa E; Zwick, Kimberly R; Neisewander, Janet L

    2012-12-01

    Both the 5-HT(2A) receptor (R) antagonist M100907 and the 5-HT(2C) R agonist MK212 attenuate cocaine-induced dopamine release and hyperlocomotion. This study examined whether these drugs interact to reduce cocaine hyperlocomotion and Fos expression in the striatum and prefrontal cortex. We first determined from dose-effect functions a low dose of both M100907 and MK212 that failed to alter cocaine (15 mg/kg, i.p.) hyperlocomotion. Subsequently, we examined whether these subthreshold doses given together would attenuate cocaine hyperlocomotion, consistent with a 5-HT(2A)/5-HT(2C) R interaction. Separate groups of rats received two sequential drug injections 5 min apart immediately before a 1-h locomotion test as follows: (1) saline + saline, (2) saline + cocaine, (3) 0.025 mg/kg M100907 + cocaine, (4) 0.125 mg/kg MK212 + cocaine, or (5) cocktail combination of 0.025 mg/kg M100907 and 0.125 mg/kg MK212 + cocaine. Brains were extracted for Fos immunohistochemistry 90 min after the second injection. We next examined the effects of 0.025 mg/kg M100907 and 0.125 mg/kg MK212, alone and in combination, on spontaneous locomotor activity. While neither drug given alone produced any effects, the M100907/MK212 cocktail attenuated cocaine hyperlocomotion as well as cocaine-induced Fos expression in the dorsolateral caudate-putamen (CPu), but had no effect on spontaneous locomotion. The findings suggest that 5-HT(2A) Rs and 5-HT(2C) Rs interact to attenuate cocaine hyperlocomotion and Fos expression in the CPu, and that the CPu is a potential locus of the interactive effects between these 5-HT(2) R subtypes on behavior. Further research investigating combined 5-HT(2A) R antagonism and 5-HT(2C) R agonism as a treatment for cocaine dependence is warranted. PMID:22886755

  20. 5-HT2A receptor blockade and 5-HT2C receptor activation interact to reduce cocaine hyperlocomotion and Fos protein expression in the caudate-putamen

    PubMed Central

    Pockros, Lara A.; Pentkowski, Nathan S.; Conway, Sineadh M.; Ullman, Teresa E.; Zwick, Kimberly R.; Neisewander, Janet L.

    2012-01-01

    Both the 5-HT2A receptor (R) antagonist M100907 and the 5-HT2CR agonist MK212 attenuate cocaine-induced dopamine release and hyperlocomotion. This study examined whether these drugs interact to reduce cocaine hyperlocomotion and Fos expression in the striatum and prefrontal cortex. We first determined from dose-effect functions a low dose of both M100907 and MK212 that failed to alter cocaine (15 mg/kg, i.p.) hyperlocomotion. Subsequently we examined whether these subthreshold doses given together would attenuate cocaine hyperlocomotion, consistent with a 5-HT2A/5-HT2CR interaction. Separate groups of rats received two sequential drug injections 5 min apart immediately before a 1-h locomotion test as follows: 1) saline + saline, 2) saline + cocaine, 3) 0.025 mg/kg M100907 + cocaine, 4) 0.125 mg/kg MK212 + cocaine, or 5) cocktail combination of 0.025 mg/kg M100907 and 0.125 mg/kg MK212 + cocaine. Brains were extracted for Fos immunohistochemistry 90 min after the second injection. We next examined the effects of 0.025 mg/kg M100907 and 0.125 mg/kg MK212, alone and in combination, on spontaneous locomotor activity. While neither drug given alone produced any effects, the M100907/MK212 cocktail attenuated cocaine hyperlocomotion as well as cocaine-induced Fos expression in the dorsolateral caudate-putamen (CPu), but had no effect on spontaneous locomotion. The findings suggest that 5-HT2ARs and 5-HT2CRs interact to attenuate cocaine hyperlocomotion and Fos expression in the CPu, and that the CPu is a potential locus of the interactive effects between these 5-HT2R subtypes on behavior. Further research investigating combined 5-HT2AR antagonism and 5-HT2CR agonism as a treatment for cocaine dependence is warranted. PMID:22886755

  1. Serotonin 5-HT4 receptors and forebrain cholinergic system: receptor expression in identified cell populations.

    PubMed

    Peñas-Cazorla, Raúl; Vilaró, M Teresa

    2015-11-01

    Activation of serotonin 5-HT4 receptors has pro-cognitive effects on memory performance. The proposed underlying neurochemical mechanism is the enhancement of acetylcholine release in frontal cortex and hippocampus elicited by 5-HT4 agonists. Although 5-HT4 receptors are present in brain areas related to cognition, e.g., hippocampus and cortex, the cellular localization of the receptors that might modulate acetylcholine release is unknown at present. We have analyzed, using dual label in situ hybridization, the cellular localization of 5-HT4 receptor mRNA in identified neuronal populations of the rat basal forebrain, which is the source of the cholinergic innervation to cortex and hippocampus. 5-HT4 receptor mRNA was visualized with isotopically labeled oligonucleotide probes, whereas cholinergic, glutamatergic, GABAergic and parvalbumin-synthesizing neurons were identified with digoxigenin-labeled oligonucleotide probes. 5-HT4 receptor mRNA was not detected in the basal forebrain cholinergic cell population. In contrast, basal forebrain GABAergic, parvalbumin synthesizing, and glutamatergic cells contained 5-HT4 receptor mRNA. Hippocampal and cortical glutamatergic neurons also express this receptor. These results indicate that 5-HT4 receptors are not synthesized by cholinergic cells, and thus would be absent from cholinergic terminals. In contrast, several non-cholinergic cell populations within the basal forebrain and its target hippocampal and cortical areas express these receptors and are thus likely to mediate the enhancement of acetylcholine release elicited by 5-HT4 agonists. PMID:25183542

  2. Distinct Circuits Underlie the Effects of 5-HT1B Receptors on Aggression and Impulsivity.

    PubMed

    Nautiyal, Katherine M; Tanaka, Kenji F; Barr, Mary M; Tritschler, Laurent; Le Dantec, Yannick; David, Denis J; Gardier, Alain M; Blanco, Carlos; Hen, René; Ahmari, Susanne E

    2015-05-01

    Impulsive and aggressive behaviors are both modulated by serotonergic signaling, specifically through the serotonin 1B receptor (5-HT1BR). 5-HT1BR knockout mice show increased aggression and impulsivity, and 5-HT1BR polymorphisms are associated with aggression and drug addiction in humans. To dissect the mechanisms by which the 5-HT1BR affects these phenotypes, we developed a mouse model to spatially and temporally regulate 5-HT1BR expression. Our results demonstrate that forebrain 5-HT1B heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. However, distinct heteroreceptors acting during adulthood are involved in mediating impulsivity. Correlating with the impulsivity, dopamine in the nucleus accumbens is elevated in the absence of 5-HT1BRs and normalized following adult rescue of the receptor. Overall, these data show that while adolescent expression of 5-HT1BRs influences aggressive behavior, a distinct set of 5-HT1B receptors modulates impulsive behavior during adulthood. PMID:25892302

  3. The 5-HT3 receptor is essential for exercise-induced hippocampal neurogenesis and antidepressant effects.

    PubMed

    Kondo, M; Nakamura, Y; Ishida, Y; Shimada, S

    2015-11-01

    Exercise has a variety of beneficial effects on brain structure and function, such as hippocampal neurogenesis, mood and memory. Previous studies have shown that exercise enhances hippocampal neurogenesis, induces antidepressant effects and improves learning behavior. Brain serotonin (5-hydroxytryptamine, 5-HT) levels increase following exercise, and the 5-HT system has been suggested to have an important role in these exercise-induced neuronal effects. However, the precise mechanism remains unclear. In this study, analysis of the 5-HT type 3A receptor subunit-deficient (htr3a(-/-)) mice revealed that lack of the 5-HT type 3 (5-HT3) receptor resulted in loss of exercise-induced hippocampal neurogenesis and antidepressant effects, but not of learning enhancement. Furthermore, stimulation of the 5-HT3 receptor promoted neurogenesis. These findings demonstrate that the 5-HT3 receptor is the critical target of 5-HT action in the brain following exercise, and is indispensable for hippocampal neurogenesis and antidepressant effects induced by exercise. This is the first report of a pivotal 5-HT receptor subtype that has a fundamental role in exercise-induced morphological changes and psychological effects. PMID:25403840

  4. Distinct circuits underlie the effects of 5-HT1B receptors on aggression and impulsivity

    PubMed Central

    Nautiyal, Katherine M.; Tanaka, Kenji F.; Barr, Mary M.; Tritschler, Laurent; Le Dantec, Yannick; David, Denis J.; Gardier, Alain M.; Blanco, Carlos; Hen, René; Ahmari, Susanne E.

    2015-01-01

    Summary Impulsive and aggressive behaviors are both modulated by serotonergic signaling, specifically through the serotonin 1B receptor (5-HT1BR). 5-HT1BR knockout mice show increased aggression and impulsivity, and 5-HT1BR polymorphisms are associated with aggression and drug addiction in humans. To dissect the mechanisms by which the 5-HT1BR affects these phenotypes, we developed a mouse model to spatially and temporally regulate 5-HT1BR expression. Our results demonstrate that forebrain 5-HT1B heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. However, distinct heteroreceptors acting during adulthood are involved in mediating impulsivity. Correlating with the impulsivity, dopamine in the nucleus accumbens is elevated in the absence of 5-HT1BRs, and normalized following adult rescue of the receptor. Overall, these data show that while adolescent expression of 5-HT1BRs influences aggressive behavior, a distinct set of 5-HT1B receptors modulate impulsive behavior during adulthood. PMID:25892302

  5. Synthesis and biological evaluation of 4-nitroindole derivatives as 5-HT2A receptor antagonists.

    PubMed

    Hayat, Faisal; Viswanath, Ambily Nath Indu; Pae, Ae Nim; Rhim, Hyewhon; Park, Woo-Kyu; Choo, Hea-Young Park

    2015-03-15

    A novel series of 4-nitroindole sulfonamides containing a methyleneamino-N,N-dimethylformamidine were prepared. The binding of these compounds to 5-HT2A and 5-HT2C was evaluated, and most of the compounds showed IC50 values of less than 1μM, and exhibited high selectivity for the 5-HT2C receptor. However, little selectivity was observed in the functional assay for 5-HT6 receptors. The computational modeling studies further validated the biological results and also demonstrated a reasonable correlation between the activity of compounds and the mode of superimposition with specified pharmacophoric features. PMID:25684421

  6. A novel aminotetralin-type serotonin (5-HT) 2C receptor-specific agonist and 5-HT2A competitive antagonist/5-HT2B inverse agonist with preclinical efficacy for psychoses.

    PubMed

    Canal, Clinton E; Morgan, Drake; Felsing, Daniel; Kondabolu, Krishnakanth; Rowland, Neil E; Robertson, Kimberly L; Sakhuja, Rajeev; Booth, Raymond G

    2014-05-01

    Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (-)-trans-(2S,4R)-4-(3'[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (-)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (-)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (-)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (-)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (-)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (-)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders. PMID:24563531

  7. A Novel Aminotetralin-Type Serotonin (5-HT) 2C Receptor-Specific Agonist and 5-HT2A Competitive Antagonist/5-HT2B Inverse Agonist with Preclinical Efficacy for Psychoses

    PubMed Central

    Morgan, Drake; Felsing, Daniel; Kondabolu, Krishnakanth; Rowland, Neil E.; Robertson, Kimberly L.; Sakhuja, Rajeev; Booth, Raymond G.

    2014-01-01

    Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (−)-trans-(2S,4R)-4-(3′[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (−)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (−)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (−)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (−)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (−)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (−)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders. PMID:24563531

  8. 5-hydroxytryptamine (5-HT) reduces total peripheral resistance during chronic infusion: direct arterial mesenteric relaxation is not involved

    PubMed Central

    2012-01-01

    Serotonin (5-hydroxytryptamine; 5-HT) delivered over 1 week results in a sustained fall in blood pressure in the sham and deoxycorticosterone acetate (DOCA)-salt rat. We hypothesized 5-HT lowers blood pressure through direct receptor-mediated vascular relaxation. In vivo, 5-HT reduced mean arterial pressure (MAP), increased heart rate, stroke volume, cardiac index, and reduced total peripheral resistance during a 1 week infusion of 5-HT (25 µg/kg/min) in the normotensive Sprague Dawley rat. The mesenteric vasculature was chosen as an ideal candidate for the site of 5-HT receptor mediated vascular relaxation given the high percentage of cardiac output the site receives. Real-time RT-PCR demonstrated that mRNA transcripts for the 5-HT2B, 5-HT1B, and 5-HT7 receptors are present in sham and DOCA-salt superior mesenteric arteries. Immunohistochemistry and Western blot validated the presence of the 5-HT2B, 5- HT1B and 5-HT7 receptor protein in sham and DOCA-salt superior mesenteric artery. Isometric contractile force was measured in endothelium-intact superior mesenteric artery and mesenteric resistance arteries in which the contractile 5- HT2A receptor was antagonized. Maximum concentrations of BW-723C86 (5- HT2B agonist), CP 93129 (5-HT1B agonist) or LP-44 (5-HT7 agonist) did not relax the superior mesenteric artery from DOCA-salt rats vs. vehicle. Additionally, 5-HT (10–9 M to 10–5 M) did not cause relaxation in either contracted mesenteric resistance arteries or superior mesenteric arteries from normotensive Sprague- Dawley rats. Thus, although 5-HT receptors known to mediate vascular relaxation are present in the superior mesenteric artery, they are not functional, and are therefore not likely involved in a 5-HT-induced fall in total peripheral resistance and MAP. PMID:22559843

  9. Involvement of 5-HT3 receptors in the action of vortioxetine in rat brain: Focus on glutamatergic and GABAergic neurotransmission.

    PubMed

    Riga, Maurizio S; Sánchez, Connie; Celada, Pau; Artigas, Francesc

    2016-09-01

    The antidepressant vortioxetine is a 5-HT3-R, 5-HT7-R and 5-HT1D-R antagonist, 5-HT1B-R partial agonist, 5-HT1A-R agonist, and serotonin (5-HT) transporter (SERT) inhibitor. Vortioxetine occupies all targets at high therapeutic doses and only SERT and 5-HT3-R at low doses. Vortioxetine increases extracellular monoamine concentrations in rat forebrain more than selective serotonin reuptake inhibitors (SSRI) and shows pro-cognitive activity in preclinical models. Given its high affinity for 5-HT3-R (Ki = 3.7 nM), selectively expressed in GABA interneurons, we hypothesized that vortioxetine may disinhibit glutamatergic and monoaminergic neurotransmission following 5-HT3-R blockade. Here we assessed vortioxetine effect on pyramidal neuron activity and extracellular 5-HT concentration using in vivo extracellular recordings of rat medial prefrontal cortex (mPFC) pyramidal neurons and microdialysis in mPFC and ventral hippocampus (vHPC). Vortioxetine, but not escitalopram, increased pyramidal neuron discharge in mPFC. This effect was prevented by SR57227A (5-HT3-R agonist) and was mimicked by ondansetron (5-HT3-R antagonist) and by escitalopram/ondansetron combinations. In microdialysis experiments, ondansetron augmented the 5-HT-enhancing effect of escitalopram in mPFC and vHPC. Local ondansetron in vHPC augmented escitalopram effect, indicating the participation of intrinsic mechanisms. Since 5-HT neurons express GABAB receptors, we examined their putative involvement in controlling 5-HT release after 5-HT3-R blockade. Co-perfusion of baclofen (but not muscimol) reversed the increased 5-HT levels produced by vortioxetine and escitalopram/ondansetron combinations in vHPC. The present results suggest that vortioxetine increases glutamatergic and serotonergic neurotransmission in rat forebrain by blocking 5-HT3 receptors in GABA interneurons. PMID:27106166

  10. BEopt-CA (Ex): A Tool for Optimal Integration of EE, DR and PV in Existing California Homes

    SciTech Connect

    Christensen, Craig; Horowitz, Scott; Maguire, Jeff; Velasco, Paulo Tabrares; Springer, David; Coates, Peter; Bell, Christy; Price, Snuller; Sreedharan, Priya; Pickrell, Katie

    2014-04-01

    This project targeted the development of a software tool, BEopt-CA (Ex) (Building Energy Optimization Tool for California Existing Homes), that aims to facilitate balanced integration of energy efficiency (EE), demand response (DR), and photovoltaics (PV) in the residential retrofit1 market. The intent is to provide utility program managers and contractors in the EE/DR/PV marketplace with a means of balancing the integration of EE, DR, and PV

  11. 5-Chloroindole: a potent allosteric modulator of the 5-HT3 receptor

    PubMed Central

    Newman, Amy S; Batis, Nikolaos; Grafton, Gillian; Caputo, Francesca; Brady, Catherine A; Lambert, Jeremy J; Peters, John A; Gordon, John; Brain, Keith L; Powell, Andrew D; Barnes, Nicholas M

    2013-01-01

    Background and Purpose The 5-HT3 receptor is a ligand-gated ion channel that is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics. However the positive allosteric modulators (PAMs) identified to date have low affinity, which hinders investigation because of non-selective effects at pharmacologically active concentrations. The present study identifies 5-chloroindole (Cl-indole) as a potent PAM of the 5-HT3 receptor. Experimental Approach 5-HT3 receptor function was assessed by the increase in intracellular calcium and single-cell electrophysiological recordings in HEK293 cells stably expressing the h5-HT3A receptor and also the mouse native 5-HT3 receptor that increases neuronal contraction of bladder smooth muscle. Key Results Cl-indole (1–100 μM) potentiated agonist (5-HT) and particularly partial agonist [(S)-zacopride, DDP733, RR210, quipazine, dopamine, 2-methyl-5-HT, SR57227A, meta chlorophenyl biguanide] induced h5-HT3A receptor-mediated responses. This effect of Cl-indole was also apparent at the mouse native 5-HT3 receptor. Radioligand-binding studies identified that Cl-indole induced a small (∼twofold) increase in the apparent affinity of 5-HT for the h5-HT3A receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. Cl-indole was able to reactivate desensitized 5-HT3 receptors. In contrast to its effect on the 5-HT3 receptor, Cl-indole did not alter human nicotinic α7 receptor responses. Conclusions and Implications The present study identifies Cl-indole as a relatively potent and selective PAM of the 5-HT3 receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5-HT3 receptor and may assist the discovery of novel therapeutic drugs targeting this receptor. Linked Articles Recent reviews on allosteric modulation can be found at: Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2

  12. Cholecystokinin release mediated by 5-HT3 receptors in rat cerebral cortex and nucleus accumbens.

    PubMed Central

    Paudice, P.; Raiteri, M.

    1991-01-01

    1. The effects of 5-hydroxytryptamine (5-HT) on the release of cholexystokinin-like immunoreactivity (CCK-LI) were examined in synaptosomes prepared from rat cerebral cortex and nucleus accumbens and depolarized by superfusion with 15 mM KCl. 2. In both areas 5-HT, tested between 0.1 and 100 nM, increased the calcium-dependent, depolarization-evoked CCK-LI release in a concentration-related manner. The concentration-response curves did not differ significantly between the two brain areas (EC50: 0.4 +/- 0.045 nM and 0.48 +/- 0.053 nM, respectively, in cortical and n. accumbens synaptosomes; maximal effect: about 60% at 10 nM 5-HT). 3. The 5-HT1/5-HT2 receptor antagonist methiothepin (300 nM) did not affect the CCK-LI release elicited by 10 nM 5-HT. However, the effects of 10 nM 5-HT were antagonized in a concentration-dependent manner by the 5-HT3 receptor antagonists (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930; 0.1-100 nM; IC50: 3.56 +/- 0.42 nM in the cortex and 3.90 +/- 0.50 nM in the n. accumbens) and ondasetron (IC50: 8.15 +/- 0.73 nM in the cerebral cortex). 5-HT (10 nM) was also strongly antagonized by 100 nM 1 alpha H, 3 alpha 5 alpha H-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222) another blocker of the 5-HT3 receptor. Moreover, the 5-HT3 receptor agonist 1-phenylbiguanide (tested in the cerebral cortex between 0.1 and 100 nM) enhanced CCK-LI release in a manner almost identical to that of 5-HT (EC50 = 0.64 +/- 0.071 nM). 4. It is concluded that 5-HT can act as a potent releaser of CCK-LI in rat cerebrocortex and nucleus accumbens through the activation of receptors of the 5-HT3 type situated on the CCK-releasing terminals. This interaction may provide a rationale for the clinical development of both 5-HT3 and CCK receptor antagonists as novel anxiolytic drugs. PMID:1933141

  13. Cervical spinal cord injury upregulates ventral spinal 5-HT2A receptors.

    PubMed

    Fuller, David D; Baker-Herman, Tracy L; Golder, Francis J; Doperalski, Nicholas J; Watters, Jyoti J; Mitchell, Gordon S

    2005-02-01

    Following chronic C2 spinal hemisection (C2HS), crossed spinal pathways to phrenic motoneurons exhibit a slow, spontaneous increase in efficacy by a serotonin (5-HT)-dependent mechanism associated with 5-HT2A receptor activation. Further, the spontaneous appearance of cross-phrenic activity following C2HS is accelerated and enhanced by exposure to chronic intermittent hypoxia (CIH). We hypothesized that chronic C2HS would increase 5-HT and 5-HT2A receptor expression in ventral cervical spinal segments containing phrenic motoneurons. In addition, we hypothesized that CIH exposure would further increase 5-HT and 5-HT2A receptor density in this region. Control, sham-operated, and C2HS Sprague-Dawley rats were studied following normoxia or CIH (11% O2-air; 5-min intervals; nights 7-14 post-surgery). At 2 weeks post-surgery, ventral spinal gray matter extending from C4 and C5 was isolated ipsilateral and contralateral to C2HS. Neither C2HS nor CIH altered 5-HT concentration measured with an ELISA on either side of the spinal cord. However, 5-HT2A receptor expression assessed with immunoblots increased in ipsilateral gray matter following C2HS, an effect independent of CIH. Immunocytochemistry revealed increased 5-HT2A receptor expression on identified phrenic motoneurons (p<0.05), as well as in the surrounding gray matter. Contralateral to injury, 5-HT2A receptor expression was elevated in CIH, but not normoxic C2HS rats (p<0.05). Our data are consistent with the hypothesis that spontaneous increase in 5-HT2A receptor expression on or near phrenic motoneurons contributes to strengthened crossed-spinal synaptic pathways to phrenic motoneurons following C2HS. PMID:15716627

  14. Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology

    PubMed Central

    Browning, Kirsteen N.

    2015-01-01

    Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut-brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity. PMID:26578870

  15. Limits on a light Higgs boson in e+e- collisions at LEP

    NASA Astrophysics Data System (ADS)

    Akrawy, M. Z.; Alexander, G.; Allison, J.; Allport, P. P.; Anderson, K. J.; Armitage, J. C.; Arnison, G. T. J.; Ashton, P.; Azuelos, G.; Baines, J. T. M.; Ball, A. H.; Banks, J.; Barker, G. J.; Barlow, R. J.; Batley, J. R.; Beck, A.; Becker, J.; Behnke, T.; Bell, K. W.; Bella, G.; Bethke, S.; Biebel, O.; Binder, U.; Bloodworth, I. J.; Bock, P.; Breuker, H.; Brown, R. M.; Brun, R.; Buijs, A.; Burckhart, H. J.; Capiluppi, P.; Carnegie, R. K.; Carter, A. A.; Carter, J. R.; Chang, C. Y.; Charlton, D. G.; Chrin, J. T. M.; Clarke, P. E. L.; Cohen, I.; Collins, W. J.; Conboy, J. E.; Couch, M.; Coupland, M.; Cuffiani, M.; Dado, S.; Dallavalle, G. M.; Debu, P.; Deninno, M. M.; Dieckmann, A.; Dittmar, M.; Dixit, M. S.; Duchovni, E.; Duerdoth, I. P.; Dumas, D.; Mamouni, H. El; Elcombe, P. A.; Estabrooks, P. G.; Etzion, E.; Fabbri, F.; Farthouat, P.; Fischer, H. M.; Fong, D. G.; French, M. T.; Fukunaga, C.; Gaidot, A.; Ganel, O.; Gary, J. W.; Gascon, J.; Geddes, N. I.; Gee, C. N. P.; Geich-Gimbel, C.; Gensler, S. W.; Gentit, F. X.; Giacomelli, G.; Gibson, V.; Gibson, W. R.; Gillies, J. D.; Goldberg, J.; Goodrick, M. J.; Gorn, W.; Granite, D.; Gross, E.; Grunhaus, J.; Hagedorn, H.; Hagemann, J.; Hansroul, M.; Hargrove, C. K.; Harris, I.; Hart, J.; Hattersley, P. M.; Hauschild, M.; Hawkes, C. M.; Heflin, E.; Hemingway, R. J.; Heuer, R. D.; Hill, J. C.; Hillier, S. J.; Ho, C.; Hobbs, J. D.; Hobson, P. R.; Hochman, D.; Holl, B.; Homer, R. J.; Hou, S. R.; Howarth, C. P.; Hughes-Jones, R. E.; Humbert, R.; Igo-Kemenes, P.; Ihssen, H.; Imrie, D. C.; Janissen, J.; Jawahery, A.; Jeffreys, P. W.; Jeremie, H.; Jimack, M.; Jobes, M.; Jones, R. W. L.; Jovanovic, P.; Karlen, D.; Kawagoe, K.; Kawamoto, T.; Kellogg, R. G.; Kennedy, B. W.; Kleinwort, C.; Klem, D. E.; Knop, G.; Kobayashi, T.; Kokott, T. P.; Köpke, L.; Kowalewski, R.; Kreutzmann, H.; Kroll, J.; Kuwano, M.; Kyberd, P.; Lafferty, G. D.; Lamarche, F.; Larson, W. J.; Layter, J. G.; Du, P. Le; Leblanc, P.; Lee, A. M.; Lehto, M. H.; Lellouch, D.; Lennert, P.; Lessard, L.; Levinson, L.; Llyod, S. L.; Loebinger, F. K.; Lorah, J. M.; Lorazo, B.; Losty, M. J.; Ludwig, J.; Ma, J.; MacBeth, A. A.; Mannelli, M.; Marcellini, S.; Maringer, G.; Martin, A. J.; Martin, J. P.; Mashimo, T.; Mättig, P.; Maur, U.; McMahon, T. J.; McNutt, J. R.; Meijers, F.; Menszner, D.; Merritt, F. S.; Mes, H.; Michelini, A.; Middleton, R. P.; Mikenberg, G.; Mildenberger, J.; Miller, D. J.; Milstene, C.; Minowa, M.; Mohr, W.; Montanari, A.; Mori, T.; Moss, M. W.; Murphy, P. G.; Murray, W. J.; Nellen, B.; Nguyen, H. H.; Nozaki, M.; O'Dowd, A. J. P.; O'Neale, S. W.; O'Neill, B. P.; Oakham, F. G.; Odorici, F.; Ogg, M.; Oh, H.; Oreglia, M. J.; Orito, S.; Pansart, J. P.; Patrick, G. N.; Pawley, S. J.; Pfister, P.; Pilcher, J. E.; Pinfold, J. L.; Plane, D. E.; Poli, B.; Pouladdej, A.; Prebys, E.; Pritchard, T. W.; Quast, G.; Raab, J.; Redmond, M. W.; Rees, D. L.; Regimbald, M.; Riles, K.; Roach, C. M.; Robins, S. A.; Rollnik, A.; Roney, J. M.; Rossberg, S.; Rossi, A. M.; Routenburg, P.; Runge, K.; Runolfsson, O.; Sanghera, S.; Sansum, R. A.; Sasaki, M.; Saunders, B. J.; Schaile, A. D.; Schaile, O.; Schappert, W.; Scharff-Hansen, P.; Schreiber, S.; Schwarz, J.; Shapira, A.; Shen, B. C.; Sherwood, P.; Simon, A.; Siroli, G. P.; Skuja, A.; Smith, A. M.; Smith, T. J.; Snow, G. A.; Springer, R. W.; Sproston, M.; Stephens, K.; Stier, H. E.; Ströhmer, R.; Strom, D.; Takeda, H.; Takeshita, T.; Thackray, N. J.; Tsukamoto, T.; Turner, M. F.; Tysarczyk-Niemeyer, G.; van den Plas, D.; Vandalen, G. J.; Vasseur, G.; Virtue, C. J.; von der Schmitt, H.; von Krogh, J.; Wagner, A.; Wahl, C.; Walker, J. P.; Ward, C. P.; Ward, D. R.; Watkins, P. M.; Watson, A. T.; Watson, N. K.; Weber, M.; Weisz, S.; Wells, P. S.; Wermes, N.; Weymann, M.; Wilson, G. W.; Wilson, J. A.; Wingerter, I.; Winterer, V.-H.; Wood, N. C.; Wotton, S.; Wuensch, B.; Wyatt, T. R.; Yaari, R.; Yang, Y.; Yekutieli, G.; Yoshida, T.; Zeuner, W.; Zorn, G. T.

    1990-11-01

    Data from e+e- collisions collected with the OPAL detector at LEP have been used to exclude a standard model Higgs boson (H0) with mass below 2mμ. The analysis used 1.2 pb-1 of data taken at centre-of-mass energies between 88.3 and 95.0 GeV to search for the reactions e+e--->Z0H0, (Z0-->e+e- or μ+μ-, H0-->undetected), e+e--->Z0H0, (Z0-->νν, H0-->e+e- or γγ). The existence of a minimal standard model H0 with mass in the range 0<=mH<=2mμ is excluded at the 95% confidence level. The limit is also valid for standard model extensions with a large branching ratio for the decay of H0 to γγ.

  16. ORBITAL ORIENTATIONS OF EXOPLANETS: HAT-P-4b IS PROGRADE AND HAT-P-14b IS RETROGRADE

    SciTech Connect

    Winn, Joshua N.; Albrecht, Simon; Howard, Andrew W.; Marcy, Geoffrey W.; Isaacson, Howard; Johnson, John Asher; Crepp, Justin R.; Morton, Timothy D.; Shporer, Avi; Bakos, Gaspar A.; Hartman, Joel D.; Holman, Matthew J.

    2011-02-15

    We present observations of the Rossiter-McLaughlin effect for two exoplanetary systems, revealing the orientations of their orbits relative to the rotation axes of their parent stars. HAT-P-4b is prograde, with a sky-projected spin-orbit angle of {lambda} = -4.9 {+-} 11.9 deg. In contrast, HAT-P-14b is retrograde, with {lambda} = 189.1 {+-} 5.1 deg. These results conform with a previously noted pattern among the stellar hosts of close-in giant planets: hotter stars have a wide range of obliquities and cooler stars have low obliquities. This, in turn, suggests that three-body dynamics and tidal dissipation are responsible for the short-period orbits of many exoplanets. In addition, our data revealed a third body in the HAT-P-4 system, which could be a second planet or a companion star.

  17. Clinical Applications of S53P4 Bioactive Glass in Bone Healing and Osteomyelitic Treatment: A Literature Review

    PubMed Central

    van Gestel, N. A. P.; Geurts, J.; Hulsen, D. J. W.; van Rietbergen, B.; Hofmann, S.; Arts, J. J.

    2015-01-01

    Nowadays, S53P4 bioactive glass is indicated as a bone graft substitute in various clinical applications. This review provides an overview of the current published clinical results on indications such as craniofacial procedures, grafting of benign bone tumour defects, instrumental spondylodesis, and the treatment of osteomyelitis. Given the reported results that are based on examinations, such as clinical examinations by the surgeons, radiographs, CT, and MRI images, S53P4 bioactive glass may be beneficial in the various reported applications. Especially in craniofacial reconstructions like mastoid obliteration and orbital floor reconstructions, in grafting bone tumour defects, and in the treatment of osteomyelitis very promising results are obtained. Randomized clinical trials need to be performed in order to determine whether bioactive glass would be able to replace the current golden standard of autologous bone usage or with the use of antibiotic containing PMMA beads (in the case of osteomyelitis). PMID:26504821

  18. Binding Patterns of Rotavirus Genotypes P[4], P[6], and P[8] in China with Histo-Blood Group Antigens.

    PubMed

    Ma, Xin; Li, Dan-di; Sun, Xiao-Man; Guo, Yan-Qing; Xiang, Jing-Yao; Wang, Wei-Huan; Zhang, Li-Xia; Gu, Qing-Jiu; Duan, Zhao-Jun

    2015-01-01

    Rotaviruses (RVs) are an important cause of severe gastroenteritis in children. It has been found that RV may recognize the histo-blood group antigens (HBGAs) as ligands or receptors and bind HBGAs in a type-dependent manner. In this study, we investigated the binding specificity of VP8* proteins from human rotaviruses (RV) that are prevalent in China including genotypes P[4], P[6], and P[8]. Through the saliva- and oligosaccharide-based binding assays, we found that the VP8* proteins of P[4] and P[8] RV showed similar reactivity with the Leb and H type 1 antigens, while P[6] RV weakly bound the Leb antigen. These findings may facilitate further research into RV host specificity and vaccine development. PMID:26274396

  19. Binding Patterns of Rotavirus Genotypes P[4], P[6], and P[8] in China with Histo-Blood Group Antigens

    PubMed Central

    Ma, Xin; Li, Dan-di; Sun, Xiao-man; Guo, Yan-qing; Xiang, Jing-yao; Wang, Wei-huan; Zhang, Li-xia; Gu, Qing-jiu; Duan, Zhao-jun

    2015-01-01

    Rotaviruses (RVs) are an important cause of severe gastroenteritis in children. It has been found that RV may recognize the histo-blood group antigens (HBGAs) as ligands or receptors and bind HBGAs in a type-dependent manner. In this study, we investigated the binding specificity of VP8* proteins from human rotaviruses (RV) that are prevalent in China including genotypes P[4], P[6], and P[8]. Through the saliva- and oligosaccharide-based binding assays, we found that the VP8* proteins of P[4] and P[8] RV showed similar reactivity with the Leb and H type 1 antigens, while P[6] RV weakly bound the Leb antigen. These findings may facilitate further research into RV host specificity and vaccine development. PMID:26274396

  20. Carbohydrates as additives for the formation of isoporous PS-b-P4VP diblock copolymer membranes.

    PubMed

    Clodt, Juliana Isabel; Rangou, Sofia; Schröder, Anne; Buhr, Kristian; Hahn, Janina; Jung, Adina; Filiz, Volkan; Abetz, Volker

    2013-01-25

    Highly porous polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) diblock copolymer membranes are prepared using carbohydrates as additives. Therefore α-cyclodextrine, α-(D)-glucose, and saccharose (cane sugar) are tested for the membrane formation of three different PS-b-P4VP polymers. The addition of the carbohydrates leads to an increasing viscosity of the membrane solutions due to hydrogen bonding between hydroxyl groups of the carbohydrates and pyridine units of the block copolymer. In all cases, the membranes made from solution with carbohydrates have higher porosity, an improved narrow pore distribution on the surface and a higher water flux as membranes made without carbohydrates with the same polymer, solvent ratio, and polymer concentration. PMID:23225180

  1. Occurrence of 17α-ethynylestradiol (EE2) in the environment and effect on exposed biota: a review.

    PubMed

    Aris, Ahmad Zaharin; Shamsuddin, Aida Soraya; Praveena, Sarva Mangala

    2014-08-01

    17α-ethynylestradiol (EE2) is a synthetic hormone, which is a derivative of the natural hormone, estradiol (E2). EE2 is an orally bio-active estrogen, and is one of the most commonly used medications for humans as well as livestock and aquaculture activity. EE2 has become a widespread problem in the environment due to its high resistance to the process of degradation and its tendency to (i) absorb organic matter, (ii) accumulate in sediment and (iii) concentrate in biota. Numerous studies have reported the ability of EE2 to alter sex determination, delay sexual maturity, and decrease the secondary sexual characteristics of exposed organisms even at a low concentration (ng/L) by mimicking its natural analogue, 17β-estradiol (E2). Thus, the aim of this review is to provide an overview of the science regarding EE2, the concentration levels in the environment (water, sediment and biota) and summarize the effects of this compound on exposed biota at various concentrations, stage life, sex, and species. The challenges in respect of EE2 include the extension of the limited database on the EE2 pollution profile in the environment, its fate and transport mechanism, as well as the exposure level of EE2 for better prediction and definition revision of EE2 toxicity end points, notably for the purpose of environmental risk assessment. PMID:24825791

  2. Nqrs Data for C24H76BLiN12O4P4 (Subst. No. 1593)

    NASA Astrophysics Data System (ADS)

    Chihara, H.; Nakamura, N.

    This document is part of Subvolume B 'Substances Containing C10H16 … Zn' of Volume 48 'Nuclear Quadrupole Resonance Spectroscopy Data' of Landolt-Börnstein - Group III 'Condensed Matter'. It contains an extract of Section '3.2 Data tables' of the Chapter '3 Nuclear quadrupole resonance data' providing the NQRS data for C24H76BLiN12O4P4 (Subst. No. 1593)

  3. P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile.

    PubMed

    Nair, Latha G; Sannigrahi, Mousumi; Bogen, Stephane; Pinto, Patrick; Chen, Kevin X; Prongay, Andrew; Tong, Xiao; Cheng, K-C; Girijavallabhan, Viyyoor; George Njoroge, F

    2010-01-15

    SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K(i)( *)=15nM, EC 90=70nM) and pharmacokinetic properties (Rat AUC (PO)=3.52microMh) compared to 1. PMID:20004570

  4. P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile

    SciTech Connect

    Nair, Latha G.; Sannigrahi, Mousumi; Bogen, Stephane; Pinto, Patrick; Chen, Kevin X.; Prongay, Andrew; Tong, Xiao; Cheng, K.-C.; Girijavallabhann, Viyyoor; Njoroge, F. George

    2010-09-03

    SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4,4-dimethyl lactam as the new P4 cap unit with improved potency (K*{sub i}, EC 90 = 70 nM) and pharmacokinetic properties (Rat AUC (PO) = 3.52 {micro}M h) compared to 1.

  5. Distribution of serotonin 5-HT1A-binding sites in the brainstem and the hypothalamus, and their roles in 5-HT-induced sleep and ingestive behaviors in rock pigeons (Columba livia).

    PubMed

    dos Santos, Tiago Souza; Krüger, Jéssica; Melleu, Fernando Falkenburger; Herold, Christina; Zilles, Karl; Poli, Anicleto; Güntürkün, Onur; Marino-Neto, José

    2015-12-15

    Serotonin 1A receptors (5-HT1ARs), which are widely distributed in the mammalian brain, participate in cognitive and emotional functions. In birds, 5-HT1ARs are expressed in prosencephalic areas involved in visual and cognitive functions. Diverse evidence supports 5-HT1AR-mediated 5-HT-induced ingestive and sleep behaviors in birds. Here, we describe the distribution of 5-HT1ARs in the hypothalamus and brainstem of birds, analyze their potential roles in sleep and ingestive behaviors, and attempt to determine the involvement of auto-/hetero-5-HT1ARs in these behaviors. In 6 pigeons, the anatomical distribution of [(3)H]8-OH-DPAT binding in the rostral brainstem and hypothalamus was examined. Ingestive/sleep behaviors were recorded (1h) in 16 pigeons pretreated with MM77 (a heterosynaptic 5-HT1AR antagonist; 23 or 69 nmol) for 20 min, followed by intracerebroventricular ICV injection of 5-HT (N:8; 150 nmol), 8-OH-DPAT (DPAT, a 5-HT1A,7R agonist, 30 nmol N:8) or vehicle. 5-HT- and DPAT-induced sleep and ingestive behaviors, brainstem 5-HT neuronal density and brain 5-HT content were examined in 12 pigeons, pretreated by ICV with the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or vehicle (N:6/group). The distribution of brainstem and diencephalic c-Fos immunoreactivity after ICV injection of 5-HT, DPAT or vehicle (N:5/group) into birds provided with or denied access to water is also described. 5-HT1ARs are concentrated in the brainstem 5-HTergic areas and throughout the periventricular hypothalamus, preoptic nuclei and circumventricular organs. 5-HT and DPAT produced a complex c-Fos expression pattern in the 5-HT1AR-enriched preoptic hypothalamus and the circumventricular organs, which are related to drinking and sleep regulation, but modestly affected c-Fos expression in 5-HTergic neurons. The 5-HT-induced ingestivebehaviors and the 5-HT- and DPAT-induced sleep behaviors were reduced by MM77 pretreatment. 5,7-DHT increased sleep per se, decreased tryptophan

  6. The 2009 Eclipse of EE Cephei: An Educational and Collaborative Journey

    NASA Astrophysics Data System (ADS)

    Pye, John; Elder, Lauren; Hopkins, Jeff

    2009-05-01

    In December 2008 Jeff Hopkins of the Hopkins Phoenix Observatory (HPO) put out a request for assistance in extracting data from images taken by the AAVSO SRO (Sonoita Research Observatory) of EE Cephei, an 11th magnitude (V) long period (5.6 years) eclipsing binary star system that was due to eclipse in January of 2009. The Hopkins Phoenix Observatory originally planned to do BVRI CCD photometry of EE Cephei for the 2009 eclipse, but equipment and logistical changes at HPO meant the EE Cephei project would not be possible. However, in the fall of 2008 Arne Henden of the AAVSO announced the availability of a remote robotic 16" telescope (the Sonoita Research Observatory) in southern Arizona for use by members of the AAVSO. Jeff Hopkins contacted Arne Henden and arrangements were made to have the EE Cephei star system imaged with BVRI filters beginning in November 2008 and running through February 2009. Image files were archived on the AAVSO web site. Soon after his initial request went out, Jeff Hopkins was contacted by John Pye from Maui Community College, who agreed to help with the project by having one of his students, Lauren Elder, examine the image files and extract EE Cephei and 3 comparison stars flux (ADU) counts for each band. The resulting data were then sent to the Hopkins Phoenix Observatory for data reduction and analysis. The project was a successful joint collaboration with 40 nights of observations for over 300 BVRI data points from 20 November 2008 to 17 February 2009. Light curves for each band as well as color indices were plotted and eclipse contact points were determined. The data were also contributed to the EE Cephei Campaign organized by Cezary Galan at the Centre for Astronomy at Nicolaus Copernicus University in Torun (Poland). Our results are plotted along with those of several dozen other observers from around the world.

  7. e+e- collisions in the multi-TeV region

    SciTech Connect

    Ellis, J.

    1983-05-01

    A leading role in the elucidation of the Standard Model during the last few years has been played by e+e- colliding beam experiments. The e+e- discoveries have been made possible by the cleanliness of the experimental conditions and the ability to tune the centre-of-mass energy with precision to the desired value, thus avoiding less interesting background events. We expect history to repeat itself in the next step of elucidating physics beyond the Standard Model. Just as past e+e- machines such as SPEAR, DORIS and CESR have uncovered physics inaccessible to hadron-hadron collisions with a centre-of-mass energy several times higher, so we feel that future e+e- colliders will provide information that could not be duplicated by hadron colliders with much larger centre-of-mass energies. There is a general consensus that the next interesting energy range is likely to be in the TeV range. It is in this energy range that whatever physics provides and stabilizes the masses of the intermediate vector bosons must be revealed. Unravelling this mass generation mechanism takes us beyond the gauge principle of the Standard Model which has been so triumphantly vindicated in recent months. Therefore we discuss here the capabilities and attributes of an e+e- collider with at least 1 TeV energy per beam. We believe that by enabling an important new energy domain to be explored in detail, such an e+e- collider provides physics opportunities which cannot be paralled by hadron-hadron colliding rings with centre-of-mass energies several times higher. (WHK)

  8. eeDAP: an evaluation environment for digital and analog pathology

    NASA Astrophysics Data System (ADS)

    Gallas, Brandon D.; Cheng, Wei-Chung; Gavrielides, Marios A.; Ivansky, Adam; Keay, Tyler; Wunderlich, Adam; Hipp, Jason; Hewitt, Stephen M.

    2014-03-01

    Purpose: The purpose of this work is to present a platform for designing and executing studies that compare pathologists interpreting histopathology of whole slide images (WSI) on a computer display to pathologists interpreting glass slides on an optical microscope. Methods: Here we present eeDAP, an evaluation environment for digital and analog pathology. The key element in eeDAP is the registration of theWSI to the glass slide. Registration is accomplished through computer control of the microscope stage and a camera mounted on the microscope that acquires images of the real time microscope view. Registration allows for the evaluation of the same regions of interest (ROIs) in both domains. This can reduce or eliminate disagreements that arise from pathologists interpreting different areas and focuses the comparison on image quality. Results: We reduced the pathologist interpretation area from an entire glass slide (≈10-30 mm)2 to small ROIs <(50 um)2. We also made possible the evaluation of individual cells. Conclusions: We summarize eeDAP's software and hardware and provide calculations and corresponding images of the microscope field of view and the ROIs extracted from the WSIs. These calculations help provide a sense of eeDAP's functionality and operating principles, while the images provide a sense of the look and feel of studies that can be conducted in the digital and analog domains. The eeDAP software can be downloaded from code.google.com (project: eeDAP) as Matlab source or as a precompiled stand-alone license-free application.

  9. Nature of 5-HT1-like receptors mediating depressor responses in vagosympathectomized rats; close resemblance to the cloned 5-ht7 receptor.

    PubMed

    De Vries, P; Villalón, C M; Heiligers, J P; Saxena, P R

    1997-07-01

    It has been suggested that the late hypotensive response to serotonin (5-hydroxytryptamine; 5-HT) in vagosympathectomized rats is mediated by '5-HT1-like' receptors since this effect is mimicked by 5-carboxamidotryptamine (5-CT), is not modified by cyproheptadine, ketanserin or MDL 72222, but it is blocked by methysergide. The present study was set out to reanalyze this suggestion in terms of the classification schemes proposed in 1994 and 1996 by the NC-IUPHAR subcommittee on the classification and nomenclature of 5-HT receptors. I.v. bolus injections of 5-CT (0.01-0.3 microg x kg(-1)), 5-HT (1-30 microg x kg(-1)) and 5-methoxytryptamine (5-MeO-T; 1-30 microg x kg(-1)) produced dose-dependent hypotensive responses with a rank order of agonist potency: 5-CT > 5-HT > 5-methoxytryptamine with sumatriptan (30-1000 microg x kg(-1)) inactive. The depressor responses to 5-HT and 5-CT were not attenuated by i.v. GR127935 (300-3000 microg x kg(-1)) or equivalent volumes of saline. In contrast, lisuride, methiothepin, mesulergine, metergoline and clozapine dose-dependently antagonized the responses to 5-HT and 5-CT; the rank order of apparent pA2 values against 5-HT and 5-CT, respectively, was: lisuride (7.7; 7.8) > methiothepin (6.8; 7.0) > or = mesulergine (6.4; 6.6) > clozapine (5.7; 5.8); metergoline displayed variable potencies (5.6; 6.4). Except for lisuride, which also affected isoprenaline-induced hypotension, the antagonism by the other drugs was selective. Based upon the above rank order of agonist potency, the blockade by a series of drugs showing high affinity for the cloned 5-ht7 receptor and the lack of blockade by GR127935, our results indicate that the 5-HT receptor mediating hypotension in vagosympathectomized rats is operationally similar to other putative 5-ht7 receptors mediating vascular and non-vascular responses (e.g. relaxation of the rabbit femoral vein, canine coronary and external carotid arteries and guinea-pig ileum as well as feline tachycardia

  10. Transcriptional profiling of genes involved in n-hexadecane compounds assimilation in the hydrocarbon degrading Dietzia cinnamea P4 strain

    PubMed Central

    Procópio, Luciano; de Cassia Pereira e Silva, Michele; van Elsas, Jan Dirk; Seldin, Lucy

    2013-01-01

    The petroleum-derived degrading Dietzia cinnamea strain P4 recently had its genome sequenced and annotated. This allowed employing the data on genes that are involved in the degradation of n-alkanes. To examine the physiological behavior of strain P4 in the presence of n-alkanes, the strain was grown under varying conditions of pH and temperature. D. cinnamea P4 was able to grow at pH 7.0–9.0 and at temperatures ranging from 35 ºC to 45 ºC. Experiments of gene expression by real-time quantitative RT-PCR throughout the complete growth cycle clearly indicated the induction of the regulatory gene alkU (TetR family) during early growth. During the logarithmic phase, a large increase in transcriptional levels of a lipid transporter gene was noted. Also, the expression of a gene that encodes the protein fused rubredoxin-alkane monooxygenase was enhanced. Both genes are probably under the influence of the AlkU regulator. PMID:24294263

  11. Pathways of cylindrical orientations in PS-b-P4VP diblock copolymer thin films upon solvent vapor annealing.

    PubMed

    Gowd, E Bhoje; Koga, Tadanori; Endoh, Maya K; Kumar, Kamlesh; Stamm, Manfred

    2014-10-21

    The orientation changes of perpendicular cylindrical microdomains in polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) thin films upon annealing in different solvent vapors were investigated by in situ grazing incidence small-angle X-ray scattering (GISAXS) and ex situ scanning force microscopy (SFM). The swelling of P4VP perpendicular cylinders (C⊥) in chloroform, a non-selective solvent vapor, leads to the reorientation to in-plane cylinders through a disordered state in a particular kinetic pathway in the phase diagram upon drying. On the other hand, the swelling of the P4VP perpendicular cylinders in a selective solvent vapor (i.e., 1,4-dioxane) induces a morphological transition from cylindrical to ellipsoidal as a transient structure to spherical microdomains; subsequent solvent evaporation resulted in shrinkage of the matrix in the vertical direction, merging the ellipsoidal domains into the perpendicularly aligned cylinders. In this paper, we have discussed the mechanism based on the selectivity of the solvent to the constituting blocks that is mainly responsible for the orientation changes. PMID:25142254

  12. Cellular Localization and Biochemical Analysis of Mammalian CDC50A, a Glycosylated β-subunit for P4 ATPases

    PubMed Central

    Folmer, Dineke E.; Mok, Kam S.; de Wee, Sebastiaan W.; Duijst, Suzanne; Hiralall, Johan K.; Seppen, Jurgen; Oude Elferink, Ronald P. J.

    2012-01-01

    CDC50 proteins are β-subunits for P4 ATPases, which upon heterodimerization form a functional phospholipid translocation complex. Emerging evidence in mouse models and men links mutations in P4 ATPase genes with human disease. This study analyzed the tissue distribution and cellular localization of CDC50A, the most abundant and ubiquitously expressed CDC50 homologue in the mouse. The authors have raised antibodies that detect mouse and human CDC50A and studied CDC50A localization and glycosylation status in mouse liver cells. CDC50A is a terminal-glycosylated glycoprotein and is expressed in hepatocytes and liver sinusoidal endothelial cells, where it resides in detergent-resistant membranes. In pancreas and stomach, CDC50A localized to secretory vesicles, whereas in the kidney, CDC50A localized to the apical region of proximal convoluted tubules of the cortex. In WIF-B9 cells, CDC50A partially costains with the trans-Golgi network. Data suggest that CDC50A is present as a fully glycosylated protein in vivo, which presumes interaction with distinct P4 ATPases. PMID:22253360

  13. Cellular localization and biochemical analysis of mammalian CDC50A, a glycosylated β-subunit for P4 ATPases.

    PubMed

    Folmer, Dineke E; Mok, Kam S; de Wee, Sebastiaan W; Duijst, Suzanne; Hiralall, Johan K; Seppen, Jurgen; Oude Elferink, Ronald P J; Paulusma, Coen C

    2012-03-01

    CDC50 proteins are β-subunits for P4 ATPases, which upon heterodimerization form a functional phospholipid translocation complex. Emerging evidence in mouse models and men links mutations in P4 ATPase genes with human disease. This study analyzed the tissue distribution and cellular localization of CDC50A, the most abundant and ubiquitously expressed CDC50 homologue in the mouse. The authors have raised antibodies that detect mouse and human CDC50A and studied CDC50A localization and glycosylation status in mouse liver cells. CDC50A is a terminal-glycosylated glycoprotein and is expressed in hepatocytes and liver sinusoidal endothelial cells, where it resides in detergent-resistant membranes. In pancreas and stomach, CDC50A localized to secretory vesicles, whereas in the kidney, CDC50A localized to the apical region of proximal convoluted tubules of the cortex. In WIF-B9 cells, CDC50A partially costains with the trans-Golgi network. Data suggest that CDC50A is present as a fully glycosylated protein in vivo, which presumes interaction with distinct P4 ATPases. PMID:22253360

  14. Irradiation Embritlement in Alloy HT-­9

    SciTech Connect

    Serrano De Caro, Magdalena

    2012-08-27

    HT-9 steel is a candidate structural and cladding material for high temperature lead-bismuth cooled fast reactors. In typical advanced fast reactor designs fuel elements will be irradiated for an extended period of time, reaching up to 5-7 years. Significant displacement damage accumulation in the steel is expected (> 200 dpa) when exposed to dpa-rates of 20-30 dpa{sub Fe}/y and high fast flux (E > 0.1 MeV) {approx}4 x 10{sup 15} n/cm{sup 2}s. Core temperatures could reach 400-560 C, with coolant temperatures at the inlet as low as 250 C, depending on the reactor design. Mechanical behavior in the presence of an intense fast flux and high dose is a concern. In particular, low temperature operation could be limited by irradiation embrittlement. Creep and corrosion effects in liquid metal coolants could set a limit to the upper operating temperature. In this report, we focus on the low temperature operating window limit and describe HT-9 embrittlement experimental findings reported in the literature that could provide supporting information to facilitate the consideration of a Code Case on irradiation effects for this class of steels in fast reactor environments. HT-9 has an extensive database available on irradiation performance, which makes it the best choice as a possible near-term candidate for clad, and ducts in future fast reactors. Still, as it is shown in this report, embrittlement data for very low irradiation temperatures (< 200 C) and very high radiation exposure (> 150 dpa) is scarce. Experimental findings indicate a saturation of DBTT shifts as a function of dose, which could allow for long lifetime cladding operation. However, a strong increase in DBTT shift with decreasing irradiation temperature could compromise operation at low service temperatures. Development of a deep understanding of the physics involved in the radiation damage mechanisms, together with multiscale computer simulation models of irradiation embrittlement will provide the basis to

  15. An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist that Corrects Motor Stereotypy in Mouse Models.

    PubMed

    Canal, Clinton E; Felsing, Daniel E; Liu, Yue; Zhu, Wanying; Wood, JodiAnne T; Perry, Charles K; Vemula, Rajender; Booth, Raymond G

    2015-07-15

    Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT7 receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT1A partial agonist with relevant affinity at 5-HT7 receptors. Herein, we report the synthesis, in vitro molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT7 (Ki = 5.8 nM, EC50 = 34 nM) and 5-HT1A (Ki = 22 nM, EC50 = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT2 agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders. PMID:26011730

  16. Highly potent, non-basic 5-HT6 ligands. Site mutagenesis evidence for a second binding mode at 5-HT6 for antagonism.

    PubMed

    Harris, Ralph N; Stabler, Russel S; Repke, David B; Kress, James M; Walker, Keith A; Martin, Renee S; Brothers, Julie M; Ilnicka, Mariola; Lee, Simon W; Mirzadegan, Tara

    2010-06-01

    A series of 5-HT(6) ligands derived from (R)-1-(amino)methyl-6-(phenyl)sulfonyltetralin was prepared that yielded several non-basic analogs having sub-nanomolar affinity. Ligand structure-activity relationships, receptor point mutation studies, and molecular modeling of these novel ligands all combined to reveal a new alternative binding mode to 5-HT(6) for antagonism. PMID:20434910

  17. Electron dynamics and γ and e-e+ production by colliding laser pulses

    NASA Astrophysics Data System (ADS)

    Jirka, M.; Klimo, O.; Bulanov, S. V.; Esirkepov, T. Zh.; Gelfer, E.; Bulanov, S. S.; Weber, S.; Korn, G.

    2016-02-01

    The dynamics of an electron bunch irradiated by two focused colliding super-intense laser pulses and the resulting γ and e-e+ production are studied. Due to attractors of electron dynamics in a standing wave created by colliding pulses the photon emission and pair production, in general, are more efficient with linearly polarized pulses than with circularly polarized ones. The dependence of the key parameters on the laser intensity and wavelength allows us to identify the conditions for the cascade development and γ e-e+ plasma creation.

  18. [Sex determination in ten crane species by DNA marker EE0.6].

    PubMed

    Mudrik, E A; Kashentseva, T A; Gamburg, E A; Politov, D V

    2013-12-01

    Using a unique DNA sequence of W-chromosome EE0.6, we carried out molecular sex determination in 383 individuals often species of cranes (Grusgrus L., G. leucogeranus Pallas, G. japonensis Muller, G. vipio Pallas, G. Canadensis L., G. antigone L., G. monacha Temminck, Anthropoides virgo L., Balearica regulorum Bennett, and B. pavonia L.) kept in zoos and other centers of captive propagation. In 211 birds, sex was determined or verified for the first time. The efficiency of using the sex marker EE0.6 for chicks and immature and adult cranes of different species, as well as for interspecific hybrids was shown. PMID:25438606

  19. [Sex determination in ten crane species by DNA marker EE0.6].

    PubMed

    2013-12-01

    Using a unique DNA sequence of W-chromosome EE0.6, we carried out molecular sex determination in 383 individuals often species of cranes (Grusgrus L., G. leucogeranus Pallas, G. japonensis Muller, G. vipio Pallas, G. Canadensis L., G. antigone L., G. monacha Temminck, Anthropoides virgo L., Balearica regulorum Bennett, and B. pavonia L.) kept in zoos and other centers of captive propagation. In 211 birds, sex was determined or verified for the first time. The efficiency of using the sex marker EE0.6 for chicks and immature and adult cranes of different species, as well as for interspecific hybrids was shown. PMID:25508137

  20. Probing the aromaticity of the [(HtAc)3(μ2-H)6], [(HtTh)3(μ2-H)6],+, and [(HtPa)3(μ2-H)6] clusters

    NASA Astrophysics Data System (ADS)

    Ramírez-Tagle, Rodrigo; Alvarado-Soto, Leonor; Arratia-Perez, Ramiro; Bast, Radovan; Alvarez-Thon, Luis

    2011-09-01

    In this study we report about the aromaticity of the prototypical [(HtAc)3(μ2-H)6], [(HtTh)3(μ2-H)6]+, and [(HtPa)3(μ2-H)6] clusters via two magnetic criteria: nucleus-independent chemical shifts (NICS) and the magnetically induced current density. All-electron density functional theory calculations were carried out using the two-component zeroth-order regular approach and the four-component Dirac-Coulomb Hamiltonian, including scalar and spin-orbit relativistic effects. Four-component current density maps and the integration of induced ring-current susceptibilities clearly show that the clusters [(HtAc)3(μ2-H)6] and [(HtTh)3(μ2-H)6]+ are non-aromatic whereas [(HtPa)3(μ2-H)6] is anti-aromatic. However, for the thorium cluster we find a discrepancy between the current density plots and the classification through the NICS index. Our results also demonstrate the increasing influence of f orbitals, on bonding and magnetic properties, with increasing atomic number in these clusters. We think that the enhanced electron mobility in [(HtPa)3(μ2-H)6] is due the significant 5f character of its valence shell. Also the participation of f orbitals in bonding is the reason why the protactinium cluster has the shortest bond lengths of the three clusters. This study provides another example showing that the magnetically induced current density approach can give more reliable results than the NICS index.

  1. 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor mRNA modulation by antidepressant treatment in the chronic mild stress model of depression: sex differences exposed.

    PubMed

    Pitychoutis, P M; Dalla, C; Sideris, A C; Tsonis, P A; Papadopoulou-Daifoti, Z

    2012-05-17

    It is well established that women experience major depression at roughly twice the rate of men. Interestingly, accumulating clinical and experimental evidence shows that the responsiveness of males and females to antidepressant pharmacotherapy, and particularly to tricyclic antidepressants (TCAs), is sex-differentiated. Herein, we investigated whether exposure of male and female rats to the chronic mild stress (CMS) model of depression, as well as treatment with the TCA clomipramine may affect serotonergic receptors' (5-HTRs) mRNA expression in a sex-dependent manner. Male and female rats were subjected to CMS for 4 weeks and during the next 4 weeks they concurrently received clomipramine treatment (10 mg/ml/kg). CMS and clomipramine's effects on 5-HT(1A)R, 5-HT(2A)R, and 5-HT(2C)R mRNA expression were assessed by in situ hybridization histochemistry in selected subfields of the hippocampus and in the lateral orbitofrontal cortex (OFC), two regions implicated in the pathophysiology of major depression. CMS and clomipramine treatment induced sex-differentiated effects on rats' hedonic status and enhanced 5-HT(1A)R mRNA expression in the cornu ammonis 1 (CA1) hippocampal region of male rats. Additionally, CMS attenuated 5-HT(1A)R mRNA expression in the OFC of male rats and clomipramine reversed this effect. Moreover, 5-HT(2A)R mRNA levels in the OFC were enhanced in females but decreased in males, while clomipramine reversed this effect only in females. CMS increased 5-HT2CR mRNA expression in the CA4 region of both sexes and this effect was attenuated by clomipramine. Present data exposed that both CMS and clomipramine treatment may induce sex-differentiated and region-distinctive effects on 5-HTRs mRNA expression and further implicate the serotonergic system in the manifestation of sexually dimorphic neurobehavioral responses to stress. PMID:22441040

  2. Linking the HOMO-LUMO gap to torsional disorder in P3HT/PCBM blends

    SciTech Connect

    McLeod, John A.; Pitman, Amy L.; Moewes, Alexander; Kurmaev, Ernst Z.; Finkelstein, Larisa D.; Zhidkov, Ivan S.; Savva, Achilleas

    2015-12-14

    The electronic structure of [6,6]-phenyl C{sub 61} butyric acid methyl ester (PCBM), poly(3-hexylthiophene) (P3HT), and P3HT/PCBM blends is studied using soft X-ray emission and absorption spectroscopy and density functional theory calculations. We find that annealing reduces the HOMO-LUMO gap of P3HT and P3HT/PCBM blends, whereas annealing has little effect on the HOMO-LUMO gap of PCBM. We propose a model connecting torsional disorder in a P3HT polymer to the HOMO-LUMO gap, which suggests that annealing helps to decrease the torsional disorder in the P3HT polymers. Our model is used to predict the characteristic length scales of the flat P3TH polymer segments in P3HT and P3HT/PCBM blends before and after annealing. Our approach may prove useful in characterizing organic photovoltaic devices in situ or even in operando.

  3. Binding of indolylalkylamines at 5-HT2 serotonin receptors: examination of a hydrophobic binding region.

    PubMed

    Glennon, R A; Chaurasia, C; Titeler, M

    1990-10-01

    Taking advantage of a proposed hydrophobic region on 5-HT2 receptors previously identified by radioligand-binding studies utilizing various phenylisopropylamine derivatives, we prepared and evaluated several N1 - and/or C7-alkyl-substituted derivatives of alpha-methyltryptamine in order to improve its affinity and selectivity. It was determined that substitution of an n-propyl or amyl group has similar effect on affinity regardless of location (i.e., N1 or C7). The low affinity of several N1-alkylpyrroleethylamines suggests that the benzene portion of the alpha-methyltryptamines is necessary for significant affinity. Whereas tryptamine derivatives generally display little selectivity for the various populations of 5-HT receptors, N1-n-propyl-5-methoxy-alpha-methyltryptamine (3h) binds with significant affinity (Ki = 12 nM) and selectivity at 5-HT2 receptors relative to 5-HT1A (Ki = 7100 nM), 5-HT1B (Ki = 5000 nM), 5-HT1C (Ki = 120 nM), and 5-HT1D (Ki greater than 10,000 nM) receptors. As a consequence, this is the most 5-HT2-selective indolylalkylamine derivative reported to date. PMID:2213830

  4. Linking the HOMO-LUMO gap to torsional disorder in P3HT/PCBM blends.

    PubMed

    McLeod, John A; Pitman, Amy L; Kurmaev, Ernst Z; Finkelstein, Larisa D; Zhidkov, Ivan S; Savva, Achilleas; Moewes, Alexander

    2015-12-14

    The electronic structure of [6,6]-phenyl C61 butyric acid methyl ester (PCBM), poly(3-hexylthiophene) (P3HT), and P3HT/PCBM blends is studied using soft X-ray emission and absorption spectroscopy and density functional theory calculations. We find that annealing reduces the HOMO-LUMO gap of P3HT and P3HT/PCBM blends, whereas annealing has little effect on the HOMO-LUMO gap of PCBM. We propose a model connecting torsional disorder in a P3HT polymer to the HOMO-LUMO gap, which suggests that annealing helps to decrease the torsional disorder in the P3HT polymers. Our model is used to predict the characteristic length scales of the flat P3TH polymer segments in P3HT and P3HT/PCBM blends before and after annealing. Our approach may prove useful in characterizing organic photovoltaic devices in situ or even in operando. PMID:26671393

  5. The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK.

    PubMed

    Lippiello, Pellegrino; Hoxha, Eriola; Speranza, Luisa; Volpicelli, Floriana; Ferraro, Angela; Leopoldo, Marcello; Lacivita, Enza; Perrone-Capano, Carla; Tempia, Filippo; Miniaci, Maria Concetta

    2016-02-01

    The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum. PMID:26482421

  6. Varenicline Interactions at the 5-HT3 Receptor Ligand Binding Site are Revealed by 5-HTBP

    PubMed Central

    2015-01-01

    Cys-loop receptors are the site of action of many therapeutic drugs. One of these is the smoking cessation agent varenicline, which has its major therapeutic effects at nicotinic acetylcholine (nACh) receptors but also acts at 5-HT3 receptors. Here, we report the X-ray crystal structure of the 5-HT binding protein (5-HTBP) in complex with varenicline, and test the predicted interactions by probing the potency of varenicline in a range of mutant 5-HT3 receptors expressed in HEK293 cells and Xenopus oocytes. The structure reveals a range of interactions between varenicline and 5-HTBP. We identified residues within 5 Å of varenicline and substituted the equivalent residues in the 5-HT3 receptor with Ala or a residue with similar chemical properties. Functional characterization of these mutant 5-HT3 receptors, using a fluorescent membrane potential dye in HEK cells and voltage clamp in oocytes, supports interactions between varenicline and the receptor that are similar to those in 5-HTBP. The structure also revealed C-loop closure that was less than in the 5-HT-bound 5-HTBP, and hydrogen bonding between varenicline and the complementary face of the binding pocket via a water molecule, which are characteristics consistent with partial agonist behavior of varenicline in the 5-HT3 receptor. Together, these data reveal detailed insights into the molecular interaction of varenicline in the 5-HT3 receptor. PMID:25648658

  7. Serotonin 5-HT2 Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

    PubMed Central

    Cunningham, Kathryn A.

    2015-01-01

    Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder. PMID:25505168

  8. Compulsive behavior in the 5-HT2C receptor knockout mouse.

    PubMed

    Chou-Green, Jennifer M; Holscher, Todd D; Dallman, Mary F; Akana, Susan F

    2003-04-01

    The efficacy of serotonergic pharmacotherapy indicates that serotonin (5-HT) plays a role in the treatment, if not the etiology, of obsessive-compulsive disorder (OCD). While some clinical evidence implicates 5-HT(2C) receptors in this disorder, a definitive function has yet to be validated. We hypothesized that 5-HT(2C) receptor knockout (KO) mice may display compulsive-like behavior. This paper describes characterization of several distinct, highly organized behaviors in mice lacking functional 5-HT(2C) receptors, which supports a compulsive-like syndrome.Compulsive-like behavior was assessed in male 5-HT(2C) receptor KO and wildtype (WT) mice. Chewing of non-nutritive clay, chewing patterns on plastic-mesh screens, and the frequency of head dipping were measured. 5-HT(2C) receptor KO mice chewed more clay, produced a distinct pattern of "neat" chewing of plastic screens and exhibited reduced habituation of head dipping activity compared to WT mice. We conclude that the 5-HT(2C) receptor null mutant mouse provides a promising model of compulsive behavior and a means to further explore the role of 5-HT in OCD. PMID:12782219

  9. Silencing of CD59 enhanced the sensitivity of HT29 cells to 5-Fluorouracil and Oxaliplatin.

    PubMed

    Yin, Haipeng; Li, Cuiling; Wang, Shaoyu; Guo, Qiang; Ren, Xia; Jiang, Guosheng

    2015-01-01

    Complement regulatory proteins (CD55 and CD59) were known to be expressed in many tumors and tumor cell lines including colorectal carcinoma, and were proposed as immunotherapy targets, however whether knocking down of CD55 and CD59 will affect the sensitivity of HT-29 cells to chemotherapy drugs for example, 5-Fluorouracil and Oxaliplatin and their possible mechanisms haven't been studied. To address this question, SiRNAs targeting CD55 and CD59 were chemically synthesized and transfected into HT-29 cells by lipofectamine. HT-29 growth curves of CD55 and CD59 knockdown cells were detected by MTT assay, HT29 inhibition curves to chemotherapy drugs (5-Fu and Oxaliplatin) were also assayed, in addition, chemotherapy sensitivity changes of HT29 affected by CD55 and CD59 knockdown were equally detected. Complement mediated lysis was examined by calcein-AM. We found that silencing CD59 in HT-29 cells could significantly enhance their sensitivity to 5-FU (P < 0.05) and Oxaliplatin (P < 0.05), and significantly reduced their IC50 concentration. On the contrary, knocking down of CD55 could inhibit HT-29 growth (P < 0.05). Mechanisms included increasing apoptosis rate of HT-29 by CD59 knocking down and G1/G0 blocking by silencing CD55. Our results thus shed light on the novel mechanism of chemotherapy resistance and provide an alternative strategy to overcome the resistance problem. PMID:25444672

  10. Sensitizing human colon carcinoma HT-29 cells to cisplatin by cyclopentenylcytosine, in vitro and in vivo.

    PubMed

    Gharehbaghi, K; Szekeres, T; Yalowitz, J A; Fritzer-Szekeres, M; Pommier, Y G; Jayaram, H N

    2000-11-24

    Cyclopentenylcytosine (CPEC) is cytotoxic to HT-29 cells in vitro and in vivo. Treatment with CPEC resulted in sensitizing HT-29 cells to cisplatin (CDDP), as evidenced by synergistic cytotoxicity. CPEC exhibits potent cytotoxicity to HT-29 cells in vitro, 2 and 24 h exposure providing an LC50 of 2.4 and 0.46 microM, respectively. Exposure of HT-29 cells to CDDP for 2 h resulted in an LC50 of 26 microM. Treatment of HT-29 cells with 1.0 or 1.25 microM CPEC and then incubating with CDDP showed synergistic cytotoxicity. Lesser synergy at very high concentrations of CPEC was demonstrated when HT-29 cells were first exposed to CDDP and then incubated with CPEC. Combination index calculations showed synergistic cytotoxicity in HT-29 cells when CPEC was combined with CDDP. Synergistic antitumor activity was demonstrable in vivo in mice transplanted with HT-29 tumor when treated with a combination of CPEC and CDDP without undue toxicity, since no excessive loss in mouse body weight or overt pathology was observed. CPEC had no influence on the total DNA adduct formation and CDDP did not affect the intracellular levels of CPEC or its metabolites, suggesting that enhanced CDDP cytotoxicity resulted from a step subsequent to excision of platinum-cross-linked DNA. These studies support a new approach for augmenting cytotoxic effect of CPEC with CDDP in treating human colon carcinoma. PMID:11132239

  11. Possible differences in modes of agonist and antagonist binding at human 5-HT6 receptors.

    PubMed

    Pullagurla, Manik R; Westkaemper, Richard B; Glennon, Richard A

    2004-09-01

    A graphics model of the human 5-HT6 receptor was constructed and automated docking studies were performed. The model suggests that 5-HT6 antagonist arylsulfonyltryptamines might bind differently than that of the agonist serotonin. Furthermore, the model explains many of the empirical results from our previous structure-affinity studies. PMID:15357994

  12. Analysis of free ACh and 5-HT in milk from four different species and their bioactivity on 5-HT(3) and nACh receptors.

    PubMed

    Gallegos-Perez, Jose-Luis; Limon, Agenor; Reyes-Ruiz, Jorge M; Alshanqeeti, Ali S; Aljohi, Mohammad A; Miledi, Ricardo

    2014-07-25

    Milk is one of the most beneficial aliments and is highly recommended in normal conditions; however, in certain disorders, like irritable bowel syndrome, cow milk and dairy products worsen the gastric symptoms and their use is not recommended. Among the most recognized milk-induced gatrointestinal symptoms are abdominal pain, nausea and vomiting, which are processes controlled by cholinergic and serotonergic transmission. Whether the presence of bioavailable ACh and 5-HT in milk may contribute to normal peristalsis, or to the developing of these symptoms, is not known. In this work we attempt to determine whether the content of free ACh and 5-HT is of physiological significance in milk from four different species: cow (bovine), goat, camel and human. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to identify and quantify free ACh and 5-HT in milk, and activation of the serotonergic and cholinergic ionotropic receptors was investigated using electrophysiological experiments. Our principal hypothesis was that milk from these four species had sufficient free ACh and 5-HT to activate their correspondent receptors expressed in a heterologous system. Our results showed a more complex picture, in which free ACh and 5-HT and their ability to activate cholinergic and serotonergic receptors are not correlated. This work is a first step to elucidate whether 5-HT and ACh, at the concentrations present in the milk, can be associated to a direct function in the GI. PMID:24820623

  13. Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D alpha and 5-HT1D beta.

    PubMed Central

    Weinshank, R L; Zgombick, J M; Macchi, M J; Branchek, T A; Hartig, P R

    1992-01-01

    The serotonin 1D (5-HT1D) receptor is a pharmacologically defined binding site and functional receptor site. Observed variations in the properties of 5-HT1D receptors in different tissues have led to the speculation that multiple receptor proteins with slightly different properties may exist. We report here the cloning, deduced amino acid sequences, pharmacological properties, and second-messenger coupling of a pair of human 5-HT1D receptor genes, which we have designated 5-HT1D alpha and 5-HT1D beta due to their strong similarities in sequence, pharmacological properties, and second-messenger coupling. Both genes are free of introns in their coding regions, are expressed in the human cerebral cortex, and can couple to inhibition of adenylate cyclase activity. The pharmacological binding properties of these two human receptors are very similar, and match closely the pharmacological properties of human, bovine, and guinea pig 5-HT1D sites. Both receptors exhibit high-affinity binding of sumatriptan, a new anti-migraine medication, and thus are candidates for the pharmacological site of action of this drug. Images PMID:1565658

  14. Effects of the serotonin 5-HT(2) antagonist, ritanserin, and the serotonin 5-HT(1A) antagonist, WAY 100635, on cocaine-seeking in rats.

    PubMed

    Schenk, S

    2000-10-01

    Manipulations of serotonergic systems have been shown to modify many of the behavioral effects of cocaine. It was recently demonstrated that serotonin (5-HT) depletions produced by inhibition of tryptophan hydroxylase reduced cocaine-seeking in an animal model. The present study was designed to determine whether pretreatment with specific 5-HT antagonists might also decrease cocaine-seeking. The effect of pretreatment with the 5-HT(2) antagonist, ritanserin (0.0, 1.0, or 10.0 mg/kg), or the 5-HT(1A) antagonist, WAY 100635 (0. 0, 0.1, 0.3, or 1.0 mg/kg), on cocaine (5.0, 10.0, or 20.0 mg/kg)-produced reinstatement of extinguished drug-taking behavior was measured. Although ritanserin was ineffective, WAY 100635 attenuated cocaine-produced reinstatement in a dose-dependent manner. These effects of WAY 100635 appeared to be specific since responding maintained by saccharin self-administration remained high following pretreatment with 0.3 or 1.0 mg/kg WAY 100635. These data suggest a role of 5-HT(1A), but not 5-HT(2), receptors in cocaine-seeking. PMID:11124402

  15. Evidence of 5-HT components in human sperm: implications for protein tyrosine phosphorylation and the physiology of motility

    PubMed Central

    Jiménez-Trejo, Francisco; Tapia-Rodríguez, Miguel; Cerbón, Marco; Kuhn, Donald M; Manjarrez-Gutiérrez, Gabriel; Mendoza-Rodríguez, C Adriana; Picazo, Ofir

    2016-01-01

    Serotonin (5-hydroxytryptamine; C10H12N2O (5-HT)) is produced in the CNS and in some cells of peripheral tissues. In the mammalian male reproductive system, both 5-HT and tryptophan hydroxylase (TPH) have been described in Leydig cells of the testis and in principal cells of the caput epididymis. In capacitated hamster sperm, it has been shown that 5-HT promotes the acrosomal reaction. The aim of this work was to explore the existence of components of the serotoninergic system and their relevance in human sperm physiology. We used both immunocytochemistry and western blot to detect serotoninergic markers such as 5-HT, TPH1, MAOA, 5-HT1B, 5-HT3, and 5HTT; HPLC for TPH enzymatic activity; Computer Assisted Semen Analysis assays to measure sperm motility parameters and pharmacological approaches to show the effect of 5-HT in sperm motility and tyrosine phosphorylation was assessed by western blot. We found the presence of serotoninergic markers (5-HT, TPH1, MAOA, 5-HT1B, 5-HT2A, 5-HT3, 5-HTT, and TPH enzymatic activity) in human sperm. In addition, we observed a significant increase in tyrosine phosphorylation and changes in sperm motility after 5-HT treatment. In conclusion, our data demonstrate the existence of components of a serotoninergic system in human sperm and support the notion for a functional role of 5-HT in mammalian sperm physiology, which can be modulated pharmacologically. PMID:23028123

  16. Analysis of the Radiation Shield of HT-7U Tokamak

    NASA Astrophysics Data System (ADS)

    Huang, Qunying; Chen, Yixue

    2003-06-01

    Analysis of the radiation shield of HT-7U fusion experimental device has been presented in this contribution. An inner shield and an outer shield, is used to reduce the dose rate to the device, workers and publics. Transport calculations and analyses have been done by 3D MCNP/4C models for neutron spectrum, γ spectrum, neutron and γ dose rate levels during operation and selection of detectors. Activation calculation have been done by inventory code FISPACT to estimate the decay γ dose rate level to workers after one pulse operation of the device and the permission time for workers to get into the shield building or device to make some maintenance or replace after discharge.

  17. Culture in cycles: considering H.T. Odum's 'information cycle'

    NASA Astrophysics Data System (ADS)

    Abel, Thomas

    2014-01-01

    'Culture' remains a conundrum in anthropology. When recast in the mold of 'information cycles,' culture is transformed. New fault lines appear. Information is splintered into parallel or nested forms. Dynamics becomes cycling. Energy is essential. And culture has function in a directional universe. The 'information cycle' is the crowning component of H.T. Odum's theory of general systems. What follows is an application of the information cycle to the cultural domains of discourse, social media, ritual, education, journalism, technology, academia, and law, which were never attempted by Odum. In information cycles, cultural information is perpetuated - maintained against Second Law depreciation. Conclusions are that culture is in fact a nested hierarchy of cultural forms. Each scale of information production is semi-autonomous, with its own evolutionary dynamics of production and selection in an information cycle. Simultaneously, each information cycle is channeled or entrained by its larger scale of information and ultimately human-ecosystem structuring.

  18. Variational calculations of the HT{sup +} rovibrational energies

    SciTech Connect

    Bekbaev, A. K.; Korobov, V. I.; Dineykhan, M.

    2011-04-15

    In this Brief Report, we use the exponential explicitly correlated variational basis set of the type exp(-{alpha}{sub n}R-{beta}{sub n}r{sub 1}-{gamma}{sub n}r{sub 2}) to calculate systematically the nonrelativistic bound-state energies for the hydrogen molecular ion HT{sup +}. We perform calculations for the states of the total orbital angular momentum L=0 and 1 with the complete set of vibrational quantum numbers v= 0-23, as well as for the states of L= 2-5 and v= 0-5. The E1 dipole transition moments, which are of importance for the planning of spectroscopic laser experiments, have been obtained as well.

  19. Contributions of 5-HT Neurons to Respiratory Control: Neuromodulatory and Trophic Effects

    PubMed Central

    Hodges, Matthew R.; Richerson, George B.

    2008-01-01

    Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter produced by a small number of neurons in the midbrain, pons and medulla. These neurons project widely throughout the neuraxis, where they release 5-HT and co-localized neuropeptides such as substance P (SP) and thyrotropin-releasing hormone (TRH). Each of these chemicals produce effects largely through G protein-coupled receptors, second messenger systems and subsequent neuromodulatory effects on target neurons. Emerging evidence suggests that 5-HT has additional modes of action during development and in adult mammals, including trophic effects (neurogenesis, cell differentiation, proliferation, migration and maturation) and influences on synaptic plasticity. Here, we discuss some of the neuromodulatory and trophic roles of 5-HT in general and in the context of respiratory control, as well as the regulation of release of modulatory neurotransmitters from 5-HT neurons. Future directions of study are also discussed. PMID:18595785

  20. Characterization of putative 5-HT7 receptors mediating tachycardia in the cat

    PubMed Central

    Villalón, Carlos M; Heiligers, Jan P C; Centurión, David; De Vries, Peter; Saxena, Pramod R

    1997-01-01

    It has been suggested that the tachycardic response to 5-hydroxytryptamine (5-HT) in the spinal-transected cat is mediated by ‘5-HT1-like' receptors since this effect, being mimicked by 5-carboxamidotryptamine (5-CT), is not modified by ketanserin or MDL 72222, but it is blocked by methiothepin, methysergide or mesulergine. The present study was set out to reanalyse this suggestion in terms of the IUPHAR 5-HT receptor classification schemes proposed in 1994 and 1996. Intravenous (i.v.) bolus injections of the tryptamine derivatives, 5-CT (0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 30 μg kg−1), 5-HT (3, 10 and 30 μg kg−1) and 5-methoxytryptamine (3, 10 and 30 μg kg−1) as well as the atypical antipsychotic drug, clozapine (1000 and 3000 μg kg−1) resulted in dose-dependent increases in heart rate, with a rank order of agonist potency of 5-CT >> 5-HT > 5-methoxytryptamine >> clozapine. The tachycardic effects of 5-HT and 5-methoxytryptamine were dose-dependently antagonized by i.v. administration of lisuride (30 and 100 μg kg−1), ergotamine (100 and 300 μg kg−1) or mesulergine (100, 300 and 1000 μg kg−1); the highest doses of these antagonists used also blocked the tachycardic effects of 5-CT. Clozapine (1000 and 3000 μg kg−1) did not affect the 5-HT-induced tachycardia, but attenuated, with its highest dose, the responses to 5-methoxytryptamine and 5-CT. However, these doses of clozapine as well as the high doses of ergotamine (300 μg kg−1) and mesulergine (300 and 1000 μg kg−1) also attenuated the tachycardic effects of isoprenaline. In contrast, 5-HT-, 5-methoxytryptamine- and 5-CT-induced tachycardia were not significantly modified after i.v. administration of physiological saline (0.1 and 0.3 ml kg−1), the 5-HT1B/1D receptor antagonist, GR127935 (500 μg kg−1) or the 5-HT3/4 receptor antagonist, tropisetron (3000 μg kg−1). Intravenous injections of the 5-HT1 receptor agonists

  1. Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT3 Receptor Ligands

    PubMed Central

    2012-01-01

    The 5-HT3 receptor, a pentameric ligand-gated ion channel (pLGIC), is an important therapeutic target. During a recent fragment screen, 6-chloro-N-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine (1) was identified as a 5-HT3R hit fragment. Here we describe the synthesis and structure–activity relationships (SAR) of a series of (iso)quinoline and quinazoline compounds that were synthesized and screened for 5-HT3R affinity using a [3H]granisetron displacement assay. These studies resulted in the discovery of several high affinity ligands of which compound 22 showed the highest affinity (pKi > 10) for the 5-HT3 receptor. The observed SAR is in agreement with established pharmacophore models for 5-HT3 ligands and is used for ligand–receptor binding mode prediction using homology modeling and in silico docking approaches. PMID:23006041

  2. Effects of age of serotonin 5-HT2 receptors in cocaine abusers and normal subjects

    SciTech Connect

    Wang, G.J.; Volkow, N.D.; Logan, J.

    1995-05-01

    We measured the effect of age on serotonin 5-HT2 receptor availability and compared it with the effects on dopamine D2 receptors on 19 chronic cocaine abusers (35.2{plus_minus}9.8 years, range 18-54 years old) and 19 age matched normal controls using positron emission tomography (PET) and F-18 N-methylspiperone (NMS). 5-HT2 Receptor availability was measure din frontal (FR), occipital (OC), cingulate (CI) and orbitofrontal (OF) cortices using the ratio of the distribution volume in the region of interest to that in the cerebelium (CB) which is a function of Bmax/Kd. D2 receptor availability in the basal ganglia was measured using the {open_quotes}ratio index{close_quotes} (slope of striatum/CB versus time over 180 min of the scan) which is a function of Bmax. 5-HT2 Receptor availability differed among regions and were as follows: CI>OF>OC>FC.5-HT2 Receptor availability decreased significantly with age. This effect was more accentuated for 5-HT2 receptor availability in FR than in OC(df=1, p<0.025). Striatal dopamine D2 receptors were also found to decrease significantly with age (r=0.63, p<0.007). In a given subject, D2 receptor availability was significantly correlated with 5-HT2 receptor availability in FR (r=0.51, p<0.035) but not in OC. The values for 5-HT2 receptor availability were not different in normal subjects and cocaine abusers. These results document a decline in 5-HT2 and D2 receptors with age and document an association between frontal 5-HT2 and striatal D2 receptor availability. These results did not show any changes in 5-HT2 receptor availability in cocaine abusers as compared to control subjects.

  3. Fusion Pore Size Limits 5-HT Release From Single Enterochromaffin Cell Vesicles.

    PubMed

    Raghupathi, Ravinarayan; Jessup, Claire F; Lumsden, Amanda L; Keating, Damien J

    2016-07-01

    Enterochromaffin cells are the major site of serotonin (5-HT) synthesis and secretion providing ∼95% of the body's total 5-HT. 5-HT can act as a neurotransmitter or hormone and has several important endocrine and paracrine roles. We have previously demonstrated that EC cells release small amounts of 5-HT per exocytosis event compared to other endocrine cells. We utilized a recently developed method to purify EC cells to demonstrate the mechanisms underlying 5-HT packaging and release. Using the fluorescent probe FFN511, we demonstrate that EC cells express VMAT and that VMAT plays a functional role in 5-HT loading into vesicles. Carbon fiber amperometry studies illustrate that the amount of 5-HT released per exocytosis event from EC cells is dependent on both VMAT and the H(+)-ATPase pump, as demonstrated with reserpine or bafilomycin, respectively. We also demonstrate that increasing the amount of 5-HT loaded into EC cell vesicles does not result in an increase in quantal release. As this indicates that fusion pore size may be a limiting factor involved, we compared pore diameter in EC and chromaffin cells by assessing the vesicle capture of different-sized fluorescent probes to measure the extent of fusion pore dilation. This identified that EC cells have a reduced fusion pore expansion that does not exceed 9 nm in diameter. These results demonstrate that the small amounts of 5-HT released per fusion event in EC cells can be explained by a smaller fusion pore that limits 5-HT release capacity from individual vesicles. PMID:26574734

  4. Characterization, solubilization and partial purification of serotonin 5-HT1C receptors

    SciTech Connect

    Yagaloff, K.A.

    1986-01-01

    /sup 125/I-Lysergic acid diethylamide (/sup 125/I-LSD) binds with high affinity to a unique serotonergic site on rat choroid plexus. These sites were localized to choroid plexus epithelial cells using a novel high resolution autoradiographic technique. In membrane preparations, the serotonergic site density was 3100 fmol/mg protein, which is 10 fold higher than the density of any other serotonergic site in brain homogenates. The pharmacology of this site, termed the 5-HT1c site, does not match that of 5-Ht1a, 5-HT1b or 5HT2 serotonergic sites. 5-Ht1c sites were solubilized from pig choroid plexus using the zwitterionic detergent, CHAPS. High affinity labelling of the solubilized site was obtained using the serotonergic radioligand, N1-methyl-2-(/sup 125/I)lysergic acid diethylamide (/sup 125/I-MIL). Choroid plexus tumors obtained from transgenic mice were examined for the presence of serotonin 5-HT1c receptors. /sup 125/I-LSD binding to choroid plexus tumors displays a pharmacological profile that matches the properties of 5-HT1c receptors in normal choroid plexus. The tumor exhibits the highest site density of serotonin receptors (6600 fmol/mg protein) found in any tissue. /sup 125/I-LSD autoradiography of brain sections from transgenic mice shows high levels of specific labelling over the tumor. The affinities of various indolealkyl, phenlakyl and beta-carboline derivatives for the serotonin 5-HT1c receptor were measured in pig choroid plexus using /sup 125/I-MIL. Serotonin precursors and metabolites were all very weak inhibitors of specific /sup 125/I-MIL binding. Structure-affinity relationships were determined for a number of indolealkylamine analogues. Only serotonin is present in cerebrospinal fluid at concentrations near its 5-HT1c inhibition constant, suggesting that serotonin is the natural 5-HT1c agonist.

  5. Toxic effects of HT-2 toxin on mouse oocytes and its possible mechanisms.

    PubMed

    Zhu, Cheng-Cheng; Zhang, Yue; Duan, Xing; Han, Jun; Sun, Shao-Chen

    2016-06-01

    T-2 toxin is one of the type A trichothecene mycotoxins that is considered to be the most toxic of the trichothecenes. T-2 toxin has been shown to exert various toxic effects in farm animals and humans, as it induces lesions in the brain and in lymphoid, hematopoietic, and gastrointestinal tissues. HT-2 toxin is the major metabolite of T-2 toxin. There is little information regarding the effects of HT-2 toxin on the female reproductive system, particularly oocyte maturation. Thus, in this study, we investigated the toxic effects of HT-2 on mouse oocyte maturation and its possible mechanisms of action. HT-2 toxin exposure disrupted oocyte maturation, reduced actin expression in both the oocyte cortex and cytoplasm, and disrupted meiotic spindle morphology by reducing p-MAPK protein level. HT-2 toxin exposure also induced oxidative stress and resulted in oocyte apoptosis, as shown by ROS accumulation, increased SOD mRNA level, and the expression of the early apoptosis marker Annexin V and increased caspase-3 and bax mRNA levels. Additionally, HT-2 toxin exposure increased LC3 and ATG12 protein levels and lc3 and atg14 mRNA levels, which indicated that HT-2 toxin induced autophagy in mouse oocytes. We also examined for possible epigenetic modifications. Fluorescence intensity analysis showed that 5mC level increased after HT-2 toxin exposure, whereas H3K9me2 and H3K27me3 levels decreased after HT-2 toxin exposure, which indicated that DNA and histone methylations were altered. Thus, our results indicated that HT-2 toxin exposure reduced mouse oocyte maturation capability by affecting cytoskeletal dynamics, apoptosis/autophagy, oxidative stress, and epigenetic modifications. PMID:26138683

  6. Effect of Peripheral 5-HT on Glucose and Lipid Metabolism in Wether Sheep

    PubMed Central

    Watanabe, Hitoshi; Saito, Ryo; Nakano, Tatsuya; Takahashi, Hideyuki; Takahashi, Yu; Sumiyoshi, Keisuke; Sato, Katsuyoshi; Chen, Xiangning; Okada, Natsumi; Iwasaki, Shunsuke; Harjanti, Dian W.; Sekiguchi, Natsumi; Sano, Hiroaki; Kitazawa, Haruki; Rose, Michael T.; Ohwada, Shyuichi; Watanabe, Kouichi; Aso, Hisashi

    2014-01-01

    In mice, peripheral 5-HT induces an increase in the plasma concentrations of glucose, insulin and bile acids, and a decrease in plasma triglyceride, NEFA and cholesterol concentrations. However, given the unique characteristics of the metabolism of ruminants relative to monogastric animals, the physiological role of peripheral 5-HT on glucose and lipid metabolism in sheep remains to be established. Therefore, in this study, we investigated the effect of 5-HT on the circulating concentrations of metabolites and insulin using five 5-HT receptor (5HTR) antagonists in sheep. After fasting for 24 h, sheep were intravenously injected with 5-HT, following which-, plasma glucose, insulin, triglyceride and NEFA concentrations were significantly elevated. In contrast, 5-HT did not affect the plasma cholesterol concentration, and it induced a decrease in bile acid concentrations. Increases in plasma glucose and insulin concentrations induced by 5-HT were attenuated by pre-treatment with Methysergide, a 5HTR 1, 2 and 7 antagonist. Additionally, decreased plasma bile acid concentrations induced by 5-HT were blocked by pre-treatment with Ketanserin, a 5HTR 2A antagonist. However, none of the 5HTR antagonists inhibited the increase in plasma triglyceride and NEFA levels induced by 5-HT. On the other hand, mRNA expressions of 5HTR1D and 1E were observed in the liver, pancreas and skeletal muscle. These results suggest that there are a number of differences in the physiological functions of peripheral 5-HT with respect to lipid metabolism between mice and sheep, though its effect on glucose metabolism appears to be similar between these species. PMID:24505376

  7. Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling.

    PubMed

    Fields, D P; Springborn, S R; Mitchell, G S

    2015-09-01

    Spinal serotonin type 7 (5-HT7) receptors elicit complex effects on motor activity. Whereas 5-HT7 receptor activation gives rise to long-lasting phrenic motor facilitation (pMF), it also constrains 5-HT2 receptor-induced pMF via "cross-talk inhibition." We hypothesized that divergent cAMP-dependent signaling pathways give rise to these distinct 5-HT7 receptor actions. Specifically, we hypothesized that protein kinase A (PKA) mediates cross-talk inhibition of 5-HT2 receptor-induced pMF whereas 5-HT7 receptor-induced pMF results from exchange protein activated by cAMP (EPAC) signaling. Anesthetized, paralyzed, and ventilated rats receiving intrathecal (C4) 5-HT7 receptor agonist (AS-19) injections expressed pMF for >90 min, an effect abolished by pretreatment with a selective EPAC inhibitor (ESI-05) but not a selective PKA inhibitor (KT-5720). Furthermore, intrathecal injections of a selective EPAC activator (8-pCPT-2'-Me-cAMP) were sufficient to elicit pMF. Finally, spinal mammalian target of rapamycin complex-1 (mTORC1) inhibition via intrathecal rapamycin abolished 5-HT7 receptor- and EPAC-induced pMF, demonstrating that spinal 5-HT7 receptors elicit pMF by an EPAC-mTORC1 signaling pathway. Thus 5-HT7 receptors elicit and constrain spinal phrenic motor plasticity via distinct signaling mechanisms that diverge at cAMP (EPAC vs. PKA). Selective manipulation of these molecules may enable refined regulation of serotonin-dependent spinal motor plasticity for therapeutic advantage. PMID:26269554

  8. Symmetrical P4 cleavage at cobalt half sandwich complexes [(η5-C5H5)Co(L)] (L = CO, NHC)--a computational case study on the mechanism of symmetrical P4 degradation to P2 ligands.

    PubMed

    Zarzycki, Bartosz; Bickelhaupt, F Matthias; Radius, Udo

    2013-05-28

    A full theoretical mechanistic investigation on the symmetrical cleavage of P4 at the active complex fragments [(η(5)-C5H5)Co(L)] (L = CO, (i)Pr2Im; (i)Pr2Im = 1,3-di-iso-propylimidazolin-2-ylidene), which results in the formation of the complex [{(η(5)-C5H5)Co}2(μ,η(2:2)-P2)2] 9, is presented. The overall reaction mechanism is a complex, multistep process. Rate-determining steps of the reaction sequence are two consecutive dissociations of the co-ligands L, which induce the decisive structural rearrangements of the P4 unit. The choice of the co-ligand L ( = CO, (i)Pr2Im) influences the kinetic barrier as well as the energy balance of the overall reaction path significantly. The calculations further reveal a strong influence of the entropic effect on the overall reaction. As a consequence, the energy balance of the overall formation of 9 starting from [(η(5)-C5H5)Co(CO)] precursors is almost thermoneutral and has to overcome high kinetic barriers, whereas the reaction starting from [(η(5)-C5H5)Co((i)Pr2Im)] precursors is exothermic, featuring lower transition barriers with stabilized intermediates. From the direct comparison of both reaction coordinates it seems that the entropic effect of the co-ligands is even stronger than their electronic influence, as for both investigated systems the reactions' energy profiles are almost identical up to intermediate [{(η(5)-C5H5)Co(L)}2(μ,η(2:2)-P4)] 5 (L = CO, (i)Pr2Im). After the formation of 5, the first CO dissociation step renders the reaction endothermic for L = CO, whereas in the case of (i)Pr2Im dissociation the reaction progresses exothermically. Energy decomposition analysis and fragment analysis provide a picture of the bonding mechanisms between the metal complex fragments and P4 in the case of the most significant intermediates and the final product. PMID:23515870

  9. Resource Materials To Support Your Environmental Education Efforts. EE-TIPS (Environmental Education Technical Information Packages).

    ERIC Educational Resources Information Center

    North American Association for Environmental Education, Troy, OH.

    This collection gathers together over 50 high-quality materials to support environmental education (EE) curricula. Because each community has unique environmental and educational needs, the guide includes a broad set of educational materials that can be adapted to a variety of settings. The materials can be used to supplement educational…

  10. The Measure of {alpha}QED in e+e-: An Alternative Approach

    SciTech Connect

    Trentadue, Luca

    2005-10-12

    We propose a method to determine the running of {alpha}QED from a measurement of small angle Bhabha scattering. The method is suited to high statistics experiments at e+e- colliders equipped with luminometers in the appropriate angular region. A new simulation code predicting small angle Bhabha scattering is also presented.

  11. 31 CFR 351.1 - What regulations govern Series EE savings bonds?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) The regulations in 31 CFR part 353 apply to definitive (paper) Series EE savings bonds that have not been converted to book-entry bonds through New Treasury Direct. (b) The regulations in 31 CFR part 363... through New Treasury Direct. (c) The regulations in 31 CFR part 370 apply to transactions for the...

  12. 31 CFR 351.1 - What regulations govern Series EE savings bonds?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) The regulations in 31 CFR part 353 apply to definitive (paper) Series EE savings bonds that have not been converted to book-entry bonds through New Treasury Direct. (b) The regulations in 31 CFR part 363... through New Treasury Direct. (c) The regulations in 31 CFR part 370 apply to transactions for the...

  13. 31 CFR 351.1 - What regulations govern Series EE savings bonds?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...) The regulations in 31 CFR part 353 apply to definitive (paper) Series EE savings bonds that have not been converted to book-entry bonds through New Treasury Direct. (b) The regulations in 31 CFR part 363... through New Treasury Direct. (c) The regulations in 31 CFR part 370 apply to transactions for the...

  14. 31 CFR 351.1 - What regulations govern Series EE savings bonds?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...) The regulations in 31 CFR part 353 apply to definitive (paper) Series EE savings bonds that have not been converted to book-entry bonds through New Treasury Direct. (b) The regulations in 31 CFR part 363... through New Treasury Direct. (c) The regulations in 31 CFR part 370 apply to transactions for the...

  15. 31 CFR 351.1 - What regulations govern Series EE savings bonds?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) The regulations in 31 CFR part 353 apply to definitive (paper) Series EE savings bonds that have not been converted to book-entry bonds through New Treasury Direct. (b) The regulations in 31 CFR part 363... through New Treasury Direct. (c) The regulations in 31 CFR part 370 apply to transactions for the...

  16. CAPS Markers for Eb, Ee, and R Genomes of the Tribe Triticeae

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Eb and Ee genomes of the genus Thinopyrum and R genome of the genus Secale produced a DNA fragment of the same length in PCR using a pair of primers designed from a RAPD marker for the Eb genome. After digestion with certain restriction endonucleases, the STS marker was converted into genome-specif...

  17. Perspectives from Emerging Researchers: What Next in EE/SE Research?

    ERIC Educational Resources Information Center

    Aguayo, Claudio; Higgins, Blanche; Field, Ellen; Nicholls, Jennifer; Pudin, Susan; Tiu, Sangion Appiee; Osborn, Maia; Hashemzadeh, Farshad; Lubuulwa, Kevin Kezabu; Boulet, Mark; Christie, Belinda A.; Mah, Jeremy

    2016-01-01

    Following the inaugural Australian Association for Environmental Education (AAEE) research symposium in November 2014, we--a group of emerging researchers in Environmental Education/Sustainability Education (EE/SE)--commenced an online collaboration to identify and articulate our responses to the main themes of the symposium. Identifying as…

  18. Standards Setting and Federal Information Policy: The Escrowed Encryption Standard (EES).

    ERIC Educational Resources Information Center

    Gegner, Karen E.; Veeder, Stacy B.

    1994-01-01

    Examines the standards process used for developing the Escrowed Encryption Standard (EES) and its possible impact on national communication and information policies. Discusses the balance between national security and law enforcement concerns versus privacy rights and economic competitiveness in the area of foreign trade and export controls. (67…

  19. The Case for a 500 GeV e+e- Linear Collider

    SciTech Connect

    Baggers, J.; Baltay, C.; Barker, T.; Barklow, T.; Bauer, U.; Bolton, T.; Brau, J.; Breidenbach, M.; Burke, D.; Burrows, P.; Dixon, L.; Fisk, H.E.; Frey, R.; Gerdes, D.; Graf, D.; Grannis, P.; Haber, H.E.; Hearty, C.; Hertzbach, S.; Heusch, C.; Hewett, J.; Hollebeek, R.; Jacobsen, R.; Jaros, J.; Kamon, T.; Karlen, D.; Koltick, D.; Kronfeld, A.; Marciano, W.; Markiewicz, T.; Murayama, H.; Nauenberg, U.; Orr, L.; Paige, F.; Para, A.; Peskin, M. E.; Porter, F.; Riles, K.; Ronan, M.; Rosenberg, L.; Schumm, B.; Stroynowski, R.; Tkaczyk, S.; Turcot, A.S.; van Bibber, K.; van Kooten, R.; Wells, J.D.; Yamamoto, H.

    2000-07-05

    Several proposals are being developed around the world for an e+e- linear collider with an initial center of mass energy of 500 GeV. In this paper, we will discuss why a project of this type deserves priority as the next major initiative in high energy physics.

  20. Transforming e-Learning into ee-Learning: The Centrality of Sociocultural Participation

    ERIC Educational Resources Information Center

    Schneider, Sandra B.; Evans, Michael A.

    2008-01-01

    Traditional e-learning efforts use information communication technologies to create and support educational opportunities that are not constrained by temporal and spatial considerations. The focus of ee-learning is to couple e-learning's approach with experiential education models that employ service-learning methodologies and with…

  1. A Case Study of eeLearning: Using Technology to Create and Facilitate Experiential Learning

    ERIC Educational Resources Information Center

    Murphrey, Theresa Pesl

    2010-01-01

    This study used a case study methodology to document an example of how technology was used to engage students in an experiential eLearning (eeLearning) process in order to enhance student learning, student engagement, course relevance, and interaction in an undergraduate course delivered online. While online course delivery has become an accepted…

  2. Study of e+e- → p p bar in the vicinity of ψ (3770)

    NASA Astrophysics Data System (ADS)

    Ablikim, M.; Achasov, M. N.; Ai, X. C.; Albayrak, O.; Albrecht, M.; Ambrose, D. J.; An, F. F.; An, Q.; Bai, J. Z.; Baldini Ferroli, R.; Ban, Y.; Bennett, J. V.; Bertani, M.; Bian, J. M.; Boger, E.; Bondarenko, O.; Boyko, I.; Braun, S.; Briere, R. A.; Cai, H.; Cai, X.; Cakir, O.; Calcaterra, A.; Cao, G. F.; Cetin, S. A.; Chang, J. F.; Chelkov, G.; Chen, G.; Chen, H. S.; Chen, J. C.; Chen, M. L.; Chen, S. J.; Chen, X.; Chen, X. R.; Chen, Y. B.; Cheng, H. P.; Chu, X. K.; Chu, Y. P.; Cronin-Hennessy, D.; Dai, H. L.; Dai, J. P.; Dedovich, D.; Deng, Z. Y.; Denig, A.; Denysenko, I.; Destefanis, M.; Ding, W. M.; Ding, Y.; Dong, C.; Dong, J.; Dong, L. Y.; Dong, M. Y.; Du, S. X.; Fan, J. Z.; Fang, J.; Fang, S. S.; Fang, Y.; Fava, L.; Feng, C. Q.; Fu, C. D.; Fuks, O.; Gao, Q.; Gao, Y.; Geng, C.; Goetzen, K.; Gong, W. X.; Gradl, W.; Greco, M.; Gu, M. H.; Gu, Y. T.; Guan, Y. H.; Guo, L. B.; Guo, T.; Guo, Y. P.; Han, Y. L.; Harris, F. A.; He, K. L.; He, M.; He, Z. Y.; Held, T.; Heng, Y. K.; Hou, Z. L.; Hu, C.; Hu, H. M.; Hu, J. F.; Hu, T.; Huang, G. M.; Huang, G. S.; Huang, H. P.; Huang, J. S.; Huang, L.; Huang, X. T.; Huang, Y.; Hussain, T.; Ji, C. S.; Ji, Q.; Ji, Q. P.; Ji, X. B.; Ji, X. L.; Jiang, L. L.; Jiang, L. W.; Jiang, X. S.; Jiao, J. B.; Jiao, Z.; Jin, D. P.; Jin, S.; Johansson, T.; Kalantar-Nayestanaki, N.; Kang, X. L.; Kang, X. S.; Kavatsyuk, M.; Kloss, B.; Kopf, B.; Kornicer, M.; Kühn, W.; Kupsc, A.; Lai, W.; Lange, J. S.; Lara, M.; Larin, P.; Leyhe, M.; Li, C. H.; Li, Cheng; Li, Cui; Li, D.; Li, D. M.; Li, F.; Li, G.; Li, H. B.; Li, J. C.; Li, K.; Li, K.; Li, Lei; Li, P. R.; Li, Q. J.; Li, T.; Li, W. D.; Li, W. G.; Li, X. L.; Li, X. N.; Li, X. Q.; Li, Z. B.; Liang, H.; Liang, Y. F.; Liang, Y. T.; Lin, D. X.; Liu, B. J.; Liu, C. L.; Liu, C. X.; Liu, F. H.; Liu, Fang; Liu, Feng; Liu, H. B.; Liu, H. H.; Liu, H. M.; Liu, J.; Liu, J. P.; Liu, K.; Liu, K. Y.; Liu, P. L.; Liu, Q.; Liu, S. B.; Liu, X.; Liu, Y. B.; Liu, Z. A.; Liu, Zhiqiang; Liu, Zhiqing; Loehner, H.; Lou, X. C.; Lu, G. R.; Lu, H. J.; Lu, H. L.; Lu, J. G.; Lu, X. R.; Lu, Y.; Lu, Y. P.; Luo, C. L.; Luo, M. X.; Luo, T.; Luo, X. L.; Lv, M.; Ma, F. C.; Ma, H. L.; Ma, Q. M.; Ma, S.; Ma, T.; Ma, X. Y.; Maas, F. E.; Maggiora, M.; Malik, Q. A.; Mao, Y. J.; Mao, Z. P.; Messchendorp, J. G.; Min, J.; Min, T. J.; Mitchell, R. E.; Mo, X. H.; Mo, Y. J.; Moeini, H.; Morales Morales, C.; Moriya, K.; Muchnoi, N. Yu.; Muramatsu, H.; Nefedov, Y.; Nerling, F.; Nikolaev, I. B.; Ning, Z.; Nisar, S.; Niu, X. Y.; Olsen, S. L.; Ouyang, Q.; Pacetti, S.; Pelizaeus, M.; Peng, H. P.; Peters, K.; Ping, J. L.; Ping, R. G.; Poling, R.; Qi, M.; Qian, S.; Qiao, C. F.; Qin, L. Q.; Qin, N.; Qin, X. S.; Qin, Y.; Qin, Z. H.; Qiu, J. F.; Rashid, K. H.; Redmer, C. F.; Ripka, M.; Rong, G.; Ruan, X. D.; Sarantsev, A.; Schoenning, K.; Schumann, S.; Shan, W.; Shao, M.; Shen, C. P.; Shen, X. Y.; Sheng, H. Y.; Shepherd, M. R.; Song, W. M.; Song, X. Y.; Spataro, S.; Spruck, B.; Sun, G. X.; Sun, J. F.; Sun, S. S.; Sun, Y. J.; Sun, Y. Z.; Sun, Z. J.; Sun, Z. T.; Tang, C. J.; Tang, X.; Tapan, I.; Thorndike, E. H.; Toth, D.; Ullrich, M.; Uman, I.; Varner, G. S.; Wang, B.; Wang, D.; Wang, D. Y.; Wang, K.; Wang, L. L.; Wang, L. S.; Wang, M.; Wang, P.; Wang, P. L.; Wang, Q. J.; Wang, S. G.; Wang, W.; Wang, X. F.; Wang, Y. D.; Wang, Y. F.; Wang, Y. Q.; Wang, Z.; Wang, Z. G.; Wang, Z. H.; Wang, Z. Y.; Wei, D. H.; Wei, J. B.; Weidenkaff, P.; Wen, S. P.; Werner, M.; Wiedner, U.; Wolke, M.; Wu, L. H.; Wu, N.; Wu, Z.; Xia, L. G.; Xia, Y.; Xiao, D.; Xiao, Z. J.; Xie, Y. G.; Xiu, Q. L.; Xu, G. F.; Xu, L.; Xu, Q. J.; Xu, Q. N.; Xu, X. P.; Xue, Z.; Yan, L.; Yan, W. B.; Yan, W. C.; Yan, Y. H.; Yang, H. X.; Yang, L.; Yang, Y.; Yang, Y. X.; Ye, H.; Ye, M.; Ye, M. H.; Yu, B. X.; Yu, C. X.; Yu, H. W.; Yu, J. S.; Yu, S. P.; Yuan, C. Z.; Yuan, W. L.; Yuan, Y.; Yuncu, A.; Zafar, A. A.; Zallo, A.; Zang, S. L.; Zeng, Y.; Zhang, B. X.; Zhang, B. Y.; Zhang, C.; Zhang, C. B.; Zhang, C. C.; Zhang, D. H.; Zhang, H. H.; Zhang, H. Y.; Zhang, J. J.; Zhang, J. Q.; Zhang, J. W.; Zhang, J. Y.; Zhang, J. Z.; Zhang, S. H.; Zhang, X. J.; Zhang, X. Y.; Zhang, Y.; Zhang, Y. H.; Zhang, Z. H.; Zhang, Z. P.; Zhang, Z. Y.; Zhao, G.; Zhao, J. W.; Zhao, Lei; Zhao, Ling; Zhao, M. G.; Zhao, Q.; Zhao, Q. W.; Zhao, S. J.; Zhao, T. C.; Zhao, X. H.; Zhao, Y. B.; Zhao, Z. G.; Zhemchugov, A.; Zheng, B.; Zheng, J. P.; Zheng, Y. H.; Zhong, B.; Zhou, L.; Zhou, Li; Zhou, X.; Zhou, X. K.; Zhou, X. R.; Zhou, X. Y.; Zhu, K.; Zhu, K. J.; Zhu, X. L.; Zhu, Y. C.; Zhu, Y. S.; Zhu, Z. A.; Zhuang, J.; Zou, B. S.; Zou, J. H.

    2014-07-01

    Using 2917 pb-1 of data accumulated at 3.773 GeV, 44.5 pb-1 of data accumulated at 3.65 GeV and data accumulated during a ψ (3770) line-shape scan with the BESIII detector, the reaction e+e- → p p bar is studied considering a possible interference between resonant and continuum amplitudes. The cross section of e+e- → ψ (3770) → p p bar , σ (e+e- → ψ (3770) → p p bar), is found to have two solutions, determined to be (0.059-0.020+0.070 ± 0.012) pb with the phase angle ϕ = (255.8-26.6+39.0 ± 4.8) ° (< 0.166 pb at the 90% confidence level), or σ (e+e- → ψ (3770) → p p bar) = (2.57-0.13+0.12 ± 0.12) pb with ϕ = (266.9-6.3+6.1 ± 0.9) ° both of which agree with a destructive interference. Using the obtained cross section of ψ (3770) → p p bar , the cross section of p p bar → ψ (3770), which is useful information for the future PANDA experiment, is estimated to be either (9.8-3.9+11.8) nb (< 27.5 nb at 90% C.L.) or (425.6-43.7+42.9) nb.

  3. Monte Carlo modeling of the spatially dispersive carrier transport in P3HT and P3HT:PCBM blends

    NASA Astrophysics Data System (ADS)

    Jiang, Xin

    2009-10-01

    The presence of traps, arising from morpohological or chemical defects, can be critical to the performance of organic semiconductor devices. Traps can reduce the charge carrier mobility, disturb the internal electrical field, drive recombination, and reduce the overall device efficiency as well as operational stability. In this work, we investigate the role of traps in determining charge transport properties of organic semiconductors and blends such as P3HT and P3HT:PCBM through Monte-Carlo (MC) simulations in conjunction with time-of-flight (TOF) mobility measurements. We employ a Marcus theory description of individual hopping events based on the molecular reorganization energy (lambda) for the MC simulations. Trap states are modeled as diffuse bands that reside at some energy away from the main transport band. This model is used to simulate TOF transients, and the results are compared to experimental data. As is expected from the Marcus theory equation, the mobility is seen to be maximum for an optimal value of lambda. This optimal value is strongly field dependent, but is found to be independent of the trap density. In comparing MC simulations with TOF data, it is found that inclusion of traps results in a much better fit to the data and provides for a mechanism to simulate dispersive transport with a long tail resulting from trapping and detrapping of carriers before they exit the device. We present results for a range of trap densities and statistical distributions and discuss the implications on the operation of bulk heterojunction organic photovoltaic devices.

  4. Systemic inflammation alters central 5-HT function as determined by pharmacological MRI.

    PubMed

    Couch, Yvonne; Martin, Chris J; Howarth, Clare; Raley, Josie; Khrapitchev, Alexandre A; Stratford, Michael; Sharp, Trevor; Sibson, Nicola R; Anthony, Daniel C

    2013-07-15

    Considerable evidence indicates a link between systemic inflammation and central 5-HT function. This study used pharmacological magnetic resonance imaging (phMRI) to study the effects of systemic inflammatory events on central 5-HT function. Changes in blood oxygenation level dependent (BOLD) contrast were detected in selected brain regions of anaesthetised rats in response to intravenous administration of the 5-HT-releasing agent, fenfluramine (10 mg/kg). Further groups of rats were pre-treated with the bacterial lipopolysaccharide (LPS; 0.5 mg/kg), to induce systemic inflammation, or the selective 5-HT2A receptor antagonist MDL100907 prior to fenfluramine. The resultant phMRI data were investigated further through measurements of cortical 5-HT release (microdialysis), and vascular responsivity, as well as a more thorough investigation of the role of the 5-HT2A receptor in sickness behaviour. Fenfluramine evoked a positive BOLD response in the motor cortex (+15.9±2%) and a negative BOLD response in the dorsal raphe nucleus (-9.9±4.2%) and nucleus accumbens (-7.7±5.3%). In all regions, BOLD responses to fenfluramine were significantly attenuated by pre-treatment with LPS (p<0.0001), but neurovascular coupling remained intact, and fenfluramine-evoked 5-HT release was not affected. However, increased expression of the 5-HT2A receptor mRNA and decreased 5-HT2A-dependent behaviour (wet-dog shakes) was a feature of the LPS treatment and may underpin the altered phMRI signal. MDL100907 (0.5 mg/kg), 5-HT2A antagonist, significantly reduced the BOLD responses to fenfluramine in all three regions (p<0.0001) in a similar manner to LPS. Together these results suggest that systemic inflammation decreases brain 5-HT activity as assessed by phMRI. However, these effects do not appear to be mediated by changes in 5-HT release, but are associated with changes in 5-HT2A-receptor-mediated downstream signalling pathways. PMID:23473937

  5. 5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists.

    PubMed

    Harmon, Jennifer L; Wills, Lauren P; McOmish, Caitlin E; Demireva, Elena Y; Gingrich, Jay A; Beeson, Craig C; Schnellmann, Rick G

    2016-04-01

    In acute organ injuries, mitochondria are often dysfunctional, and recent research has revealed that recovery of mitochondrial and renal functions is accelerated by induction of mitochondrial biogenesis (MB). We previously reported that the nonselective 5-HT2 receptor agonist DOI [1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine] induced MB in renal proximal tubular cells (RPTCs). The goal of this study was to determine the role of 5-HT2 receptors in the regulation of mitochondrial genes and oxidative metabolism in the kidney. The 5-HT2C receptor agonist CP-809,101 [2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine] and antagonist SB-242,084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] were used to examine the induction of renal mitochondrial genes and oxidative metabolism in RPTCs and in mouse kidneys in the presence and absence of the 5-HT2C receptor. Unexpectedly, both CP-809,101 and SB-242,084 increased RPTC respiration and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA expression in RPTCs at 1-10 nM. In addition, CP-809,101 and SB-242,084 increased mRNA expression of PGC-1α and the mitochondrial proteins NADH dehydrogenase subunit 1 and NADH dehydrogenase (ubiquinone) β subcomplex 8 in mice. These compounds increased mitochondrial genes in RPTCs in which the 5-HT2C receptor was downregulated with small interfering RNA and in the renal cortex of mice lacking the 5-HT2C receptor. By contrast, the ability of these compounds to increase PGC-1α mRNA and respiration was blocked in RPTCs treated with 5-HT2A receptor small interfering RNA or the 5-HT2A receptor antagonist eplivanserin. In addition, the 5-HT2A receptor agonist NBOH-2C-CN [4-[2-[[(2-hydroxyphenyl)methyl]amino]ethyl]-2,5-dimethoxybenzonitrile] increased RPTC respiration at 1-100 nM. These results suggest that agonism of the 5-HT2A receptor induces MB and that the classic 5-HT2C receptor agonist CP

  6. Systemic inflammation alters central 5-HT function as determined by pharmacological MRI

    PubMed Central

    Couch, Yvonne; Martin, Chris J.; Howarth, Clare; Raley, Josie; Khrapitchev, Alexandre A.; Stratford, Michael; Sharp, Trevor; Sibson, Nicola R.; Anthony, Daniel C.

    2013-01-01

    Considerable evidence indicates a link between systemic inflammation and central 5-HT function. This study used pharmacological magnetic resonance imaging (phMRI) to study the effects of systemic inflammatory events on central 5-HT function. Changes in blood oxygenation level dependent (BOLD) contrast were detected in selected brain regions of anaesthetised rats in response to intravenous administration of the 5-HT-releasing agent, fenfluramine (10 mg/kg). Further groups of rats were pre-treated with the bacterial lipopolysaccharide (LPS; 0.5 mg/kg), to induce systemic inflammation, or the selective 5-HT2A receptor antagonist MDL100907 prior to fenfluramine. The resultant phMRI data were investigated further through measurements of cortical 5-HT release (microdialysis), and vascular responsivity, as well as a more thorough investigation of the role of the 5-HT2A receptor in sickness behaviour. Fenfluramine evoked a positive BOLD response in the motor cortex (+ 15.9 ± 2%) and a negative BOLD response in the dorsal raphe nucleus (− 9.9 ± 4.2%) and nucleus accumbens (− 7.7 ± 5.3%). In all regions, BOLD responses to fenfluramine were significantly attenuated by pre-treatment with LPS (p < 0.0001), but neurovascular coupling remained intact, and fenfluramine-evoked 5-HT release was not affected. However, increased expression of the 5-HT2A receptor mRNA and decreased 5-HT2A-dependent behaviour (wet-dog shakes) was a feature of the LPS treatment and may underpin the altered phMRI signal. MDL100907 (0.5 mg/kg), 5-HT2A antagonist, significantly reduced the BOLD responses to fenfluramine in all three regions (p < 0.0001) in a similar manner to LPS. Together these results suggest that systemic inflammation decreases brain 5-HT activity as assessed by phMRI. However, these effects do not appear to be mediated by changes in 5-HT release, but are associated with changes in 5-HT2A-receptor-mediated downstream signalling pathways. PMID:23473937

  7. A coordinated set of ecosystem research platforms open to international research in ecotoxicology, AnaEE-France.

    PubMed

    Mougin, Christian; Azam, Didier; Caquet, Thierry; Cheviron, Nathalie; Dequiedt, Samuel; Le Galliard, Jean-François; Guillaume, Olivier; Houot, Sabine; Lacroix, Gérard; Lafolie, François; Maron, Pierre-Alain; Michniewicz, Radika; Pichot, Christian; Ranjard, Lionel; Roy, Jacques; Zeller, Bernd; Clobert, Jean; Chanzy, André

    2015-10-01

    The infrastructure for Analysis and Experimentation on Ecosystems (AnaEE-France) is an integrated network of the major French experimental, analytical, and modeling platforms dedicated to the biological study of continental ecosystems (aquatic and terrestrial). This infrastructure aims at understanding and predicting ecosystem dynamics under global change. AnaEE-France comprises complementary nodes offering access to the best experimental facilities and associated biological resources and data: Ecotrons, seminatural experimental platforms to manipulate terrestrial and aquatic ecosystems, in natura sites equipped for large-scale and long-term experiments. AnaEE-France also provides shared instruments and analytical platforms dedicated to environmental (micro) biology. Finally, AnaEE-France provides users with data bases and modeling tools designed to represent ecosystem dynamics and to go further in coupling ecological, agronomical, and evolutionary approaches. In particular, AnaEE-France offers adequate services to tackle the new challenges of research in ecotoxicology, positioning its various types of platforms in an ecologically advanced ecotoxicology approach. AnaEE-France is a leading international infrastructure, and it is pioneering the construction of AnaEE (Europe) infrastructure in the field of ecosystem research. AnaEE-France infrastructure is already open to the international community of scientists in the field of continental ecotoxicology. PMID:26315587

  8. 77 FR 41475 - El Expreso Group, LLC-Asset Acquisition-CUSA EE, LLC D/B/A El Expreso

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-13

    ... Surface Transportation Board El Expreso Group, LLC--Asset Acquisition--CUSA EE, LLC D/B/A El Expreso..., 2012, noncarrier El Expreso Group, LLC (El Expreso Group or Applicant) filed an application for approval under 49 U.S.C. 14303 to acquire control of the assets of CUSA EE, LLC d/b/a El Expreso (CUSA...

  9. 31 CFR 351.20 - What is the investment yield (interest) during the original maturity period of Series EE savings...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., 1980, through April 1, 1995? 351.20 Section 351.20 Money and Finance: Treasury Regulations Relating to... Series EE Savings Bonds Series Ee Savings Bonds with Issue Dates Prior to May 1, 1995 § 351.20 What is... issue dates from January 1, 1980, through April 1, 1995? The redemption value of a bond on a...

  10. A novel enzyme-linked immunosorbent assay for ethynylestradiol using a long-chain biotinylated EE2 derivative.

    PubMed

    Schneider, Christian; Schöler, Heinz F; Schneider, Rudolf J

    2004-04-01

    Ethynylestradiol (EE2) is one of the most potent endocrine disrupting compounds capable to induce estrogenic effects even at trace level concentrations in the aquatic environment. Methods for detecting EE2 in such concentrations are generally based on GC or HPLC coupled to at least one mass spectrometer. Another approach are immunoassays and sensor systems but for most designs, derivatives of EE2 are required (e.g. for coupling to carrier proteins, enzyme or fluorescent labels, etc.). Here we present the straightforward synthesis and complete characterization of a new long-chain biotinylated EE2 derivative. The new EE2 derivative is used as tracer in a direct competitive enzyme-linked immunosorbent assay (ELISA) for the determination of EE2. With pure water, the limit of detection (LOD, signal-to-noise ratio, S/N = 3) and the test midpoint were found to be 14 and 136 ng l(-1), respectively. Cross reactivity (CR) was tested for 10 endogenous steroids and the BSA-conjugate used for immunization, as well as a synthetic precursor of the conjugate. Among the naturally occurring compounds, CR was determined to be maximum for metabolites of EE2 conjugated at ring-position 3 (17% and 37% for 3-glucuronide and 3-sulphate, respectively). Assay stability was tested against humic substances and organic solvents. Increasing amounts of organic solvents in the sample caused a clear decrease in sensitivity, presence of humic substances lead to an overestimation of EE2. PMID:15183690

  11. 31 CFR 351.83 - May Public Debt issue Series EE savings bonds only in book-entry form?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false May Public Debt issue Series EE savings bonds only in book-entry form? 351.83 Section 351.83 Money and Finance: Treasury Regulations... Debt issue Series EE savings bonds only in book-entry form? We reserve the right to issue bonds only...

  12. Novel Antimicrobial Peptides EeCentrocins 1, 2 and EeStrongylocin 2 from the Edible Sea Urchin Echinus esculentus Have 6-Br-Trp Post-Translational Modifications

    PubMed Central

    Solstad, Runar Gjerp; Li, Chun; Isaksson, Johan; Johansen, Jostein; Svenson, Johan; Stensvåg, Klara; Haug, Tor

    2016-01-01

    The global problem of microbial resistance to antibiotics has resulted in an urgent need to develop new antimicrobial agents. Natural antimicrobial peptides are considered promising candidates for drug development. Echinoderms, which rely on innate immunity factors in the defence against harmful microorganisms, are sources of novel antimicrobial peptides. This study aimed to isolate and characterise antimicrobial peptides from the Edible sea urchin Echinus esculentus. Using bioassay-guided purification and cDNA cloning, three antimicrobial peptides were characterised from the haemocytes of the sea urchin; two heterodimeric peptides and a cysteine-rich peptide. The peptides were named EeCentrocin 1 and 2 and EeStrongylocin 2, respectively, due to their apparent homology to the published centrocins and strongylocins isolated from the green sea urchin Strongylocentrotus droebachiensis. The two centrocin-like peptides EeCentrocin 1 and 2 are intramolecularly connected via a disulphide bond to form a heterodimeric structure, containing a cationic heavy chain of 30 and 32 amino acids and a light chain of 13 amino acids. Additionally, the light chain of EeCentrocin 2 seems to be N-terminally blocked by a pyroglutamic acid residue. The heavy chains of EeCentrocins 1 and 2 were synthesised and shown to be responsible for the antimicrobial activity of the natural peptides. EeStrongylocin 2 contains 6 cysteines engaged in 3 disulphide bonds. A fourth peptide (Ee4635) was also discovered but not fully characterised. Using mass spectrometric and NMR analyses, EeCentrocins 1 and 2, EeStrongylocin 2 and Ee4635 were all shown to contain post-translationally brominated Trp residues in the 6 position of the indole ring. PMID:27007817

  13. Novel Antimicrobial Peptides EeCentrocins 1, 2 and EeStrongylocin 2 from the Edible Sea Urchin Echinus esculentus Have 6-Br-Trp Post-Translational Modifications.

    PubMed

    Solstad, Runar Gjerp; Li, Chun; Isaksson, Johan; Johansen, Jostein; Svenson, Johan; Stensvåg, Klara; Haug, Tor

    2016-01-01

    The global problem of microbial resistance to antibiotics has resulted in an urgent need to develop new antimicrobial agents. Natural antimicrobial peptides are considered promising candidates for drug development. Echinoderms, which rely on innate immunity factors in the defence against harmful microorganisms, are sources of novel antimicrobial peptides. This study aimed to isolate and characterise antimicrobial peptides from the Edible sea urchin Echinus esculentus. Using bioassay-guided purification and cDNA cloning, three antimicrobial peptides were characterised from the haemocytes of the sea urchin; two heterodimeric peptides and a cysteine-rich peptide. The peptides were named EeCentrocin 1 and 2 and EeStrongylocin 2, respectively, due to their apparent homology to the published centrocins and strongylocins isolated from the green sea urchin Strongylocentrotus droebachiensis. The two centrocin-like peptides EeCentrocin 1 and 2 are intramolecularly connected via a disulphide bond to form a heterodimeric structure, containing a cationic heavy chain of 30 and 32 amino acids and a light chain of 13 amino acids. Additionally, the light chain of EeCentrocin 2 seems to be N-terminally blocked by a pyroglutamic acid residue. The heavy chains of EeCentrocins 1 and 2 were synthesised and shown to be responsible for the antimicrobial activity of the natural peptides. EeStrongylocin 2 contains 6 cysteines engaged in 3 disulphide bonds. A fourth peptide (Ee4635) was also discovered but not fully characterised. Using mass spectrometric and NMR analyses, EeCentrocins 1 and 2, EeStrongylocin 2 and Ee4635 were all shown to contain post-translationally brominated Trp residues in the 6 position of the indole ring. PMID:27007817

  14. Solution structure and metal-ion binding of the P4 element from bacterial RNase P RNA.

    PubMed Central

    Schmitz, M; Tinoco, I

    2000-01-01

    We determined the solution structure of two 27-nt RNA hairpins and their complexes with cobalt(III)-hexammine (Co(NH3)3+(6)) by NMR spectroscopy. The RNA hairpins used in this study are the P4 region from Escherichia coli RNase P RNA and a C-to-U mutant that confers altered divalent metal-ion specificity (Ca2+ replaces Mg2+) for catalytic activity of this ribozyme. Co(NH3)3+(6) is a useful spectroscopic probe for Mg(H2O)2+(6)-binding sites because both complexes have octahedral symmetry and have similar radii. The thermodynamics of binding to both RNA hairpins was studied using chemical shift changes upon titration with Mg2+, Ca2+, and Co(NH3)3+(6). We found that the equilibrium binding constants for each of the metal ions was essentially unchanged when the P4 model RNA hairpin was mutated, although the NMR structures show that the RNA hairpins adopt different conformations. In the C-to-U mutant a C.G base pair is replaced by U.G, and the conserved bulged uridine in the P4 wild-type stem shifts in the 3' direction by 1 nt. Intermolecular NOE cross-peaks between Co(NH3)3+(6) and RNA protons were used to locate the site of Co(NH3)3+(6) binding to both RNA hairpins. The metal ion binds in the major groove near a bulge loop, but is shifted 5' by more than 1 bp in the mutant. The change of the metal-ion binding site provides a possible explanation for changes in catalytic activity of the mutant RNase P in the presence of Ca2+. PMID:10999599

  15. Effect of biomimetic conditions on mechanical and structural integrity of PGA/P4HB and electrospun PCL scaffolds.

    PubMed

    Klouda, Leda; Vaz, Claudia M; Mol, Anita; Baaijens, Frank P T; Bouten, Carlijn V C

    2008-03-01

    The selection of an appropriate scaffold represents one major key to success in tissue engineering. In cardiovascular applications, where a load-bearing structure is required, scaffolds need to demonstrate sufficient mechanical properties and importantly, reliable retention of these properties during the developmental phase of the tissue engineered construct. The effect of in vitro culture conditions, time and mechanical loading on the retention of mechanical properties of two scaffold types was investigated. First candidate tested was a poly-glycolic acid non-woven fiber mesh, coated with poly-4-hydroxybutyrate (PGA/P4HB), the standard scaffold used successfully in cardiovascular tissue engineering applications. As an alternative, an electrospun poly-epsilon-caprolactone (PCL) scaffold was used. A 15-day dynamic loading protocol was applied to the scaffolds. Additionally, control scaffolds were incubated statically. All studies were performed in a simulated physiological environment (phosphate-buffered saline solution, T=37 degrees C). PGA/P4HB scaffolds showed a dramatic decrease in mechanical properties as a function of incubation time and straining. Mechanical loading had a significant effect on PCL scaffold properties. Degradation as well as fiber fatigue caused by loading promote loss of mechanical properties in PGA/P4HB scaffolds. For PCL, fiber reorganization due to straining seems to be the main reason behind the brittle behavior that was pronounced in these scaffolds. It is suggested that those changes in scaffolds' mechanical properties must be considered at the application of in vitro tissue engineering protocols and should ideally be taken over by tissue formation to maintain mechanically stable tissue constructs. PMID:17701317

  16. Proteomic Analysis of the Rat Canalicular Membrane Reveals Expression of a Complex System of P4-ATPases in Liver

    PubMed Central

    Chaubey, Pururawa Mayank; Hofstetter, Lia; Roschitzki, Bernd; Stieger, Bruno

    2016-01-01

    Transport processes in the canalicular membrane are key elements in bile formation and are the driving force of the enterohepatic circulation of bile salts. The canalicular membrane is constantly exposed to the detergent action of bile salts. One potential element protecting the canalicular membrane from the high canalicular bile salt concentrations may be bile salt resistant microdomains, however additional factors are likely to play a role. To obtain more insights into the molecular composition of the canalicular membrane, the proteome of highly purified rat canalicular membrane vesicles was determined. Isolated rat canalicular membrane vesicles were stripped from adhering proteins, deglycosylated and protease digested before subjecting the samples to shot gun proteomic analysis. The expression of individual candidates was studied by PCR, Western blotting and immunohistochemistry. A total of 2449 proteins were identified, of which 1282 were predicted to be membrane proteins. About 50% of the proteins identified here were absent from previously published liver proteomes. In addition to ATP8B1, four more P4-ATPases were identified. ATP8A1 and ATP9A showed expression specific to the canalicular membrane, ATP11C at the bLPM and ATP11A in an intracellular vesicular compartment partially colocalizing with RAB7A and EEA1 as markers of the endosomal compartment. This study helped to identify additional P4-ATPases from rat liver particularly in the canalicular membrane, previously not known to be expressed in liver. These P4-ATPases might be contributing for maintaining transmembrane lipid homeostasis in hepatocytes. PMID:27347675

  17. Proteomic Analysis of the Rat Canalicular Membrane Reveals Expression of a Complex System of P4-ATPases in Liver.

    PubMed

    Chaubey, Pururawa Mayank; Hofstetter, Lia; Roschitzki, Bernd; Stieger, Bruno

    2016-01-01

    Transport processes in the canalicular membrane are key elements in bile formation and are the driving force of the enterohepatic circulation of bile salts. The canalicular membrane is constantly exposed to the detergent action of bile salts. One potential element protecting the canalicular membrane from the high canalicular bile salt concentrations may be bile salt resistant microdomains, however additional factors are likely to play a role. To obtain more insights into the molecular composition of the canalicular membrane, the proteome of highly purified rat canalicular membrane vesicles was determined. Isolated rat canalicular membrane vesicles were stripped from adhering proteins, deglycosylated and protease digested before subjecting the samples to shot gun proteomic analysis. The expression of individual candidates was studied by PCR, Western blotting and immunohistochemistry. A total of 2449 proteins were identified, of which 1282 were predicted to be membrane proteins. About 50% of the proteins identified here were absent from previously published liver proteomes. In addition to ATP8B1, four more P4-ATPases were identified. ATP8A1 and ATP9A showed expression specific to the canalicular membrane, ATP11C at the bLPM and ATP11A in an intracellular vesicular compartment partially colocalizing with RAB7A and EEA1 as markers of the endosomal compartment. This study helped to identify additional P4-ATPases from rat liver particularly in the canalicular membrane, previously not known to be expressed in liver. These P4-ATPases might be contributing for maintaining transmembrane lipid homeostasis in hepatocytes. PMID:27347675

  18. Long-term EEJ variations by using the improved EE-index

    NASA Astrophysics Data System (ADS)

    Fujimoto, A.; Uozumi, T.; Abe, Sh.; Matsushita, H.; Imajo, Sh.; Ishitsuka, J. K.; Yoshikawa, A.

    2016-03-01

    In 2008, International Center for Space Weather Science and Education, Kyushu University (ICSWSE) proposed the EE-index, which is an index to monitor the equatorial geomagnetic phenomena. EE-index has been improved with the development of the MAGnetic Data Acquisition System and the Circum-pan Pacific Magnetometer Network (MAGDAS/CPMN) and the enormous archive of MAGDAS/CPMN data over 10 years since the initial article. Using the improved EE-index, we examined the solar cycle variation of equatorial electrojet (EEJ) by the time series analysis for EUEL (one part of EE-index) at Ancon in Peru and the solar activity from September 18, 1998 to March 31, 2015. We found that the long-term variation of daily EEJ peak intensity has a trend similar to that of F10.7 (the solar activity). The power spectrum of the daily EEJ peak has clearly two dominant peaks throughout the analysis interval: 14.5 days and 180 days (semi-annual). The solar cycle variation of daily EEJ peak correlates well with that of F10.7 (the correlation coefficient 0.99). We conclude that the daily EEJ peak intensity is roughly determined as the summation of the long-period trend of the solar activity resulting from the solar cycle and day-to-day variations caused by various sources such as lunar tides, geometric effects, magnetospheric phenomena and atmospheric phenomena. This work presents the primary evidence for solar cycle variations of EEJ on the long-term study of the EE-index

  19. Proceedings, High-Precision $\\alpha_s$ Measurements from LHC to FCC-ee

    SciTech Connect

    d'Enterria, David; Skands, Peter Z.

    2015-01-01

    This document provides a writeup of all contributions to the workshop on "High precision measurements of $\\alpha_s$: From LHC to FCC-ee" held at CERN, Oct. 12--13, 2015. The workshop explored in depth the latest developments on the determination of the QCD coupling $\\alpha_s$ from 15 methods where high precision measurements are (or will be) available. Those include low-energy observables: (i) lattice QCD, (ii) pion decay factor, (iii) quarkonia and (iv) $\\tau$ decays, (v) soft parton-to-hadron fragmentation functions, as well as high-energy observables: (vi) global fits of parton distribution functions, (vii) hard parton-to-hadron fragmentation functions, (viii) jets in $e^\\pm$p DIS and $\\gamma$-p photoproduction, (ix) photon structure function in $\\gamma$-$\\gamma$, (x) event shapes and (xi) jet cross sections in $e^+e^-$ collisions, (xii) W boson and (xiii) Z boson decays, and (xiv) jets and (xv) top-quark cross sections in proton-(anti)proton collisions. The current status of the theoretical and experimental uncertainties associated to each extraction method, the improvements expected from LHC data in the coming years, and future perspectives achievable in $e^+e^-$ collisions at the Future Circular Collider (FCC-ee) with $\\cal{O}$(1--100 ab$^{-1}$) integrated luminosities yielding 10$^{12}$ Z bosons and jets, and 10$^{8}$ W bosons and $\\tau$ leptons, are thoroughly reviewed. The current uncertainty of the (preliminary) 2015 strong coupling world-average value, $\\alpha_s(m_Z)$ = 0.1177 $\\pm$ 0.0013, is about 1\\%. Some participants believed this may be reduced by a factor of three in the near future by including novel high-precision observables, although this opinion was not universally shared. At the FCC-ee facility, a factor of ten reduction in the $\\alpha_s$ uncertainty should be possible, mostly thanks to the huge Z and W data samples available.

  20. Interaction between 5-HT1B receptors and nitric oxide in zebrafish responses to novelty.

    PubMed

    Maximino, Caio; Lima, Monica Gomes; Batista, Evander de Jesus Oliveira; Oliveira, Karen Renata Herculano Matos; Herculano, Anderson Manoel

    2015-02-19

    Nitric oxide (NO) and serotonin (5-HT) interact at the molecular and systems levels to control behavioral variables, including agression, fear, and reactions to novelty. In zebrafish, the 5-HT1B receptor has been implicated in anxiety and reactions to novelty, while the 5-HT1A receptor is associated with anxiety-like behavior; this role of the 5-HT1A receptor is mediated by NO. This work investigated whether NO also participates in the mediation of novelty responses by the 5-HT1B receptor. The 5-HT1B receptor inverse agonist SB 224,289 decreased bottom-dwelling and erratic swimming in zebrafish; the effects on bottom-dwelling, but not on erratic swimming, were blocked by pre-treatment with the nitric oxide synthase inhibitor L-NAME. These effects underline a novel mechanism by which 5-HT controls zebrafish reactivity to novel environments, with implications for the study of neotic reactions, exploratory behavior, and anxiety-like states. PMID:25545556

  1. 5-HT1A receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function

    PubMed Central

    Garcia-Garcia, Alvaro; Tancredi, Adrian Newman-; Leonardo, E. David

    2014-01-01

    Rationale Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in both disorders. Objectives In this review, we examine the function of 5-HT1A receptor sub-populations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor vs heteroreceptor) and the temporal (developmental vs adult) roles of the endogenous 5-HT1A receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors. Results It is difficult to unambiguously distinguish the effects of different populations of the 5-HT1A receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for distinct roles of these populations in governing emotion related behavior are emerging. Conclusions There is strong and growing evidence for a functional dissociation between auto and heteroreceptor populations in mediating anxiety and depressive-like behaviors respectively. Furthermore, while it is well established that 5-HT1A receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT1A heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects. PMID:24337875

  2. The 5-HT7 receptor in learning and memory. Importance of the hippocampus

    PubMed Central

    Roberts, Amanda J.; Hedlund, Peter B.

    2011-01-01

    The 5-HT7 receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood. The present paper reviews to what extent the use of animal models of learning and memory and other techniques have implicated the 5-HT7 receptor in such processes. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior and cellular mechanisms. In tests such as the Barnes maze, contextual fear conditioning and novel location recognition that involve spatial learning and memory there is a considerable amount of evidence supporting an involvement of the 5-HT7 receptor. Supporting evidence has also been obtained in studies of mRNA expression and cellular signaling as well as in electrophysiological experiments. Especially interesting are the subtle but distinct effects observed in hippocampus-dependent models of place learning where impairments have been described in mice lacking the 5-HT7 receptor or after administration of a selective antagonist. While more work is required, it appears that 5-HT7 receptors are particularly important in allocentric representation processes. In instrumental learning tasks both procognitive effects and impairments in memory have been observed using pharmacological tools targeting the 5-HT7 receptor. In conclusion, the use of pharmacological and genetic tools in animal studies of learning and memory suggest a potentially important role for the 5-HT7 receptor in cognitive processes. PMID:21484935

  3. Impact of Lipid Raft Integrity on 5-HT3 Receptor Function and its Modulation by Antidepressants

    PubMed Central

    Nothdurfter, Caroline; Tanasic, Sascha; Di Benedetto, Barbara; Rammes, Gerhard; Wagner, Eva-Maria; Kirmeier, Thomas; Ganal, Vanessa; Kessler, Julia S; Rein, Theo; Holsboer, Florian; Rupprecht, Rainer

    2010-01-01

    Because of the biochemical colocalization of the 5-HT3 receptor and antidepressants within raft-like domains and their antagonistic effects at this ligand-gated ion channel, we investigated the impact of lipid raft integrity for 5-HT3 receptor function and its modulation by antidepressants. Treatment with methyl-β-cyclodextrine (MβCD) markedly reduced membrane cholesterol levels and caused a more diffuse membrane distribution of the lipid raft marker protein flotillin-1 indicating lipid raft impairment. Both amplitude and charge of serotonin evoked cation currents were diminished following cholesterol depletion by either MβCD or simvastatin (Sim), whereas the functional antagonistic properties of the antidepressants desipramine (DMI) and fluoxetine (Fluox) at the 5-HT3 receptor were retained. Although both the 5-HT3 receptor and flotillin-1 were predominantly found in raft-like domains in western blots following sucrose density gradient centrifugation, immunocytochemistry revealed only a coincidental degree of colocalization of these two proteins. These findings and the persistence of the antagonistic effects of DMI and Fluox against 5-HT3 receptors after lipid raft impairment indicate that their modulatory effects are likely mediated through non-raft 5-HT3 receptors, which are not sufficiently detected by means of sucrose density gradient centrifugation. In conclusion, lipid raft integrity appears to be important for 5-HT3 receptor function in general, whereas it is not a prerequisite for the antagonistic properties of antidepressants such as DMI and Fluox at this ligand-gated ion channel. PMID:20200506

  4. Two transmembrane Cys residues are involved in 5-HT4 receptor dimerization.

    PubMed

    Berthouze, Magali; Rivail, Lucie; Lucas, Alexandre; Ayoub, Mohammed A; Russo, Olivier; Sicsic, Sames; Fischmeister, Rodolphe; Berque-Bestel, Isabelle; Jockers, Ralf; Lezoualc'h, Frank

    2007-05-11

    The 5-HT(4) receptor (5-HT(4)R) belongs to the G-protein-coupled receptor (GPCR) family and is of considerable interest for the development of new drugs to treat gastrointestinal diseases and memory disorders. The 5-HT(4)R exists as a constitutive dimer but its molecular determinants are still unknown. Using co-immunoprecipitation and Bioluminescence Resonance Energy Transfer (BRET) techniques, we show here that 5-HT(4)R homodimerization but not 5-HT(4)R-beta(2) adrenergic receptor (beta(2)AR) heterodimerization is largely decreased under reducing conditions suggesting the participation of disulfide bonds in 5-HT(4)R dimerization. Molecular modeling and protein docking experiments identified four cysteine (Cys) residues potentially involved in the dimer interface through intramolecular or intermolecular disulfide bonds. We show that disulfide bridges between Cys112 and Cys145 located within TM3 and TM4, respectively, are of critical importance for 5-HT(4)R dimer formation. Our data suggest that two disulfide bridges between two transmembrane Cys residues are involved in the dimerization interface of a GPCR. PMID:17379184

  5. Structures, spectroscopic studies and solid-state thermal transformations of coordination polymers from P 4Se 3 and CuX (X=Cl, Br, I)

    NASA Astrophysics Data System (ADS)

    Biegerl, Andreas; Gröger, Christian; Kalbitzer, Hans R.; Pfitzner, Arno; Wachter, Joachim; Weihrich, Richard; Zabel, Manfred

    2011-07-01

    The formation of coordination polymers (CuCl)P 4Se 3 ( 1), (CuBr) 3(P 4Se 3) 2 ( 2), (CuI) 3(P 4Se 3) 2 ( 3) and (CuI)P 4Se 3 ( 4), from solutions of copper(I) halides and P 4Se 3 by diffusion methods has been studied. The new compounds were characterized by X-ray crystallography, solid-state 31P MAS NMR and Raman spectroscopy. Theoretical studies on the DFT level in the crystalline phase allowed the unequivocal assignment of the recorded Raman shifts between 200 and 480 cm -1. The structure of 1 consists of a 2D network of castellated [CuCl] n chains and bidentate P 4Se 3 molecules. The 3D network of 2 comprises [CuBr] n chains, which are linked by tridentate P 4Se 3 molecules. Compound 3 is a three-dimensional polymer composed of four-membered (CuI) 2 rings and castellated [CuI] n chains, which are linked by tridentate P 4Se 3 molecules involving two basal and the apical P atoms. Thermal conversion of 1 at 230 °C gives (CuCl) 3(P 4Se 3) 2 ( 5), which is isostructural with 2. The thermal conversion of (CuI) 3P 4S 3, which was studied for comparison gave at 371 °C (CuI) 3P 4S 4, Cu 3PS 4 and small amounts of Cu 6PS 5I.

  6. Mediation of 5-HT-induced external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs by the putative 5-HT7 receptor

    PubMed Central

    Villalón, Carlos M; Centurión, David; Luján-Estrada, Miguel; Terrón, José A; Sánchez-López, Araceli

    1997-01-01

    The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 μg kg−1, i.v.).One-minute intracarotid (i.c.) infusions of 5-HT (0.330 μg min−1), 5-carboxamidotryptamine (5-CT; 0.010.3 μg min−1), 5-methoxytryptamine (1100 μg min−1) and lisuride (31000 μg min−1) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5-CT>>5-HT⩾5-methoxytryptamine>lisuride, whereas cisapride (1001000 μg min−1, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85±7 μg kg−1, i.c.), but not cisapride (mean dose of 67±7 μg kg−1, i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8-OH-DPAT (33000 μg min−1) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200±33 μg kg−1, i.c.) the agonist-induced vasodilator responses.The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (±)-pindolol (4

  7. Effects of physical training on functional activity of 5-HT1B receptors in rat central nervous system: role of 5-HT-moduline.

    PubMed

    Chennaoui, M; Grimaldi, B; Fillion, M P; Bonnin, A; Drogou, C; Fillion, G; Guezennec, C Y

    2000-06-01

    The effect of physical exercise was examined on the sensitivity of 5-HT1B receptors and on 5-HT-moduline tissue concentration in the central nervous system of rats. Rats were trained for 7 consecutive weeks to run on a treadmill. Three groups of animals were selected: group 1, sedentary rats (controls); group 2, animals running for 1 h at 18 m/min for 5 days per week (moderate training) and group 3, animals running for 2 h, at 30 m/min on a 7% grade for 5 days per week (intensive training). The animals were sacrificed 24 h after the last running. Rat brains were dissected out to obtain hippocampus and substantia nigra and kept at -80 degrees C until use. 5-HT1B receptor activity was determined by studying [35S]GTPgammaS binding in a substantia nigra membrane preparation from individual animals, after stimulation by a selective 5-HT1B receptor agonist (CP 93,129). 5-HT-moduline tissue content in hippocampus from individual animals was determined by ELISA using a polyclonal anti-5-HT-moduline antibody. In moderately trained animals (n=5), the CP 93,129-stimulated [35S]GTPgammaS binding curve was shifted to the right compared with controls (n=6), whereas the binding was totally suppressed in intensely trained animals (n=5). In parallel, 5-HT-moduline tissue concentration in the hippocampus was slightly increased in moderately trained animals (117.3 +/- 8.9%) (n=5), whereas it was significantly increased in intensely trained animals (182.6 +/- 29.5%) (n=5) compared to controls (100 +/- 6.11%) (n=6). These results show that 5-HT1B receptors are slightly desensitized in moderately trained animals and totally desensitized in intensely trained animals; moreover, they suggest that the observed desensitization is related to an increase of 5-HT-moduline tissue content; this mechanism may play a role in various pathophysiological conditions. PMID:10882034

  8. Unraveling mechanisms underlying partial agonism in 5-HT3A receptors.

    PubMed

    Corradi, Jeremías; Bouzat, Cecilia

    2014-12-10

    Partial agonists have emerged as attractive therapeutic molecules. 2-Me-5HT and tryptamine have been defined as partial agonists of 5-HT3 receptors on the basis of macroscopic measurements. Because several mechanisms may limit maximal responses, we took advantage of the high-conductance form of the mouse serotonin type 3A (5-HT3A) receptor to understand their molecular actions. Individual 5-HT-bound receptors activate in long episodes of high open probability, consisting of groups of openings in quick succession. The activation pattern is similar for 2-Me-5HT only at very low concentrations since profound channel blockade takes place within the activating concentration range. In contrast, activation episodes are significantly briefer in the presence of tryptamine. Generation of a full activation scheme reveals that the fully occupied receptor overcomes transitions to closed preopen states (primed states) before opening. Reduced priming explains the partial agonism of tryptamine. In contrast, 2-Me-5HT is not a genuine partial agonist since priming is not dramatically affected and its low apparent efficacy is mainly due to channel blockade. The analysis also shows that the first priming step is the rate-limiting step and partial agonists require an increased number of priming steps for activation. Molecular docking suggests that interactions are similar for 5-HT and 2-Me-5HT but slightly different for tryptamine. Our study contributes to understanding 5-HT3A receptor activation, extends the novel concept of partial agonism within the Cys-loop family, reveals novel aspects of partial agonism, and unmasks molecular actions of classically defined partial agonists. Unraveling mechanisms underlying partial responses has implications in the design of therapeutic compounds. PMID:25505338

  9. Pet imaging of human pituitary 5-HT2 receptors with F-18 setoperone

    SciTech Connect

    Fischman, A.J.; Bonab, A.A.; Babich, J.W.

    1995-05-01

    Serotonin (5-HT) receptors play an important role in the regulation of pituitary function. In particular, 5HT agonists stimulate ACTH, {beta}-endorphin, prolactin and growth hormone secretion but inhibit TSH release. 5-HT binding sites have been identified by autoradiographic studies of rat and human pituitary. In the present investigation, we used PET with F-18 setoperone to image 5-HT2 receptors in normal humans. Setoperone, a piperidine derivative with potent 5-HT2 receptor blocking properties was labelled with F-18 by nucleophilic substitution on the nitro derivative. After HPLC purification, specific activity was between 10,000 and 15,000 mCi/{mu} mole and radiochemical purity was >98%. Six healthy male volunteers were injected with 5-7 mCi of F-18. Setoperone and serial PET images and arterial blood samples were collected over 2 hrs. Specific binding to 5-HT2 receptors in the frontal cortex (FC), striatum (ST) and pituitary (P) was quantitated using the cerebellum (C) as reference. The tracer showed clear retention in FC, ST and P (known to contain a high density of 5-HT2 receptors) relative to C (known to be devoid of 5-HT2 receptors). In all subjects, FC/C, ST/C and P/C ratios increased during the first hr. and remained stable thereafter. For FC and ST, the ratios reached similar values; 3.92{plus_minus}0.73 and 3.53{plus_minus}0.32. For pituitary, a significantly higher ratio, was measured at all times; 6.53{plus_minus}1.82 (p<0.01). These results indicate that F-18 setoperone is an effective PET radiopharmaceutical for imaging 5-HT2 receptors in the human pituitary. Future applications of this agent could provide important new insights into neuroendocrine function.

  10. Mutational analysis of the promoter and the coding region of the 5-HT1A gene

    SciTech Connect

    Erdmann, J.; Noethen, M.M.; Shimron-Abarbanell, D.

    1994-09-01

    Disturbances of serotonergic pathways have been implicated in many neuropsychiatric disorders. Serotonin (5HT) receptors can be subdivided into at least three major families (5HT1, 5HT2, and 5HT3). Five human 5HT1 receptor subtypes have been cloned, namely 1A, 1D{alpha}, 1D{beta}, 1E, and 1F. Of these, the 5HT1A receptor is the best characterized subtype. In the present study we sought to identify genetic variation in the 5HT1A receptor gene which through alteration of protein function or level of expression might contribute to the genetics of neuropsychiatric diseases. The coding region and the 5{prime} promoter region of the 5HT1A gene from 159 unrelated subjects (45 schizophrenic, 46 bipolar affective, and 43 patients with Tourette`s syndrome, as well as 25 controls) were analyzed using SSCA. SSCA revealed the presence of two mutations both located in the coding region of the 5HT1A receptor gene. The first mutation is a rare silent C{r_arrow}T substitution at nucleotide position 549. The second mutation is characterized by a base pair substitution (A{r_arrow}G) at the first position of codon 28 and results in an amino acid exchange (Ile{r_arrow}Val). Since Val28 was found only in a single schizophrenic patient and in none of the other patients or controls, we decided to extend our samples and to use a restriction assay for screening a further 74 schizophrenic, 95 bipolar affective, and 49 patients with Tourette`s syndrome, as well as 185 controls, for the presence of the mutation. In total, the mutation was found in 2 schizophrenic patients, in 3 bipolars, in 1 Tourette patient, and in 5 controls. To our knowledge the Ile-28-Val substitution reported here is the first natural occuring molecular variant which has been identified for a serotonin receptor so far.

  11. Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders.

    PubMed

    Higgins, Guy A; Fletcher, Paul J

    2015-07-15

    The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014. PMID:25870913

  12. Vascular reactivity, 5-HT uptake, and blood pressure in the serotonin transporter knockout rat.

    PubMed

    Linder, A Elizabeth; Diaz, Jessica; Ni, Wei; Szasz, Theo; Burnett, Robert; Watts, Stephanie W

    2008-04-01

    The handling of serotonin [5-hydroxytryptamine (5-HT)] depends on the serotonin transporter (SERT). A SERT knockout (KO) rat is a useful model to test the hypothesis that SERT is the primary mechanism for arterial 5-HT uptake and to investigate the impact of SERT removal on blood pressure. Wild-type (WT) and KO rats were used to measure 5-HT content (plasma, raphe, aorta, carotid, and mesenteric artery), aortic isometric contraction, and blood pressure. HPLC supported the lack of circulating 5-HT in plasma (ng/ml plasma, WT, 310 +/- 96; and KO, 1.0 +/- 0.5; P < 0.05). Immunohistochemistry and Western blot analyses validated the presence of the SERT protein in the WT rats and a lesser expression in the KO rat. The aorta isolated from KO rats had a normal contraction to phenylephrine and norepinephrine and a normal relaxation to the endothelium-dependent agonist acetylcholine compared with the aorta from WT. In contrast, the potency of 5-HT was increased in the aorta from KO rats compared with WT rats [-log EC(50) (M); WT, 5.71 +/- 0.08; and KO, 6.7 +/- 0.18] and maximum contraction was reduced [%phenylephrine (10 muM) contraction, WT, 113 +/- 6%; and KO, 52 +/- 12%]. 5-HT uptake was reduced but not abolished in arteries of the KO compared with the WT rats. Diurnal mean arterial blood pressure, heart rate, and locomotor activity level of the KO rats were similar to the WT rats. These data suggest that there are other mechanisms of 5-HT uptake in the arteries of the rat and that although the absence of circulating 5-HT and/or SERT function sensitizes arteries to 5-HT, SERT dysfunction does not impair normal blood pressure. PMID:18263707

  13. Familial Risk for Major Depression is Associated with Lower Striatal 5-HT4 Receptor Binding

    PubMed Central

    Madsen, Karine; Torstensen, Eva; Holst, Klaus K.; Haahr, Mette E.; Knorr, Ulla; Frokjaer, Vibe G.; Brandt-Larsen, Malene; Iversen, Pernille; Fisher, Patrick M.

    2015-01-01

    Background: The 5-HT4 receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT4 receptor’s in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study was to determine whether familial risk for MDD is associated with cerebral 5-HT4 receptor binding as measured with [11C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD. Methods: We studied 57 healthy individuals (mean age 36 yrs, range 20–86; 21 women), 26 of which had first-degree relatives treated for MDD. Results: We found that having a family history of MDD was associated with lower striatal 5-HT4 receptor binding (p = 0.038; in individuals below 40 years, p = 0.013). Further, we found evidence for a “risk-dose effect” on 5-HT4 receptor binding, since the number of first-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012). Conclusions: Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression, and that lower striatal 5-HT4 receptor binding is associated with increased risk for developing MDD. The finding is intriguing considering that the 5-HT4 receptor has been suggested to be an effective target for antidepressant treatment. PMID:25522384

  14. Cutaneous and Labyrinthine Tolerance of Bioactive Glass S53P4 in Mastoid and Epitympanic Obliteration Surgery: Prospective Clinical Study

    PubMed Central

    Bernardeschi, Daniele; Nguyen, Yann; Russo, Francesca Yoshie; Mosnier, Isabelle; Ferrary, Evelyne; Sterkers, Olivier

    2015-01-01

    Objective. To evaluate the cutaneous and the inner ear tolerance of bioactive glass S53P4 when used in the mastoid and epitympanic obliteration for chronic otitis surgery. Material and Methods. Forty-one cases have been included in this prospective study. Cutaneous tolerance was clinically evaluated 1 week, 1 month, and 3 months after surgery with a physical examination of the retroauricular and external auditory canal (EAC) skin and the presence of otalgia; the inner ear tolerance was assessed by bone-conduction hearing threshold 1 day after surgery and by the presence of vertigo or imbalance. Results. All surgeries but 1 were uneventful: all patients maintained the preoperative bone-conduction hearing threshold except for one case in which the round window membrane was opened during the dissection of the cholesteatoma in the hypotympanum and this led to a dead ear. No dizziness or vertigo was reported. Three months after surgery, healing was achieved in all cases with a healthy painless skin. No cases of revision surgery for removal of the granules occurred in this study. Conclusion. The bioactive glass S53P4 is a well-tolerated biomaterial for primary or revision chronic otitis surgery, as shown by the local skin reaction which lasted less than 3 months and by the absence of labyrinthine complications. PMID:26504792

  15. Thionations using a P4S10-pyridine complex in solvents such as acetonitrile and dimethyl sulfone.

    PubMed

    Bergman, Jan; Pettersson, Birgitta; Hasimbegovic, Vedran; Svensson, Per H

    2011-03-18

    Tetraphosphorus decasulfide (P(4)S(10)) in pyridine has been used as a thionating agent for a long period of time. The moisture-sensitive reagent has now been isolated in crystalline form, and the detailed structure has been determined by X-ray crystallography. The thionating power of this storable reagent has been studied and transferred to solvents such as acetonitrile in which it has proven to be synthetically useful and exceptionally selective. Its properties have been compared with the so-called Lawesson reagent (LR). Particularly interesting are the results from thionations at relatively high temperatures (∼165 °C) in dimethyl sulfone as solvent. Under these conditions, for instance, acridone and 3-acetylindole could quickly be transformed to the corresponding thionated derivatives. Glycylglycine similarly gave piperazinedithione. At these temperatures, LR is inefficient due to rapid decomposition. The thionated products are generally cleaner and more easy to obtain because in the crystalline reagent, impurities which invariably are present in the conventional reagents, P(4)S(10) in pyridine or LR, have been removed. PMID:21341727

  16. Influence of SrO substitution for CaO on the properties of bioactive glass S53P4.

    PubMed

    Massera, Jonathan; Hupa, Leena

    2014-03-01

    Commercial melt-quenched bioactive glasses consist of the oxides of silicon, phosphorus, calcium and sodium. Doping of the glasses with oxides of some other elements is known to affect their capability to support hydroxyapatite formation and thus bone tissue healing but also to modify their high temperature processing parameters. In the present study, the influence of gradual substitution of SrO for CaO on the properties of the bioactive glass S53P4 was studied. Thermal analysis and hot stage microscopy were utilized to measure the thermal properties of the glasses. The in vitro bioactivity and solubility was measured by immersing the glasses in simulated body fluid for 6 h to 1 week. The formation of silica rich and hydroxyapatite layers was assessed from FTIR spectra analysis and SEM images of the glass surface. Increasing substitution of SrO for CaO decreased all characteristic temperatures and led to a slightly stronger glass network. The initial glass dissolution rate increased with SrO content. Hydroxyapatite layer was formed on all glasses but on the SrO containing glasses the layer was thinner and contained also strontium. The results suggest that substituting SrO for CaO in S53P4 glass retards the bioactivity. However, substitution greater than 10 mol% allow for precipitation of a strontium substituted hydroxyapatite layer. PMID:24338267

  17. Extraction of poly (3-hexylthiophene) (P3HT) properties from dark current voltage characteristics in a P3HT/n-crystalline-silicon solar cell

    NASA Astrophysics Data System (ADS)

    Nolasco, J. C.; Cabré, R.; Ferré-Borrull, J.; Marsal, L. F.; Estrada, M.; Pallarès, J.

    2010-02-01

    The dark current-voltage characteristics of poly (3-hexylthiophene) (P3HT)/n-type crystalline silicon solar cells were analyzed using an electrical equivalent circuit. We found that without illumination transport occurs due to hopping between localized states at the P3HT/silicon interface not only at low voltages, through multitunneling capture emission, but also at medium voltages, through tunneling-enhanced recombination. At high voltages the current is limited by series resistance and space-charge limited mechanisms. At low reverse voltages the current is limited by shunt resistance. From the temperature dependence of the equivalent circuit's fitting parameters, we were able to estimate some physical parameters of the P3HT layer, namely the electron affinity, the charge carrier concentration and the characteristic temperature of the exponential trap distribution. The extracted P3HT values are in good agreement with previously reported values obtained using different methods but our approach takes into account that the P3HT layer is in a solar cell.

  18. Neuronal Ablation of p-Akt at Ser473 Leads to Altered 5-HT1A/2A Receptor Function

    PubMed Central

    Saunders, Christine; Siuta, Michael; Robertson, Sabrina D.; Davis, Adeola R.; Sauer, Jennifer; Matthies, Heinrich J.G.; Gresch, Paul J.; Airey, David; Lindsley, Craig W.; Schetz, John A.; Niswender, Kevin D.

    2014-01-01

    The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function. PMID:24090638

  19. Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists

    PubMed Central

    2015-01-01

    A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization. PMID:25815155

  20. Mechanism for the acute effects of organophosphate pesticides on the adult 5-HT system

    PubMed Central

    Judge, Sarah J.; Savy, Claire Y.; Campbell, Matthew; Dodds, Rebecca; Gomes, Larissa Kruger; Laws, Grace; Watson, Anna; Blain, Peter G.; Morris, Christopher M.; Gartside, Sarah E.

    2016-01-01

    The neurotransmitter serotonin (5-HT) is involved in mood disorder aetiology and it has been reported that (organophosphate) OP exposure affects 5-HT turnover. The aim of this study was to elucidate the mechanism underlying OP effects on the adult 5-HT system. First, acute in vivo administration of the OP diazinon (0, 1.3, 13 or 39 mg/kg i.p.) to male Hooded Lister rats inhibited the activity of the cholinergic enzyme acetylcholinesterase in blood and in the hippocampus, dorsal raphe nucleus (DRN), striatum and prefrontal cortex. Diazinon-induced cholinesterase inhibition was greatest in the DRN, the brain's major source of 5-HT neurones. Second, acute in vivo diazinon exposure (0 or 39 mg/kg i.p.) increased the basal firing rate of DRN neurones measured ex vivo in brain slices. The excitatory responses of DRN neurones to α1-adrenoceptor or AMPA/kainate receptor activation were not affected by in vivo diazinon exposure but the inhibitory response to 5-HT was attenuated, indicating 5-HT1A autoreceptor down-regulation. Finally, direct application of the diazinon metabolite diazinon oxon to naive rat brain slices increased the firing rate of DRN 5-HT neurones, as did chlorpyrifos-oxon, indicating the effect was not unique to diazinon. The oxon-induced augmentation of firing was blocked by the nicotinic acetylcholine receptor antagonist mecamylamine and the AMPA/kainate glutamate receptor antagonist DNQX. Together these data indicate that 1) acute OP exposure inhibits DRN cholinesterase, leading to acetylcholine accumulation, 2) the acetylcholine activates nicotinic receptors on 5-HT neurones and also on glutamatergic neurones, thus releasing glutamate and activating 5-HT neuronal AMPA/kainate receptors 3) the increase in 5-HT neuronal activity, and resulting 5-HT release, may lead to 5-HT1A autoreceptor down-regulation. This mechanism may be involved in the reported increase in risk of developing anxiety and depression following occupational OP exposure. PMID

  1. Organic solar cells: evaluation of the stability of P3HT using time-delayed degradation

    NASA Astrophysics Data System (ADS)

    Poh, Chung-How; Poh, Chung-Kiak; Bryant, Glenn; Belcher, Warwick; Dastoor, Paul

    2011-12-01

    Despite the fact that the performance of organic solar cells is generally susceptible to degradation by moisture exposure, there has been suggestion that the photoactive layer (P3HT) is surprisingly resilient. This work attempts to confirm the stability of P3HT as an organic solar cell material by deliberately introducing water into the photoactive layer. A dramatic step drop in device performance during cell characterization is observed approximately one day after the device has been fabricated. The time-delayed step drop in output efficiency strongly suggests that moisture has little effect on the P3HT conducting polymer.

  2. Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT4R) partial agonist and 5-HT6R antagonist activities, as potential treatment of Alzheimer's disease.

    PubMed

    Yahiaoui, Samir; Hamidouche, Katia; Ballandonne, Céline; Davis, Audrey; de Oliveira Santos, Jana Sopkova; Freret, Thomas; Boulouard, Michel; Rochais, Christophe; Dallemagne, Patrick

    2016-10-01

    5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip. PMID:27266998

  3. Bidirectional impact of atrazine-induced elvations in progesterone (P4) on the LH Surge in the ovariectomized (OVX), estradiol (E2)-primed rat

    EPA Science Inventory

    Multiple daily exposures to the herbicide atrazine (ATZ) have been reported to suppress the luteinizing hormone surge (LHS) in female rats. Exposure has also been found to elevate P4 concentrations, and an increase in P4 is known to have a different directional effect on LH depen...

  4. Bidirectional impact of atrazine-induced elevations in progesterone (P4) on the LH surge in the ovariectomized, estradiol (E2)-primed rat

    EPA Science Inventory

    Multiple daily exposures to the herbicide atrazine (ATZ) have been reported to suppress the luteinizing hormone surge (LHS) in female rats. Exposure has also been found to elevate P4 concentrations, and an increase in P4 is known to have a different directional effect on LH depe...

  5. Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: potential utility as antipsychotic medications

    PubMed Central

    Morgan, Drake; Kondabolu, Krishnakanth; Kuipers, Allison; Sakhuja, Rajeev; Robertson, Kimberly L.; Rowland, Neil E.; Booth, Raymond G.

    2013-01-01

    Background Desired serotonin 5HT2 receptor pharmacology for treatment of psychoses is 5HT2A antagonism and/or 5HT2C agonism. No selective 5HT2A antagonist has been approved for psychosis and the only approved 5HT2C agonist (for obesity) also activates 5HT2A and 5HT2B receptors, which can lead to clinical complications. Studies herein tested the hypothesis that a dual-function 5HT2A antagonist/5HT2C agonist that does not activate 5HT2B receptors would be suitable for development as an antipsychotic drug, without liability for weight gain. Methods The novel compounds (+)- and (−)-trans-4-(4′-chlorophenyl)-N,N-dimethyl-2-aminotetralin (p-Cl-PAT) were synthesized, characterized in vitro for affinity and functional activity at human 5HT2 receptors, and administered by intraperitoneal (i.p.) and oral (gavage) routes to mice in behavioral paradigms that assessed antipsychotic efficacy and effects on feeding behavior. Results (+)- and (−)-p-Cl-PAT activated 5HT2C receptors, with (+)-p-Cl-PAT being 12-times more potent, consistent with its higher affinity across 5HT2 receptors. Neither p-Cl-PAT enantiomer activated 5HT2A or 5HT2B receptors at concentrations up to 300-times greater than their respective affinity (Ki), and (+)-p-Cl-PAT was shown to be a 5HT2A competitive antagonist. When administered i.p. or orally, (+)- and (−)-p-Cl-PAT attenuated the head-twitch response (HTR) in mice elicited by the 5HT2 agonist (−)-2,5-dimethoxy-4-iodoamphetamine (DOI) and reduced intake of a highly palatable food in non-food-deprived mice, with (+)-p-Cl-PAT being more potent across behavioral assays. Conclusions The novel in vitro pharmacology of (+)-p-Cl-PAT (5HT2A antagonism/5HT2C agonism without activation of 5HT2B) translated in vivo to an orally-active drug candidate with preclinical efficacy to treat psychoses without liability for weight gain. PMID:23665356

  6. Phase stability of an HT-9 duct irradiated in FFTF

    NASA Astrophysics Data System (ADS)

    Anderoglu, O.; Van den Bosch, J.; Hosemann, P.; Stergar, E.; Sencer, B. H.; Bhattacharyya, D.; Dickerson, R.; Dickerson, P.; Hartl, M.; Maloy, S. A.

    2012-11-01

    A fuel test assembly known as the ACO-3 duct made out of a normalized and fully tempered ferritic/martensitic steel (HT-9) was previously irradiated in the Fast Flux Test Reactor Facility (FFTF) up to 155 dpa at a temperature range of 380-504 °C. The microstructures of the samples from five different zones along a face of the duct were analyzed using a combination of transmission electron microscopy (TEM) based techniques, small angle neutron scattering (SANS) and atom probe tomography (APT). A high density of Cr rich α' precipitates together with a moderate density of G-phase precipitates with average sizes of ˜4 and 11 nm respectively were found in the 20 dpa, 380 °C zone. It was found that precipitation of the second phases is more sensitive to the temperature history then to the exposed neutron dose. In general, the density of both precipitates decreases with increasing irradiation temperature. No significant change is observed in average size of α' while the average size of G-phase precipitates increases up to 27 nm at 440 °C. Voids are observed after irradiation at 100 dpa (irradiation temperature of 410 °C) and 155 dpa (irradiation temperature of 440 °C) but no voids were detected after irradiation to 96 dpa (irradiation temperature of 466 °C). In contrast to what is previously reported in the literature, no Laves, M6C or Chi phases were found in any of the zones.

  7. Phase Stability of an HT-9 Duct Irradiated in FFTF

    SciTech Connect

    O. Anderoglu; J. Van den Bosch; B. H. Sencer; E. Stergar; D. Bhattacharya; P. Dickerson; M. Hartl; S.A. Maloy; P. Hosemann

    2012-11-01

    A fuel test assembly known as ACO-3 duct made out of a fully tempered ferritic/martensitic steel (HT-9) was previously irradiated in the Fast Flux Test Reactor Facility (FFTF) up to 155 dpa at a temperature range of 380-504°C. The microstructures of the samples from 5 different zones along the face of the duct were analyzed using a combination of TEM based techniques, SANS and APT. A high density of Cr rich a' precipitates together with moderate density G-phase precipitates with an average sizes of 5 and 11 nm respectively were found at 20 dpa, 380°C zone. It was found that the precipitations of the second phases are more sensitive to temperature then the dose. In general, the density of both precipitates decreases with increasing irradiation temperature. No significant change is observed in average size of a' while the average size of G-phase precipitates increases up to 27 nm at 440°C. Voids are seen at 100 (410°C) and 155 (440°C) dpa zones but none was detected at 96 dpa (466°C) zone. In contrast to what is reported in the literature, no laves or Chi phases were found in any of the zones.

  8. Autoradiographic Evaluation of [(18)F]FECUMI-101, a High Affinity 5-HT1AR Ligand in Human Brain.

    PubMed

    Kumar, J S Dileep; Underwood, Mark D; Simpson, Norman R; Kassir, Suham A; Prabhakaran, Jaya; Majo, Vattoly J; Bakalian, Mihran J; Parsey, Ramin V; Mann, J John; Arango, Victoria

    2016-05-12

    [(18)F]FECUMI-101 ([(18)F]1) is a 5HT1AR ligand demonstrating specific binding in brain regions corresponding to the distribution of 5-HT1AR in baboons. However, we detected moderate uptake of [(18)F]1 in baboon thalamus, a brain region lacking 5-HT1AR. We sought to investigate the relative binding of [(18)F]1 to 5-HT1AR, α1R, and 5-HT7R in vitro. Using autoradiography in human brain sections, specific binding of [(18)F]1 to 5-HT1AR was confirmed. However, [(18)F]1 also showed 26% binding to α1R in PFC. The hippocampal formation exhibited 51% and 92% binding of [(18)F]1 to α1R and 5-HT1AR, respectively. Thalamus and cerebellum showed very little binding. There is no measurable specific binding of [(18)F]1 to 5-HT7R and no effect of temperature on [(18)F]1 specific binding to 5-HT1AR or α1R. These results indicate that, while [(18)F]FECUMI-101 is not a completely selective 5-HT1AR ligand for receptor quantification, it may be useful for occupancy measurements of drugs acting at 5-HT1AR in vivo. PMID:27190597

  9. Identification of spinal 5-HT sub 3 receptors and their role in the modulation of nociceptive responses in the rat

    SciTech Connect

    Glaum, S.R.

    1988-01-01

    The project consisted of two related studies: (1) the characterization of serotonin binding sites in crude and purified synaptic membranes prepared from the rat spinal cord, and (2) the association of serotonin binding sites with functional 5-HT receptor responses in the modulation of nociceptive information at the level of the spinal cord. The first series of experiments involved the preparation of membranes from the dorsal and ventral halves of the rat spinal cord and the demonstration of specific ({sup 3}H)serotonin binding to these membranes. High affinity binding sites which conformed to the 5-HT{sub 3} subtype were identified in dorsal, but not ventral spinal cord synaptic membranes. These experiments also confirmed the presence of high affinity ({sup 3}H)5-HT binding sites in dorsal spinal cord synaptic membranes of the 5-HT{sub 1} subtype. The second group of studies demonstrated the ability of selective 5-HT{sub 3} antagonists to inhibit the antinociceptive response to intrathecally administered 5-HT, as measured by a change in tail flick and hot plate latencies. Intrathecal pretreatment with the selective 5-HT{sub 3} antagonists ICS 205-930 or MDL 72222 abolished the antinociceptive effects of 5-HT. Furthermore, the selective 5-HT{sub 3} agonist 2-methyl-5-HT mimicked the antinociceptive effects of 5-HT.

  10. Fluorescence emission of Disperse Red 1 in PS-b-P4VP micelles controlled by a toluene/ethanol solvent mixture.

    PubMed

    Ali, Nauman; Park, Soo-Young

    2009-12-01

    The effects of Disperse Red 1 (DR1) in the poly(styrene-block-4-vinylpyridine) (PS-b-P4VP) micelle on micellar morphology and fluorescence emission were studied using small-angle X-ray scattering (SAXS), generalized indirect Fourier transform (GIFT), Fourier transform infrared (FT-IR), transmission electron microscopy (TEM), and photoluminescence (PL). PS-b-P4VP was coupled with DR1 in 10 mg/mL toluene/ethanol mixture solutions where ethanol and toluene were P4VP and PS selective, respectively. Hydrogen bonds were formed between the -OH group of DR1 and the pyridine ring in PS-b-P4VP. DR1 (which was coupled with P4VP) was confined in the core or corona of the micelle depending on the location of P4VP. The micellar structure was strongly dependent on varphi (weight percentage of toluene in a toluene/ethanol mixture). The PS-b-P4VP-DR1 complex in the mixture solutions showed the spherical micelle with the cores of P4VP and PS in ethanol-rich and toluene-rich solvents, respectively. The quenching phenomenon was observed for DR1 in the corona of PS-b-P4VP micelles [at varphi = 0 (ethanol)], while the fluorescence quantum yield decreased. However, significant increases in the fluorescence quantum yields at varphi = 100 were observed when DR1 was confined in the core of the PS-b-P4VP micelles. The confinement of DR1 in the hard core was more effective in fluorescence emission than that in the soft corona due to the slow trans-to-cis transition of DR1. PMID:19764779

  11. Application of an Integrated GPCR SAR-Modeling Platform To Explain the Activation Selectivity of Human 5-HT2C over 5-HT2B.

    PubMed

    Heifetz, Alexander; Storer, R Ian; McMurray, Gordon; James, Tim; Morao, Inaki; Aldeghi, Matteo; Bodkin, Mike J; Biggin, Philip C

    2016-05-20

    Agonism of the 5-HT2C serotonin receptor has been associated with the treatment of a number of diseases including obesity, psychiatric disorders, sexual health, and urology. However, the development of effective 5-HT2C agonists has been hampered by the difficulty in obtaining selectivity over the closely related 5-HT2B receptor, agonism of which is associated with irreversible cardiac valvulopathy. Understanding how to design selective agonists requires exploration of the structural features governing the functional uniqueness of the target receptor relative to related off targets. X-ray crystallography, the major experimental source of structural information, is a slow and challenging process for integral membrane proteins, and so is currently not feasible for every GPCR or GPCR-ligand complex. Therefore, the integration of existing ligand SAR data with GPCR modeling can be a practical alternative to provide this essential structural insight. To demonstrate this, we integrated SAR data from 39 azepine series 5-HT2C agonists, comprising both selective and unselective examples, with our hierarchical GPCR modeling protocol (HGMP). Through this work we have been able to demonstrate how relatively small differences in the amino acid sequences of GPCRs can lead to significant differences in secondary structure and function, as supported by experimental data. In particular, this study suggests that conformational differences in the tilt of TM7 between 5-HT2B and 5-HT2C, which result from differences in interhelical interactions, may be the major source of selectivity in G-protein activation between these two receptors. Our approach also demonstrates how the use of GPCR models in conjunction with SAR data can be used to explain activity cliffs. PMID:26900768

  12. Distinct effect of 5-HT1A and 5-HT2A receptors in the medial nucleus of the amygdala on tonic immobility behavior.

    PubMed

    de Paula, Bruna Balbino; Leite-Panissi, Christie Ramos Andrade

    2016-07-15

    The tonic immobility (TI) response is an innate fear behavior associated with intensely dangerous situations, exhibited by many species of invertebrate and vertebrate animals. In humans, it is possible that TI predicts the severity of posttraumatic stress disorder symptoms. This behavioral response is initiated and sustained by the stimulation of various groups of neurons distributed in the telencephalon, diencephalon and brainstem. Previous research has found the highest Fos-IR in the posteroventral part of the medial nucleus of the amygdala (MEA) during TI behavior; however, the neurotransmission of this amygdaloid region involved in the modulation of this innate fear behavior still needs to be clarified. Considering that a major drug class used for the treatment of psychopathology is based on serotonin (5-HT) neurotransmission, we investigated the effects of serotonergic receptor activation in the MEA on the duration of TI. The results indicate that the activation of the 5HT1A receptors or the blocking of the 5HT2 receptors of the MEA can promote a reduction in fear and/or anxiety, consequently decreasing TI duration in guinea pigs. In contrast, blocking the 5HT1A receptors or activating the 5HT2 receptors in this amygdalar region increased the TI duration, suggesting an increase in fear and/or anxiety. These alterations do not appear to be due to a modification of spontaneous motor activity, which might non-specifically affect TI duration. Thus, these results suggest a distinct role of the 5HT receptors in the MEA in innate fear modulation. PMID:27150816

  13. Photocatalytic degradation of 17α-ethinylestradiol (EE2) in the presence of TiO2-doped zeolite.

    PubMed

    Pan, Zhong; Stemmler, Elizabeth A; Cho, Hong Je; Fan, Wei; LeBlanc, Lawrence A; Patterson, Howard H; Amirbahman, Aria

    2014-08-30

    Current design limitations and ineffective remediation techniques in wastewater treatment plants have led to concerns about the prevalence of pharmaceutical and personal care products (PPCPs) in receiving waters. A novel photocatalyst, TiO2-doped low-silica X zeolite (TiO2-LSX), was used to study the degradation of the pharmaceutical compound, 17α-ethinylestradiol (EE2). The catalyst was synthesized and characterized using XRD, BET surface analysis, SEM-EDAX, and ICP-OES. The effects of different UV light intensities, initial EE2 concentrations, and catalyst dosages on the EE2 removal efficiency were studied. A higher EE2 removal efficiency was attained with UV-TiO2-LSX when compared with UV-TiO2 or UV alone. The EE2 degradation process followed pseudo-first-order kinetics. A comprehensive empirical model was developed to describe the EE2 degradation kinetics under different conditions using multiple linear regression analysis. The EE2 degradation mechanism was proposed based on molecular calculations, identification of photoproducts using HPLC-MS/MS, and reactive species quenching experiments; the results showed that oxidative degradation pathways initiated by hydroxyl radicals were predominant. This novel TiO2-doped zeolite system provides a promising application for the UV disinfection process in wastewater treatment plants. PMID:25036996

  14. Polarised interleukin 8 secretion by HT 29/19A cells.

    PubMed Central

    Lammers, K M; Jansen, J; Bijlsma, P B; Ceska, M; Tytgat, G N; Laboisse, C L; van Deventer, S J

    1994-01-01

    Interleukin 8 is a neutrophil chemotactic and stimulating cytokine induced by various inflammatory stimuli, including tumour necrosis factor, interleukin 1, and endotoxin. The ability of HT 29/19A enterocytes to synthesise interleukin 8 was studied. The results show that interleukin 1 is an important stimulus for interleukin 8 synthesis and secretion by HT 29/19A cells, being more potent than tumour necrosis factor. The tumour necrosis factor and interleukin 1 induced interleukin 8 secretion by HT 29/19A cells was seen to be polarised according to the direction of stimulation. These results support the concept that mucosal cells (enterocytes) may play an important part in initiating mucosal inflammation. Furthermore, it is proposed that HT 29/19A cells constitute a tool to study stimulus directed polarised cytokine secretion. Images Figure 3 PMID:8150343

  15. Functional antagonistic properties of clozapine at the 5-HT3 receptor.

    PubMed

    Hermann, B; Wetzel, C H; Pestel, E; Zieglgänsberger, W; Holsboer, F; Rupprecht, R

    1996-08-23

    The atypical neuroleptic clozapine is thought to exert its psychopharmacological actions through a variety of neurotransmitter receptors. It binds preferentially to D4 and 5-HT2 receptors; however, little is known on it's interaction with the 5-HT3 receptor. Using a cell line stably expressing the 5-HT3 receptor, whole-cell voltage-clamp analysis revealed functional antagonistic properties of clozapine at low nanomolar concentrations in view of a binding affinity in the upper nanomolar range. Because the concentration of clozapine required for an interaction with the 5-HT3 receptor can be achieved with therapeutical doses, functional antagonistic properties at this ligand-gated ion channel may contribute to its unique psychopharmacological profile. PMID:8780717

  16. Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity.

    PubMed

    Miller, Keith J

    2005-10-01

    Obesity continues to be a burgeoning health problem worldwide. Before their removal from the market, fenfluramine and the more active enantiomer dexfenfluramine were considered to be among the most effective of weight loss agents. Much of the weight loss produced by fenfluramine was attributed to the direct activation of serotonin 5-HT(2C) receptors in the central nervous system via the desmethyl-metabolite of fenfluramine, norfenfluramine. Norfenfluramine, however, is non-selective, activating additional serotonin receptors, such as 5-HT(2A) and 5-HT(2B), which likely mediated the heart valve hypertrophy seen in many patients. Development of highly selective 5-HT(2C) agonists may recapitulate the clinical anti-obesity properties observed with fenfluramine while avoiding the significant cardiovascular and pulmonary side effects. PMID:16249524

  17. Regulation of the amyloid precursor protein ectodomain shedding by the 5-HT4 receptor and Epac.

    PubMed

    Robert, Sylvain; Maillet, Marjorie; Morel, Eric; Launay, Jean-Marie; Fischmeister, Rodolphe; Mercken, Luc; Lezoualc'h, Frank

    2005-02-14

    The serotonin 5-hydroxytryptamine (5-HT4) receptor is of potential interest for the treatment of Alzheimer's disease because it increases memory and learning. In this study, we investigated the effect of zinc metalloprotease inhibitors on the amyloid precursor protein (APP) processing induced by the serotonin 5-HT4 receptor in vitro. We show that secretion of the non-amyloidogenic form of APP, sAPPalpha induced by the 5-HT4(e) receptor isoform was not due to a general boost of the constitutive secretory pathway but rather to its specific effect on alpha-secretase activity. Although the h5-HT4(e) receptor increased IP3 production, inhibition of PKC did not modify its effect on sAPPalpha secretion. In addition, we found that alpha secretase activity is regulated by the cAMP-regulated guanine nucleotide exchange factor, Epac and the small GTPase Rac. PMID:15710402

  18. Au-Sn SLID Bonding: A Reliable HT Interconnect and Die Attach Technology

    NASA Astrophysics Data System (ADS)

    Tollefsen, Torleif André; Larsson, Andreas; Taklo, Maaike Margrete Visser; Neels, Antonia; Maeder, Xavier; Høydalsvik, Kristin; Breiby, Dag W.; Aasmundtveit, Knut

    2013-04-01

    Au-Sn solid-liquid interdiffusion (SLID) bonding is an established reliable high temperature (HT) die attach and interconnect technology. This article presents the life cycle of an optimized HT Au-Sn SLID bond, from fabrication, via thermal treatment, to mechanical rupture. The layered structure of a strong and uniform virgin bond was identified by X-ray diffraction to be Au/ζ (Au0.85Sn0.15)/Au. During HT exposure, it was transformed to Au/β (Au1.8Sn0.2)/Au. After HT exposure, the die shear strength was reduced by 50 pct, from 14 Pa to 70 MPa, which is still remarkably high. Fractographic studies revealed a change in fracture mode; it was changed from a combination of adhesive Au/Ni and cohesive SiC fracture to a cohesive β-phase fracture. Design rules for high quality Au-Sn SLID bonds are given.

  19. Phloroglucinol induces apoptosis via apoptotic signaling pathways in HT-29 colon cancer cells

    PubMed Central

    KANG, MI-HYE; KIM, IN-HYE; NAM, TAEK-JEO NG

    2014-01-01

    Phloroglucinol is a polyphenolic compound that is used to treat and prevent several human diseases, as it exerts beneficial biological activities, including anti-oxidant, anti-inflammatory and anticancer properties. The aim of the present study was to investigate the effects of phloroglucinol on apoptotic signaling pathways in HT-29 colon cancer cells. The results indicated that phloroglucinol suppressed cell viability and induced apoptosis in HT-29 cells in a concentration-dependent manner. Phloroglucinol treatment of HT-29 cells resulted in characteristic apoptosis-related changes: altered Bcl-2 family proteins, cytochrome c release, and activation of caspase-3 and caspase-8. This study also showed that proteins involved in apoptosis were stimulated by treatment with phloroglucinol. These findings demonstrated that phloroglucinol exerts anticancer activity in HT-29 colon cancer cells through induction of apoptosis. PMID:25070748

  20. A Switchable Molecular Dielectric with Two Sequential Reversible Phase Transitions: [(CH3)4P]4[Mn(SCN)6].

    PubMed

    Li, Qiang; Shi, Ping-Ping; Ye, Qiong; Wang, Hui-Ting; Wu, De-Hong; Ye, Heng-Yun; Fu, Da-Wei; Zhang, Yi

    2015-11-16

    A new organic-inorganic hybrid switchable and tunable dielectric compound, [(CH3)4P]4[Mn(SCN)6] (1), exhibits three distinct dielectric states above room temperature and undergoes two reversible solid-state phase transitions, including a structural phase transition at 330 K and a ferroelastic phase transition with the Aizu notation of mmmF2/m at 352 K. The variable-temperature structural analyses disclose that the origin of the phase transitions and dielectric anomalies can be ascribed to the reorientation or motion of both the [(CH3)4P](+) cations and [Mn(SCN)6](4-) anions in solid-state crystals. PMID:26512411

  1. Theoretical study of frequency and temperature dependence of dipole-quadrupole polarizability of P4 and adamantane

    NASA Astrophysics Data System (ADS)

    Shedge, Sapana V.; Pal, Sourav; Köster, Andreas M.

    2012-11-01

    The frequency and temperature dependence of dipole-quadrupole polarizability of tetrahedral P4 and adamantane molecules have been studied using first-principle all-electron density functional theory calculation. The recently developed time-dependent auxiliary density functional theory is extended for the calculation of dynamic dipole-quadrupole polarizabilities. Temperature effects are incorporated by Born-Oppenheimer molecular dynamics (BOMD) simulations recorded up to 100 ps. The dynamic dipole-quadrupole polarizabilities are calculated along these trajectories. The frequency and temperature effects can be significant for the accurate calculation of dipole-quadrupole polarizability. We have also identified the main reason for the observed discrepancy between experiment and theory in the case of adamantane.

  2. 5-HT7 receptor modulates GABAergic transmission in the rat dorsal raphe nucleus and controls cortical release of serotonin

    PubMed Central

    Kusek, Magdalena; Sowa, Joanna; Kamińska, Katarzyna; Gołembiowska, Krystyna; Tokarski, Krzysztof; Hess, Grzegorz

    2015-01-01

    The 5-HT7 receptor is one of the several serotonin (5-HT) receptor subtypes that are expressed in the dorsal raphe nucleus (DRN). Some earlier findings suggested that 5-HT7 receptors in the DRN were localized on GABAergic interneurons modulating the activity of 5-HT projection neurons. The aim of the present study was to find out how the 5-HT7 receptor modulates the GABAergic synaptic input to putative 5-HT DRN neurons, and whether blockade of the 5-HT7 receptor would affect the release of 5-HT in the target structure. Male Wistar rats with microdialysis probes implanted in the prefrontal cortex (PFC) received injections of the 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB 269970), which induced an increase in the levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the PFC. In another set of experiments whole-cell recordings from presumed projection neurons were carried out using DRN slices. SB 269970 application resulted in depolarization and in an increase in the firing frequency of the cells. In order to activate 5-HT7 receptors, 5-carboxamidotryptamine (5-CT) was applied in the presence of N-[2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635). Hyperpolarization of cells and a decrease in the firing frequency were observed after activation of the 5-HT7 receptor. Blockade of 5-HT7 receptors caused a decrease in the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), while its activation induced an increase. The mechanism of these effects appears to involve tonically-active 5-HT7 receptors modulating firing and/or GABA release from inhibitory interneurons which regulate the activity of DRN serotonergic projection neurons. PMID:26347612

  3. Repair, sidetrack, drilling, and completion of EE-2A for Phase 2 reservoir production service

    SciTech Connect

    Dreesen, D.S.; Cocks, G.G.; Nicholson, R.W.; Thomson, J.C.

    1989-08-01

    Hot Dry Rock (HDR) geothermal energy well EE-2 at Fenton Hill, New Mexico, was sidetracked and redrilled into the HDR Phase II reservoir after two unsuccessful attempts to repair damage in the lower wellbore. Before sidetracking was begun, six cement slurries were pumped to plug the abandoned lower wellbore and to support the production casing where drilling wear was predicted and where sidetracking was to occur. This work and the redrill of EE-2A were completed in November 1987. Specifications were prepared for a state-of-the-art tie-back casing, which was procured, manufactured, and delivered to Fenton Hill in May 1988. The well was then completed in June 1988 for hot-water production service by cementing in a liner and the upper section of production casing and installing and cementing a tie-back casing string. 24 refs., 17 figs., 5 tabs.

  4. Anisotropy studies around the Galactic Centre at EeV energies with the Auger Observatory

    SciTech Connect

    Aglietta, M.; Aguirre, C.; Allard, D.; Allekotte, I.; Allison, P.; Alvarez, C.; Alvarez-Muniz, J.; Ambrosio, M.; Anchordoqui, L.; Anjos, J.C.; Aramo, C.; /Centro Atomico Bariloche /Buenos Aires, IAFE /Buenos Aires, CONICET /Pierre Auger Observ. /La Plata U. /Natl. Tech. U., San Rafael /Adelaide U. /Catholic U. of Bolivia, La Paz /Bolivia U. /Rio de Janeiro, CBPF /Sao Paulo U.

    2006-07-01

    Data from the Pierre Auger Observatory are analyzed to search for anisotropies near the direction of the Galactic Centre at EeV energies. The exposure of the surface array in this part of the sky is already significantly larger than that of the fore-runner experiments. Our results do not support previous findings of localized excesses in the AGASA and SUGAR data. We set an upper bound on a point-like flux of cosmic rays arriving from the Galactic Centre which excludes several scenarios predicting sources of EeV neutrons from Sagittarius A. Also the events detected simultaneously by the surface and fluorescence detectors (the ''hybrid'' data set), which have better pointing accuracy but are less numerous than those of the surface array alone, do not show any significant localized excess from this direction.

  5. Study of baryon production mechanism in e+e- annihilation into hadrons

    NASA Astrophysics Data System (ADS)

    Topaz Collaboration; Aoki, M.; Itoh, R.; Watanabe, Y.; Kaneyuki, K.; Ohshima, Y.; Ochi, A.; Tanimori, T.; Abe, K.; Abe, T.; Adachi, I.; Adachi, K.; Aoki, M.; Emi, K.; Enomoto, R.; Fujii, H.; Fujii, T.; Fujii, K.; Fujimoto, J.; Fujiwara, N.; Hayashii, H.; Hirano, H.; Howell, B.; Ikeda, H.; Inoue, Y.; Itami, S.; Iwasaki, H.; Iwasaki, M.; Kajikawa, R.; Kato, S.; Kawabata, S.; Kichimi, H.; Kobayashi, M.; Koltick, D.; Levine, I.; Mamada, H.; Miyabayashi, K.; Miyamoto, A.; Nagai, K.; Nakabayashi, K.; Nakamura, M.; Nakano, E.; Nitoh, O.; Noguchi, S.; Ochiai, F.; Ohishi, N.; Ohnishi, Y.; Okuno, H.; Okusawa, T.; Shibata, E.; Sugiyama, A.; Suzuki, S.; Takahashi, K.; Takahashi, T.; Teramoto, Y.; Tauchi, T.; Tomoto, M.; Tsukamoto, T.; Tsumura, T.; Uno, S.; Yamamoto, A.; Yamauchi, M.

    1998-11-01

    The mechanism of baryon-anti-baryon pair production in e+e- annihilation into hadrons has been studied using the TOPAZ detector at the TRISTAN e+e- collider at an average center-of-mass energy of 58 GeV. The distributions of various p¯p correlations were compared with two prominent models: the cluster-fragmentation model and the string-fragmentation model. We rejected the cluster-fragmentation model at the 90% C.L. Furthermore, in the context of the string-fragmentation model, we favor the ``popcorn'' model, rejecting the ``diquark'' model, where a diquark is considered to be a fundamental entity, at the 95% C.L.

  6. Anisotropy studies around the galactic centre at EeV energies with the Auger Observatory

    NASA Astrophysics Data System (ADS)

    Abraham, J.; Aglietta, M.; Aguirre, C.; Allard, D.; Allekotte, I.; Allison, P.; Alvarez, C.; Alvarez-Muñiz, J.; Ambrosio, M.; Anchordoqui, L.; Anjos, J. C.; Aramo, C.; Arisaka, K.; Armengaud, E.; Arneodo, F.; Arqueros, F.; Asch, T.; Asorey, H.; Atulugama, B. S.; Aublin, J.; Ave, M.; Avila, G.; Bacelar, J.; Bäcker, T.; Badagnani, D.; Barbosa, A. F.; Barbosa, H. M. J.; Barkhausen, M.; Barnhill, D.; Barroso, S. L. C.; Bauleo, P.; Beatty, J.; Beau, T.; Becker, B. R.; Becker, K. H.; Bellido, J. A.; Benzvi, S.; Berat, C.; Bergmann, T.; Bernardini, P.; Bertou, X.; Biermann, P. L.; Billoir, P.; Blanch-Bigas, O.; Blanco, F.; Blasi, P.; Bleve, C.; Blümer, H.; Boghrat, P.; Boháčová, M.; Bonifazi, C.; Bonino, R.; Boratav, M.; Brack, J.; Brunet, J. M.; Buchholz, P.; Busca, N. G.; Caballero-Mora, K. S.; Cai, B.; Camin, D. V.; Capdevielle, J. N.; Caruso, R.; Castellina, A.; Cataldi, G.; Cazón, L.; Cester, R.; Chauvin, J.; Chiavassa, A.; Chinellato, J. A.; Chou, A.; Chye, J.; Claes, D.; Clark, P. D. J.; Clay, R. W.; Clay, S. B.; Connolly, B.; Cordier, A.; Cotti, U.; Coutu, S.; Covault, C. E.; Cronin, J.; Dagoret-Campagne, S.; Quang, T. Dang; Darriulat, P.; Daumiller, K.; Dawson, B. R.; de Almeida, R. M.; de Carvalho, L. A.; de Donato, C.; de Jong, S. J.; de Mello, W. J. M.; de Mello Neto, J. R. T.; de Mitri, I.; de Oliveira, M. A. L.; de Souza, V.; Del Peral, L.; Deligny, O.; Della Selva, A.; Delle Fratte, C.; Dembinski, H.; di Giulio, C.; Diaz, J. C.; Dobrigkeit, C.; D'Olivo, J. C.; Dornic, D.; Dorofeev, A.; Dova, M. T.; D'Urso, D.; Duvernois, M. A.; Engel, R.; Epele, L.; Erdmann, M.; Escobar, C. O.; Etchegoyen, A.; Ewers, A.; Facal San Luis, P.; Falcke, H.; Fauth, A. C.; Fazio, D.; Fazzini, N.; Fernández, A.; Ferrer, F.; Ferry, S.; Fick, B.; Filevich, A.; Filipčič, A.; Fleck, I.; Fokitis, E.; Fonte, R.; Fuhrmann, D.; Fulgione, W.; García, B.; Garcia-Pinto, D.; Garrard, L.; Garrido, X.; Geenen, H.; Gelmini, G.; Gemmeke, H.; Geranios, A.; Ghia, P. L.; Giller, M.; Gitto, J.; Glass, H.; Gobbi, F.; Gold, M. S.; Gomez Albarracin, F.; Gómez Berisso, M.; Gómez Herrero, R.; Gonçalves Do Amaral, M.; Gongora, J. P.; Gonzalez, D.; Gonzalez, J. G.; González, M.; Góra, D.; Gorgi, A.; Gouffon, P.; Grassi, V.; Grillo, A.; Grunfeld, C.; Grupen, C.; Guarino, F.; Guedes, G. P.; Gutiérrez, J.; Hague, J. D.; Hamilton, J. C.; Harakeh, M. N.; Harari, D.; Harmsma, S.; Hartmann, S.; Harton, J. L.; Haungs, A.; Healy, M. D.; Hebbeker, T.; Heck, D.; Hojvat, C.; Homola, P.; Hörandel, J.; Horneffer, A.; Horvat, M.; Hrabovský, M.; Huege, T.; Iarlori, M.; Insolia, A.; Kaducak, M.; Kalashev, O.; Kampert, K. H.; Keilhauer, B.; Kemp, E.; Klages, H. O.; Kleifges, M.; Kleinfeller, J.; Knapik, R.; Knapp, J.; Koang, D.-H.; Kolotaev, Y.; Kopmann, A.; Krömer, O.; Kuhlman, S.; Kuijpers, J.; Kunka, N.; Kusenko, A.; Lachaud, C.; Lago, B. L.; Lebrun, D.; Lebrun, P.; Lee, J.; Letessier-Selvon, A.; Leuthold, M.; Lhenry-Yvon, I.; Longo, G.; López, R.; Lopez Agüera, A.; Lucero, A.; Maldera, S.; Malek, M.; Maltezos, S.; Mancarella, G.; Manceñido, M. E.; Mandat, D.; Mantsch, P.; Mariazzi, A. G.; Maris, I. C.; Martello, D.; Martinez, N.; Martínez, J.; Martínez, O.; Mathes, H. J.; Matthews, J.; Matthews, J. A. J.; Matthiae, G.; Maurin, G.; Maurizio, D.; Mazur, P. O.; McCauley, T.; McEwen, M.; McNeil, R. R.; Medina, G.; Medina, M. C.; Medina Tanco, G.; Meli, A.; Melo, D.; Menichetti, E.; Menshikov, A.; Meurer, Chr.; Meyhandan, R.; Micheletti, M. I.; Miele, G.; Miller, W.; Mollerach, S.; Monasor, M.; Monnier Ragaigne, D.; Montanet, F.; Morales, B.; Morello, C.; Moreno, E.; Morris, C.; Mostafá, M.; Muller, M. A.; Mussa, R.; Navarra, G.; Nellen, L.; Newman-Holmes, C.; Newton, D.; Thi, T. Nguyen; Nichol, R.; Nierstenhöfer, N.; Nitz, D.; Nogima, H.; Nosek, D.; Nožka, L.; Oehlschläger, J.; Ohnuki, T.; Olinto, A.; Oliveira, L. F. A.; Olmos-Gilbaja, V. M.; Ortiz, M.; Ostapchenko, S.; Otero, L.; Palatka, M.; Pallotta, J.; Parente, G.; Parizot, E.; Parlati, S.; Patel, M.; Paul, T.; Payet, K.; Pech, M.; PeĶala, J.; Pelayo, R.; Pepe, I. M.; Perrone, L.; Petrera, S.; Petrinca, P.; Petrov, Y.; Pham Ngoc, D.; Pham Thi, T. N.; Piegaia, R.; Pierog, T.; Pisanti, O.; Porter, T. A.; Pouryamout, J.; Prado, L.; Privitera, P.; Prouza, M.; Quel, E. J.; Rautenberg, J.; Reis, H. C.; Reucroft, S.; Revenu, B.; Řídký, J.; Risi, A.; Risse, M.; Rivière, C.; Rizi, V.; Robbins, S.; Roberts, M.; Robledo, C.; Rodriguez, G.; Rodríguez Frías, D.; Rodriguez Martino, J.; Rodriguez Rojo, J.; Ros, G.; Rosado, J.; Roth, M.; Roucelle, C.; Rouillé-D'Orfeuil, B.; Roulet, E.; Rovero, A. C.; Salamida, F.; Salazar, H.; Salina, G.; Sánchez, F.; Santander, M.; Santos, E. M.; Sarkar, S.; Sato, R.; Scherini, V.; Schieler, H.; Schmidt, T.; Scholten, O.; Schovánek, P.; Schüssler, F.; Sciutto, S. J.; Scuderi, M.; Semikoz, D.; Sequeiros, G.; Shellard, R. C.; Siffert, B. B.; Sigl, G.; Skelton, P.; Slater, W.; de Grande, N. Smetniansky; Smiałkowski, A.; Šmída, R.; Smith, B. E.; Snow, G. R.; Sokolsky, P.; Sommers, P.; Sorokin, J.; Spinka, H.; Strazzeri, E.; Stutz, A.; Suarez, F.; Suomijärvi, T.; Supanitsky, A. D.; Swain, J.; Szadkowski, Z.; Tamashiro, A.; Tamburro, A.; Tascau, O.; Ticona, R.; Timmermans, C.; Tkaczyk, W.; Todero Peixoto, C. J.; Tonachini, A.; Torresi, D.; Travnicek, P.; Tripathi, A.; Tristram, G.; Tscherniakhovski, D.; Tueros, M.; Tunnicliffe, V.; Ulrich, R.; Unger, M.; Urban, M.; Valdés Galicia, J. F.; Valiño, I.; Valore, L.; van den Berg, A. M.; van Elewyck, V.; Vazquez, R. A.; Veberič, D.; Veiga, A.; Velarde, A.; Venters, T.; Verzi, V.; Videla, M.; Villaseñor, L.; Vo van, T.; Vorobiov, S.; Voyvodic, L.; Wahlberg, H.; Wainberg, O.; Waldenmaier, T.; Walker, P.; Warner, D.; Watson, A. A.; Westerhoff, S.; Wiebusch, C.; Wieczorek, G.; Wiencke, L.; Wilczyńska, B.; Wilczyński, H.; Wileman, C.; Winnick, M. G.; Xu, J.; Yamamoto, T.; Younk, P.; Zas, E.; Zavrtanik, D.; Zavrtanik, M.; Zech, A.; Zepeda, A.; Zha, M.; Ziolkowski, M.; Pierre Auger Collaboration

    2007-04-01

    Data from the Pierre Auger Observatory are analyzed to search for anisotropies near the direction of the Galactic Centre at EeV energies. The exposure of the surface array in this part of the sky is already significantly larger than that of the fore-runner experiments. Our results do not support previous findings of localized excesses in the AGASA and SUGAR data. We set an upper bound on a point-like flux of cosmic rays arriving from the Galactic Centre which excludes several scenarios predicting sources of EeV neutrons from Sagittarius A. Also the events detected simultaneously by the surface and fluorescence detectors (the ‘hybrid’ data set), which have better pointing accuracy but are less numerous than those of the surface array alone, do not show any significant localized excess from this direction.

  7. Identification of ginsenoside interaction sites in 5-HT3A receptors.

    PubMed

    Lee, Byung-Hwan; Lee, Jun-Ho; Lee, Sang-Mok; Jeong, Sang Min; Yoon, In-Soo; Lee, Joon-Hee; Choi, Sun-Hye; Pyo, Mi Kyung; Rhim, Hyewhon; Kim, Hyoung-Chun; Jang, Choon-Gon; Lee, Byoung-Cheol; Park, Chul-Seung; Nah, Seung-Yeol

    2007-03-01

    We previously demonstrated that 20(S)-ginsenoside Rg(3) (Rg(3)), one of the active components of Panax ginseng, non-competitively inhibits 5-HT(3A) receptor channel activity on extracellular side of the cell. Here, we sought to elucidate the molecular mechanisms underlying Rg(3)-induced 5-HT(3A) receptor regulation. We used the two-microelectrode voltage-clamp technique to investigate the effect of Rg(3) on 5-HT-mediated ion currents (I(5-HT)) in Xenopus oocytes expressing wild-type or 5-HT(3A) receptors harboring mutations in the gating pore region of transmembrane domain 2 (TM2). In oocytes expressing wild-type 5-HT(3A) receptors, Rg(3) dose-dependently inhibited peak I(5-HT) with an IC(50) of 27.6+/-4.3microM. Mutations V291A, F292A, and I295A in TM2 greatly attenuated or abolished the Rg(3)-induced inhibition of peak I(5-HT). Mutation V291A but not F292A and I295A induced constitutively active ion currents with decrease of current decay rate. Rg(3) accelerated the rate of current decay with dose-dependent manner in the presence of 5-HT. Rg(3) and TMB-8, an open channel blocker, dose-dependently inhibited constitutively active ion currents. The IC(50) values of constitutively active ion currents in V291A mutant receptor were 72.4+/-23.1 and 6.5+/-0.7microM for Rg(3) and TMB-8, respectively. Diltiazem did not prevent Rg(3)-induced inhibition of constitutively active ion currents in occlusion experiments. These results indicate that Rg(3) inhibits 5-HT(3A) receptor channel activity through interactions with residues V291, F292, and I295 in the channel gating region of TM2 and further demonstrate that Rg(3) regulates 5-HT(3A) receptor channel activity in the open state at different site(s) from those of TMB-8 and diltiazem. PMID:17257631

  8. Increase in VEGF secretion from human fibroblast cells by bioactive glass S53P4 to stimulate angiogenesis in bone.

    PubMed

    Detsch, Rainer; Stoor, Patricia; Grünewald, Alina; Roether, Judith A; Lindfors, Nina C; Boccaccini, Aldo R

    2014-11-01

    Bioactive glasses (BAGs) are being investigated for the repair and reconstruction of bone defects, as they exhibit osteoconductive and osteostimulatory potential. However, successful bone regeneration requires also the neovascularization of the construct which is, among other factors, guided by vascular endothelial growth factor (VEGF). In this study, BAG S53P4 (53% SiO2 , 23% Na2 O, 20% CaO, 4% P2 O5 ) is investigated in relation to VEGF-release and response of fibroblast cells. Human CD-18CO fibroblasts were cultivated in contact with different granules of different sizes (0.5-0.8 mm, 1.0-2.0 mm, and 2.0-3.15 mm) and at different concentrations (0-1 wt/vol % of BAG) for 72 h. The analysis of morphology revealed no toxic effect for all granule sizes and concentrations. Compared with the reference, lactate dehydrogenase-activity of CCD-18CO cells increased in contact with BAG samples. The VEGF release from CCD-18CO fibroblasts cultured on different granule sizes and at different concentrations after 72 h of incubation was quantified. It was found that particles of 0.5-0.8 mm and 1.0-2.0 mm in size enhanced VEGF release, whereas BAG particle sizes of 2.0-3.15 mm led to inhibition of VEGF release. The results are relevant to understand the influence of the particle size and concentration of BAG S53P4 on VEGF expression and neovascularization. PMID:24357515

  9. Memory formation, amnesia, improved memory and reversed amnesia: 5-HT role.

    PubMed

    Perez-Garcia, G; Meneses, A

    2008-12-16

    Traditionally, the search for memory circuits has been focused on examinations of amnesic and AD patients, cerebral lesions and neuroimaging. A complementary alternative has become the use of autoradiography with radioligands, aiming to identify neurobiological markers associated with memory formation, amnesia states and (more recently) recovery from memory deficits. Indeed, ex vivo autoradiographic studies offer the advantage of detecting functionally active receptors altered by pharmacological tools during memory formation, amnesia states and memory recovery. Moreover, serotonin (5-hydroxytryptamine, 5-HT) systems have become a pharmacological and genetic target in the treatment of memory disorders. Herein evidence from studies involving expression of 5-HT(1A), 5-HT(2A), 5-HT(4), and 5-HT(6) receptors in memory formation, amnesia conditions (e.g., pharmacological models or aging) and recovery of memory is reviewed. Thus, specific 5-HT receptors were expressed in trained animals relative to untrained in brain areas such as cortex, hippocampus and amygdala. However, relative to the control group, rats showing amnesia or recovered memory, showed in the hippocampus, region where explicit memory is formed, a complex pattern of 5-HT receptor expression. An intermediate expression occurred in amygdala, septum and some cortical areas in charge of explicit memory storage. Even in brain areas thought to be in charge of procedural memory such as basal ganglia, animals showing recovered memory displayed an intermediate expression, while amnesic groups, depending on the pharmacological amnesia model, showed up- or down-regulation. In conclusion, evidence indicates that autoradiography, by using specific radioligands, offers excellent opportunities to map dynamic changes in brain areas engaged in these cognitive processes. The 5-HT modulatory role strengthens or suppresses memory is critically depend on the timing of the memory formation. PMID:18221797

  10. The function of 5-HT3 receptors on colonic transit in rats.

    PubMed

    Haga, K; Asano, K; Fukuda, T; Kobayakawa, T

    1995-12-01

    The function of serotonin (5-HT)3 receptors on colonic transit was investigated in unanesthetized rats. The colonic transit was accelerated by 5-HT (10 mg/kg, s.c.), 2-methyl-5-HT (30 mg/kg, s.c.), neostigmine (0.03-0.1 mg/kg, s.c.), corticotropin releasing factor (CRF; 1 microgram intracerebroventricular administration) and restraint stress (for 45 minutes). A potent and selective 5-HT3 receptor antagonist, azasetron (+/-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro- 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide monohydrochloride ; 0.01-10 mg/kg, p.o. inhibited the 5-HT-, CRF- and stress-accelerated colonic transit in a dose-dependent manner. Ondansetron (10 mg/kg, p.o.) and granisetron (1 mg/kg, p.o) also inhibited the stress-accelerated colonic transit, but azasetron was more effective than these two drugs. Atropine methylbromide (0.1 mg/kg, s.c.) and tetrodotoxin (0.01 mg/kg, s.c.) inhibited the accelerated colonic transit under stress conditions, but methysergide (10 mg/kg, s.c.), SDZ205-557 (10 mg/kg, s.c.), domperidone (30 mg/kg, p.o.), trimebutine (300 mg/kg, p.o.), did not. Azasetron (10 micrograms) administered intracerebroventricularly did not inhibit the stress-induced acceleration. These results suggest that endogenous 5-HT which is released through stress accelerates the colonic transit via the 5-HT3 receptors and finally a cholinergic mechanism. It is considered that azasetron inhibits colonic transit particularly under stress conditions through the blockade of the peripheral 5-HT3 receptors. Azasetron may improve bowel function in stress-related colonic dysfunction like irritable bowel syndrome. PMID:8653566

  11. 5-HT6 Receptor Antagonists: Potential Efficacy for the Treatment of Cognitive Impairment in Schizophrenia.

    PubMed

    de Bruin, Natasja M W J; Kruse, Chris G

    2015-01-01

    5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer's disease. PMID:26044973

  12. 5-HT3 receptors as important mediators of nausea and vomiting due to chemotherapy.

    PubMed

    Navari, Rudolph M

    2015-10-01

    Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, dexamethasone, and a neurokinin-1 (NK-1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. The first generation 5-HT3 receptor antagonists have been very effective in the control of chemotherapy induced emesis in the first 24 h postchemotherapy (acute emesis), but have not been as effective against delayed emesis (24-120 h postchemotherapy). Palonosetron, a second generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity, and a different mechanism of action than the first generation 5-HT3 receptor antagonists appears to be the most effective agent in its class. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a FDA approved antipsychotic that blocks multiple neurotransmitters: dopamine at D1, D2, D3, D4 brain receptors, serotonin at 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors, has emerged in recent trials as an effective preventative agent for chemotherapy-induced emesis and nausea, as well as a very effective agent for the treatment of breakthrough emesis and nausea. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID:25838122

  13. Anxiolytic effects of prelimbic 5-HT(1A) receptor activation in the hemiparkinsonian rat.

    PubMed

    Hui, Yan Ping; Wang, Tao; Han, Ling Na; Li, Li Bo; Sun, Yi Na; Liu, Jian; Qiao, Hong Fei; Zhang, Qiao Jun

    2015-01-15

    This study sought to assess whether unilateral lesions of the medial forebrain bundle (MFB) using 6-hydroxydopamine in rats are able to induce anxiety-like behaviors, the role of serotonin-1A (5-HT1A) receptors of the prelimbic (PrL) sub-region of ventral medial prefrontal cortex in the regulation of these behaviors, the density of 5-HT neurons in the dorsal raphe nucleus (DRN) and co-localization of 5-HT1A receptor and neuronal glutamate transporter EAAC1-immunoreactive (EAAC1-ir) cells in the PrL. Unilaterally lesioning the MFB induced anxiety-like behaviors as measured by the open-field and elevated plus maze tests when compared to sham-operated rats. Intra-PrL injection of 5-HT1A receptor agonist 8-OH-DPAT (50, 100, and 500 ng/rat) decreased the percentage of time spent in the center of the open-field and percentages of open arm entries and open arm time in sham-operated rats, indicating the induction of anxiogenic responses, and administration of 5-HT1A receptor antagonist WAY-100635 (60, 120, and 240 ng/rat) showed anxiolytic effects. However, 8-OH-DPAT, at the same doses, increased the percentage of time spent in the center of the open-field and percentages of open arm entries and open arm time in the lesioned rats, indicating the induction of anxiolytic effects, and WAY-100635 produced anxiogenic responses. Unilateral MFB lesion decreased the density of 5-HT neurons in the DRN, and percentage of EAAC1-ir cells expressing 5-HT1A receptors in the PrL. These results suggest that unilateral lesions of the MFB in rats may induce anxiety-like behaviors, and activation of 5-HT1A receptors in the PrL has anxiolytic effects in the rat model of Parkinson's disease. PMID:24906197

  14. The 5-HT and alpha-adrenoceptor antagonist effect of four benzylisoquinoline alkaloids on rat aorta.

    PubMed

    Catret, M; Ivorra, M D; D'Ocón, M P; Anselmi, E

    1998-03-01

    The action of four benzylisoquinoline alkaloids (two aporphines-glaucine and apomorphine, a benzylisoquinoline-papaverine and a bisbenzyltetrahydroisoquinoline-antioquine) on 5-HT-induced contraction in rat thoracic aorta has been examined and compared with that of the control drugs: ketanserin, nifedipine, prazosin and phentolamine. The relaxant action on 5-HT-induced contraction was contrasted with that on the contraction induced by noradrenaline and KCl. The results obtained with control drugs show that ketanserin has clear selectivity for 5-HT receptors, whereas prazosin and phentolamine have high selectivity for the alpha1-adrenoceptor and nifedipine seems to have a more potent effect on KCl-induced contraction than on that induced by 5-HT or noradrenaline. The contraction evoked by 5-HT (10 microM) was inhibited in a concentration-dependent manner by all the alkaloids. The order of potency was: papaverine = glaucine > apomorphine > antioquine. Papaverine had a non-specific relaxant action on 5-HT-, noradrenaline- and KCl-induced contraction, antioquine had a weak relaxant action on the agonist assays, and glaucine and apomorphine inhibited noradrenaline- and 5-HT-induced contraction more potently than they inhibited the K+-depolarized response. These results indicate that the aporphines assayed, S-glaucine and R-aporphine, had selective action against agonist (noradrenaline or 5-HT)-induced contraction rather than against KCl-depolarization of rat aorta. In contrast papaverine, a benzylisoquinoline alkaloid, relaxes all agents used non-selectively as could be expected from the lack of specificity that characterizes this alkaloid. PMID:9600725

  15. High yield and efficient expression and purification of the human 5-HT3A receptor

    PubMed Central

    Wu, Zhong-shan; Cui, Zhi-cheng; Cheng, Hao; Fan, Chen; Melcher, Karsten; Jiang, Yi; Zhang, Cheng-hai; Jiang, Hua-liang; Cong, Yao; Liu, Qian; Xu, H Eric

    2015-01-01

    Aim: To establish a method for efficient expression and purification of the human serotonin type 3A receptor (5-HT3A) that is suitable for structural studies. Methods: Codon-optimized cDNA of human 5-HT3A was inserted into a modified BacMam vector, which contained an IgG leader sequence, an 8×His tag linked with two-Maltose Binding Proteins (MBP), and a TEV protease cleavage site. The BacMam construct was used to generate baculoviruses for expression of 5-HT3A in HEK293F cells. The proteins were solubilized from the membrane with the detergent C12E 9, and purified using MBP affinity chromatography. The affinity tag was removed by TEV protease treatment and immobilized metal ion affinity chromatography. The receptors were further purified by size-exclusion chromatography (SEC). Western blot and SDS-PAGE were used to detect 5-HT3A during purification. The purified receptor was used in crystallization and analyzed with negative stain electron microscopy (EM). Results: The BacMam system yielded 0.5 milligram of the human 5-HT3A receptor per liter of cells. MBP affinity purification resulted in good yields with high purity and homogeneity. SEC profiles indicated that the purified receptors were pentameric. No protein crystals were obtained; however, a reconstructed 3D density map generated from the negative stain EM data fitted well with the mouse 5-HT3A structure. Conclusion: With the BacMam system, robust expression of the human 5-HT3A receptor is obtained, which is monodisperse, therefore enabling 3D reconstruction of an EM map. This method is suitable for high-throughput screening of different constructs, thus facilitating structural and biochemical studies of the 5-HT3A receptor. PMID:26073329

  16. PET imaging of the serotonin transporter and 5HT1A receptor in alcohol dependence

    PubMed Central

    Martinez, Diana; Slifstein, Mark; Gil, Roberto; Hwang, Dah-Ren; Huang, Yiyun; Perez, Audrey; Frankle, W. Gordon; Laruelle, Marc; Krystal, John; Abi-Dargham, Anissa

    2009-01-01

    Background Rodent models as well as studies in humans have suggested alterations in serotonin (5HT) innervation and transmission in early onset genetically determined or type II alcoholism. This study examines two indices of serotonergic transmission, 5HT transporter levels and 5-HT1A availability, in vivo, in type II alcoholism. This is the first report of combined tracers for pre and post-synaptic serotonergic transmission in the same alcoholic subjects and the first study of 5HT1A receptors in alcoholism. Method Fourteen alcohol dependent subjects were scanned (11 with both tracers, 1 with [11C]DASB only and two with [11C]WAY100635 only). Twelve healthy controls (HC) subjects were scanned with [11C]DASB and another 13 were scanned with [11C]WAY100635. Binding Potential (BPp, mL/cm3) and the specific to nonspecific partition coefficient (BPND, unitless) were derived for both tracers using 2 tissue compartment model and compared to HC across different brain regions. Relationships to severity of alcoholism were assessed. Results No significant differences were observed in regional BPp or BPND between patients and controls in any of the regions examined. No significant relationships were observed between regional 5HT transporter availability, 5-HT1A availability, and disease severity with the exception of a significant negative correlation between SERT and years of dependence in amygdala and insula. Conclusion This study did not find alterations in measures of 5-HT1A or 5HT transporter levels in patients with type II alcoholism. PMID:18962444

  17. Function and Distribution of 5-HT2 Receptors in the Honeybee (Apis mellifera)

    PubMed Central

    Thamm, Markus; Rolke, Daniel; Jordan, Nadine; Balfanz, Sabine; Schiffer, Christian; Baumann, Arnd; Blenau, Wolfgang

    2013-01-01

    Background Serotonin plays a pivotal role in regulating and modulating physiological and behavioral processes in both vertebrates and invertebrates. In the honeybee (Apis mellifera), serotonin has been implicated in division of labor, visual processing, and learning processes. Here, we present the cloning, heterologous expression, and detailed functional and pharmacological characterization of two honeybee 5-HT2 receptors. Methods Honeybee 5-HT2 receptor cDNAs were amplified from brain cDNA. Recombinant cell lines were established constitutively expressing receptor variants. Pharmacological properties of the receptors were investigated by Ca2+ imaging experiments. Quantitative PCR was applied to explore the expression patterns of receptor mRNAs. Results The honeybee 5-HT2 receptor class consists of two subtypes, Am5-HT2α and Am5-HT2β. Each receptor gene also gives rise to alternatively spliced mRNAs that possibly code for truncated receptors. Only activation of the full-length receptors with serotonin caused an increase in the intracellular Ca2+ concentration. The effect was mimicked by the agonists 5-methoxytryptamine and 8-OH-DPAT at low micromolar concentrations. Receptor activities were blocked by established 5-HT receptor antagonists such as clozapine, methiothepin, or mianserin. High transcript numbers were detected in exocrine glands suggesting that 5-HT2 receptors participate in secretory processes in the honeybee. Conclusions This study marks the first molecular and pharmacological characterization of two 5-HT2 receptor subtypes in the same insect species. The results presented should facilitate further attempts to unravel central and peripheral effects of serotonin mediated by these receptors. PMID:24324783

  18. Selective 5-HT2C receptor agonists: Design and synthesis of pyridazine-fused azepines.

    PubMed

    Green, Martin P; McMurray, Gordon; Storer, R Ian

    2016-08-15

    Heterocycle-fused azepines are discussed as potent 5-HT2C receptor agonists with excellent selectivity over 5-HT2B agonism. Synthesis and structure activity relationships are outlined for a series of bicyclic pyridazino[3,4-d]azepines. By comparison with earlier published work, in vitro assays predict a high probability for achieving CNS penetration for a potent and selective compound 15a, a pre-requisite to achieve in vivo efficacy. PMID:27381086

  19. Impaired Social Behavior in 5-HT3A Receptor Knockout Mice

    PubMed Central

    Smit-Rigter, Laura A.; Wadman, Wytse J.; van Hooft, Johannes A.

    2010-01-01

    The 5-HT3 receptor is a ligand-gated ion channel expressed on interneurons throughout the brain. So far, analysis of the 5-HT3A knockout mouse revealed changes in nociceptive processing and a reduction in anxiety related behavior. Recently, it was shown that the 5-HT3 receptor is also expressed on Cajal-Retzius cells which play a key role in cortical development and that knockout mice lacking this receptor showed aberrant growth of the dendritic tree of cortical layer II/III pyramidal neurons. Other mouse models in which serotonergic signaling was disrupted during development showed similar morphological changes in the cortex, and in addition, also deficits in social behavior. Here, we subjected male and female 5-HT3A knockout mice and their non-transgenic littermates to several tests of social behavior. We found that 5-HT3A knockout mice display impaired social communication in the social transmission of food preference task. Interestingly, we showed that in the social interaction test only female 5-HT3A knockout mice spent less time in reciprocal social interaction starting after 5 min of testing. Moreover, we observed differences in preference for social novelty for male and female 5-HT3A knockout mice during the social approach test. However, no changes in olfaction, exploratory activity and anxiety were detected. These results indicate that the 5-HT3A knockout mouse displays impaired social behavior with specific changes in males and females, reminiscent to other mouse models in which serotonergic signaling is disturbed in the developing brain. PMID:21103015

  20. The Havemann-Taylor Fast Radiative Transfer Code (HT-FRTC) and its applications

    NASA Astrophysics Data System (ADS)

    Thelen, Jean-Claude; Havemann, Stephan; Lewis, Warren

    2015-09-01

    The Havemann-Taylor Fast Radiative Transfer Code (HT-FRTC) is a component of the Met Office NEON Tactical Decision Aid (TDA). Within NEON, the HT-FRTC has for a number of years been used to predict the IR apparent thermal contrasts between different surface types as observed by an airborne sensor. To achieve this, the HT-FRTC is supplied with the inherent temperatures and spectral properties of these surfaces (i.e. ground target(s) and background). A key strength of the HT-FRTC is its ability to take into account the detailed properties of the atmosphere, which in the context of NEON tend to be provided by a Numerical Weather Prediction (NWP) forecast model. While water vapour and ozone are generally the most important gases, additional trace gases are now being incorporated into the HT-FRTC. The HT-FRTC also includes an exact treatment of atmospheric scattering based on spherical harmonics. This allows the treatment of several different aerosol species and of liquid and ice clouds. Recent developments can even account for rain and falling snow. The HT-FRTC works in Principal Component (PC) space and is trained on a wide variety of atmospheric and surface conditions, which significantly reduces the computational requirements regarding memory and time. One clear-sky simulation takes approximately one millisecond. Recent developments allow the training to be completely general and sensor independent. This is significant as the user of the code can add new sensors and new surfaces/targets by simply supplying extra files which contain their (possibly classified) spectral properties. The HT-FRTC has been extended to cover the spectral range of Photopic and NVG sensors. One aim here is to give guidance on the expected, directionally resolved sky brightness, especially at night, again taking the actual or forecast atmospheric conditions into account. Recent developments include light level predictions during the period of twilight.

  1. Uncertainty of the beam energy measurement in the e+e- collision using Compton backscattering

    NASA Astrophysics Data System (ADS)

    Mo, Xiao-Hu

    2014-10-01

    The beam energy is measured in the e+e- collision by using Compton backscattering. The uncertainty of this measurement process is studied by virtue of analytical formulas, and the special effects of variant energy spread and energy drift on the systematic uncertainty estimation are also studied with the Monte Carlo sampling technique. These quantitative conclusions are especially important for understanding the uncertainty of the beam energy measurement system.

  2. Extracting the kaon Collins function from e+e- hadron pair production data

    NASA Astrophysics Data System (ADS)

    Anselmino, M.; Boglione, M.; D'Alesio, U.; Hernandez, J. O. Gonzalez; Melis, S.; Murgia, F.; Prokudin, A.

    2016-02-01

    The latest data released by the BABAR Collaboration on azimuthal correlations measured for pion-kaon and kaon-kaon pairs produced in e+e- annihilations allow, for the first time, a direct extraction of the kaon Collins functions. These functions are then used to compute the kaon Collins asymmetries in semi-inclusive deep inelastic scattering processes, which result in good agreement with the measurements performed by the HERMES and COMPASS collaborations.

  3. Experiment 2074: post-drilling reservoir flow testing through EE-3A first revision

    SciTech Connect

    Brown, Donald W.; Robinson, Bruce A.

    1987-11-20

    As previously outlined in memorandum ESS-4-87-305 (11/12/87), EE-3A will be pressurized with the Kobe pumps for the next week, and then a sequence of reservoir flow tests and logs will be conducted for a one to two week period beginning Tuesday, 12/1/87. The purpose of this memorandum is to better define this flow test and sequence of logs, organized as a "formal" experiment.

  4. Measurements of the Collins asymmetries for kaons and pions in e+e- annihilations at BABAR

    NASA Astrophysics Data System (ADS)

    Filippi, A.

    2016-07-01

    New measurements of the Collins asymmetries were performed by BABAR exploiting inclusive e+e- → h1h2 X annihilations (with h1,2 = π and/or K) mainly at the energy of the ϒ(4S), which corresponds to a squared transferred momentum Q2 ~ 110 GeV2c4. For the first time asymmetries following strange quarks fragmentation could be derived as a function of the fractional energy carried out by inclusively emitted hadron pairs.

  5. Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research.

    PubMed

    Celada, Pau; Bortolozzi, Analía; Artigas, Francesc

    2013-09-01

    Psychiatric disorders represent a large economic burden in modern societies. However, pharmacological treatments are still far from optimal. Drugs used in the treatment of major depressive disorder (MDD) and anxiety disorders (selective serotonin [5-HT] reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors [SNRIs]) are pharmacological refinements of first-generation tricyclic drugs, discovered by serendipity, and show low efficacy and slowness of onset. Moreover, antipsychotic drugs are partly effective in positive symptoms of schizophrenia, yet they poorly treat negative symptoms and cognitive deficits. The present article reviews the neurobiological basis of 5-HT1A receptor (5-HT1A-R) function and the role of pre- and postsynaptic 5-HT1A-Rs in the treatment of MDD, anxiety and psychotic disorders. The activation of postsynaptic 5-HT1A-Rs in corticolimbic areas appears beneficial for the therapeutic action of antidepressant drugs. However, presynaptic 5-HT1A-Rs play a detrimental role in MDD, since individuals with high density or function of presynaptic 5-HT1A-Rs are more susceptible to mood disorders and suicide, and respond poorly to antidepressant drugs. Moreover, the indirect activation of presynaptic 5-HT1A-Rs by SSRIs/SNRIs reduces 5-HT neuron activity and terminal 5-HT release, thus opposing the elevation of extracellular 5-HT produced by blockade of the serotonin transporter (SERT) in the forebrain. Chronic antidepressant treatment desensitizes presynaptic 5-HT1A-Rs, thus reducing the effectiveness of the 5-HT1A autoreceptor-mediated negative feedback. The prevention of this process by the non-selective partial agonist pindolol accelerates clinical antidepressant effects. Two new antidepressant drugs, vilazodone (marketed in the USA) and vortioxetine (in development) incorporate partial 5-HT1A-R agonist properties with SERT blockade. Several studies with transgenic mice have also established the respective role of pre- and

  6. Search for a narrow resonance in e+e- collisions between ECM = 58 and 60 GeV

    NASA Astrophysics Data System (ADS)

    Abe, K.; Adachi, I.; Awa, S.; Aoki, M.; Belusevic, R.; Emi, K.; Enomoto, R.; Fujii, H.; Fujii, K.; Fujii, T.; Fujimoto, J.; Fujita, K.; Fujiwara, N.; Hayashii, H.; Howell, B.; Iida, N.; Ikeda, H.; Itoh, R.; Iwasaki, H.; Iwasaki, M.; Kajikawa, R.; Kato, S.; Kawabata, S.; Kichimi, H.; Kishida, T.; Kobayashi, M.; Koltick, D.; Levine, I.; Miyabayashi, K.; Miyamoto, A.; Muramutsu, K.; Nagai, K.; Nagira, T.; Nakabayashi, K.; Nakano, E.; Nitoh, O.; Noguchi, S.; Ochiai, F.; Ohnishi, Y.; Okuno, H.; Okusawa, T.; Shimozawa, K.; Shinohara, T.; Sugiyama, A.; Sugiyama, N.; Suzuki, S.; Takahashi, K.; Takahashi, T.; Takemoto, M.; Tanimori, T.; Tauchi, T.; Teramae, F.; Teramoto, Y.; Toomi, N.; Toyama, T.; Tsukamoto, T.; Uno, S.; Watanabe, Y.; Yamaguchi, A.; Yamamoto, A.; Yamamoto, S.; Yamauchi, M.

    1993-04-01

    We carried out the energy scan between ECM = 58 and 60 GeV at the TRISTAN e+e- collider to search for the possible narrow resonance suggested by the L3 experiment at LEP. The total cross sections are measured for γγ, multihadron, e+e- and μ + μ- production at ten energy points covering this energy range almost uniformly. The results are in good agreement with the Standard Model predictions, and 95% confidence level upper limits are set to Γee × BR of the hypothetical scalar and tensor resonances.

  7. Characterizing invisible electroweak particles through single-photon processes at high energy e+e- colliders

    NASA Astrophysics Data System (ADS)

    Choi, Seong Youl; Han, Tao; Kalinowski, Jan; Rolbiecki, Krzysztof; Wang, Xing

    2015-11-01

    We explore the scenarios where the only accessible new states at the electroweak scale consist of a pair of color-singlet electroweak particles, the masses of which are degenerate at the tree level and split only by electroweak symmetry breaking at the loop level. For the sake of illustration, we consider a supersymmetric model and study the following three representative cases with the lower-lying states as (a) two spin-1 /2 Higgsino SU(2 ) L doublets, (b) a spin-1 /2 wino SU(2 ) L triplet and (c) a spin-0 left-handed slepton SU(2 ) L doublet. Due to the mass degeneracy, those lower-lying electroweak states are difficult to observe at the LHC and rather challenging to detect at the e+e- collider as well. We exploit the pair production in association with a hard photon radiation in high energy e+e- collisions. If kinematically accessible, such single-photon processes at e+e- colliders with polarized beams enable us to characterize each scenario by measuring the energy of the associated hard photon and to determine the spin of the nearly invisible particles unambiguously through the threshold behavior in the photon energy distribution.

  8. Production and decay of the diphoton resonance at future e+e- colliders

    NASA Astrophysics Data System (ADS)

    Ito, Hayato; Moroi, Takeo

    2016-07-01

    Motivated by the ATLAS and CMS announcements of the excesses of diphoton events, we discuss the production and decay processes of diphoton resonance at future e+e- colliders. We assume that the excess of the diphoton events at the LHC is explained by a scalar resonance decaying into a pair of photons. In such a case, the scalar interacts with standard model gauge bosons and, consequently, the production of such a scalar is possible at the e+e- colliders. We study the production of the scalar resonance via the associated production with the photon or Z , as well as via the vector-boson fusion, and calculate the cross sections of these processes. We also study the backgrounds, and discuss the detectability of the signals of scalar production with various decay processes of the scalar resonance. We also consider the case where the scalar resonance has an invisible decay mode, and study how the invisible decay can be observed at the e+e- colliders.

  9. CN-GELFrEE - Clear Native Gel-eluted Liquid Fraction Entrapment Electrophoresis.

    PubMed

    Melani, Rafael D; Seckler, Henrique S; Skinner, Owen S; Do Vale, Luis H F; Catherman, Adam D; Havugimana, Pierre C; Valle de Sousa, Marcelo; Domont, Gilberto B; Kelleher, Neil L; Compton, Philip D

    2016-01-01

    Protein complexes perform an array of crucial cellular functions. Elucidating their non-covalent interactions and dynamics is paramount for understanding the role of complexes in biological systems. While the direct characterization of biomolecular assemblies has become increasingly important in recent years, native fractionation techniques that are compatible with downstream analysis techniques, including mass spectrometry, are necessary to further expand these studies. Nevertheless, the field lacks a high-throughput, wide-range, high-recovery separation method for native protein assemblies. Here, we present clear native gel-eluted liquid fraction entrapment electrophoresis (CN-GELFrEE), which is a novel separation modality for non-covalent protein assemblies. CN-GELFrEE separation performance was demonstrated by fractionating complexes extracted from mouse heart. Fractions were collected over 2 hr and displayed discrete bands ranging from ~30 to 500 kDa. A consistent pattern of increasing molecular weight bandwidths was observed, each ranging ~100 kDa. Further, subsequent reanalysis of native fractions via SDS-PAGE showed molecular-weight shifts consistent with the denaturation of protein complexes. Therefore, CN-GELFrEE was proved to offer the ability to perform high-resolution and high-recovery native separations on protein complexes from a large molecular weight range, providing fractions that are compatible with downstream protein analyses. PMID:26967310

  10. Serotonin decreases aggression via 5-HT1A receptors in the fighting fish Betta splendens.

    PubMed

    Clotfelter, Ethan D; O'Hare, Erin P; McNitt, Meredith M; Carpenter, Russ E; Summers, Cliff H

    2007-01-01

    The role of the monoamine neurotransmitter serotonin (5-HT) in the modulation of conspecific aggression in the fighting fish (Betta splendens) was investigated using pharmacological manipulations. We used a fish's response to its mirror image as our index of aggressive behavior. We also investigated the effects of some manipulations on monoamine levels in the B. splendens brain. Acute treatment with 5-HT and with the 5-HT1A receptor agonist 8-OH-DPAT both decreased aggressive behavior; however, treatment with the 5-HT1A receptor antagonist WAY-100635 did not increase aggression. Chronic treatment with the selective serotonin reuptake inhibitor fluoxetine caused no significant changes in aggressive behavior and a significant decline in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations. Treatment with the serotonin synthesis inhibitor p-chlorophenylalanine resulted in no change in aggression, yet serotonergic activity decreased significantly. Finally, a diet supplemented with L-tryptophan (Trp), the precursor to 5-HT, showed no consistent effects on aggressive behavior or brain monoamine concentrations. These results suggest a complex role for serotonin in the expression of aggression in teleost fishes, and that B. splendens may be a useful model organism in pharmacological and toxicological studies. PMID:17553555

  11. 5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure

    PubMed Central

    Janssen, Wiebke; Schymura, Yves; Novoyatleva, Tatyana; Luitel, Himal; Tretyn, Aleksandra; Pullamsetti, Soni Savai; Weissmann, Norbert; Seeger, Werner; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo

    2015-01-01

    Objective. The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid) or SB204741 (5 mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF. PMID:25667920

  12. The 5-HT2A serotonin receptor in executive function: Implications for neuropsychiatric and neurodegenerative diseases.

    PubMed

    Aznar, Susana; Hervig, Mona El-Sayed

    2016-05-01

    Executive function entails the interplay of a group of cognitive processes enabling the individual to anticipate consequences, attain self-control, and undertake appropriate goal-directed behaviour. Serotonin signalling at serotonin 2A receptors (5-HT2AR) has important effects on these behavioural and cognitive pathways, with the prefrontal cortex (PFC) as the central actor. Indeed, the 5-HT2ARs are highly expressed in PFC, where they modulate cortical activity and local network oscillations (brain waves). Numerous psychiatric and neurodegenerative diseases result in disrupted executive function. Animal and human studies have linked these disorders with alterations in the 5-HT2AR system, making this an important pharmacological target for the treatment of disorders with impaired cognitive function. This review aims to describe the current state of knowledge on the role of 5-HT2AR signalling in components of executive function, and how 5-HT2AR systems may relate to executive dysfunctions occurring in psychiatric and neurodegenerative diseases. We hope thereby to provide insight into how pharmacotherapy targeting the 5-HT2AR may ameliorate (or exacerbate) aspects of these disorders. PMID:26891819

  13. 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants

    PubMed Central

    Richardson-Jones, Jesse W; Craige, Caryne P; Guiard, Bruno P; Stephen, Alisson; Metzger, Kayla L; Kung, Hank F; Gardier, Alain M; Dranovsky, Alex; David, Denis J; Beck, Sheryl G; Hen, René; Leonardo, E David

    2010-01-01

    Summary Most depressed patients don't respond to their first drug treatment, and the reasons for this treatment resistance remain enigmatic. Human studies implicate a polymorphism in the promoter of the serotonin-1A (5-HT1A) receptor gene in increased susceptibility to depression and decreased treatment response. Here we develop a new strategy to manipulate 5-HT1A autoreceptors in raphe nuclei without affecting 5-HT1A heteroreceptors, generating mice with higher (1A-High) or lower (1A-Low) autoreceptor levels. We show that this robustly affects raphe firing rates, but has no effect on either basal forebrain serotonin levels or conflict-anxiety measures. However, compared to 1A-Low mice, 1A-High mice show a blunted physiological response to acute stress, increased behavioral despair, and no behavioral response to antidepressant, modeling patients with the 5-HT1A risk allele. Furthermore, reducing 5-HT1A autoreceptor levels prior to antidepressant treatment is sufficient to convert non-responders into responders. These results establish a causal relationship between 5-HT1A autoreceptor levels, resilience under stress, and response to antidepressants. PMID:20152112

  14. Optimising PET approaches to measuring 5-HT release in human brain.

    PubMed

    Tyacke, Robin J; Nutt, David J

    2015-10-01

    A major goal in neuroscience is the measurement of neurotransmitters in living human brain. To date this has only been done reliably with dopamine using certain PET and SPECT radiotracers. The use of this technique has greatly advanced our understanding of dopamine and the dopaminergic system in normal and abnormal brain function. Transferring this technology to other neurotransmitter systems has proved less fruitful. The serotonergic system (5-HT) is one such system. 5-HT has been implicated in a wide range of brain functions and their disorders. The ability to measure 5-HT using this technique would be invaluable. In this article, we explore the key pharmacological features of current radiotracers for 5-HT receptors that might be sensitive to endogenous 5-HT. We also estimate the likely brain concentrations of the current available tranche of agents that might be used to enhance synaptic 5-HT concentration, so taking into account the potential for these to interact with the receptors directly and produce a spurious displacement signal. PMID:26089243

  15. Radiometric calibration of G-LiHT's imaging spectrometer using GLAMR for satellite sensor intercalibration

    NASA Astrophysics Data System (ADS)

    Angal, Amit; McCorkel, Joel; Cook, Bruce; Corp, Lawrence A.; Thome, Kurt

    2015-09-01

    NASA Goddard's Lidar, Hyperspectral and Thermal Imager (G-LiHT) facilitates simultaneous measurements beneficial to variety of applications. Of the suite of "off-the shelf" instruments of G-LiHT, the Visible Near-Infrared (VNIR) Imaging Spectrometer acquires high resolution spectral measurements (1.5 nm resolution) from 0.4 to 1 μm. Goddard Space Flight Center's Laser for Absolute Measurement of Response (GLAMR) was used to measure the absolute spectral response (ASR) of the G-LiHT's imaging spectrometer. Continuously tunable lasers coupled to an integrating sphere allow a radiance-based calibration for the detectors at reflective solar wavelengths. GLAMR measurements, covering a wavelength range from 0.58 to 0.99 μm were acquired between July 30 to August 2, 2013. In order to account for the large field-of-view (50°), G-LiHT was rotated in 2 degree increments so that the same area of the sphere is viewed by all detectors. Using this data along with the coincident Silicon trap radiometer measurements, the ASR was computed. The derived calibration parameters for G-LiHT's Imaging Spectrometer are to be transferred to near-simultaneous measurements of Landsat sensors. Calibration uncertainty of G-LiHT is 1-3% depending spectral region and transferring this traceability to coincident satellite sensors has 3-5% depending on spectral region.

  16. Morphology Evolution of Molecular Weight Dependent P3HT: PCBM Solar Cells

    NASA Astrophysics Data System (ADS)

    Liu, Feng; Chen, Dian; Briseno, Alejandro; Russell, Thomas

    2011-03-01

    Effective strategies to maximize the performance of bulk heterojunction (BHJ) photovoltaic devices have to be developed and understood to realize their full potential. In BHJ solar cells, the morphology of the active layer is a critical issue to improve device efficiency. In this work, we choose poly(3-hexyl-thiophene) (P3HT) and phenyl-C61-butyric acid methyl ester (PCBM) system to study the morphology evolution. Different molecular weight P3HTs were synthesized by using Grignard Metathesis (GRIM)~method. In device optimization, polymer with a molecular weight between 20k-30k shows the highest efficiency. It was observed that the as-spun P3HT: PCBM (1:1) blends do not have high order by GISAXS. Within a few seconds of thermal annealing at 150& circ; the crystallinity of P3HT increaased substantially and the polymer chains adopted an edge-on orientation. An-bicontinous morphology was also developed within this short thermal treatment. The in situ GISAXS experiment showed that P3HT of high molecular weight was more easily crystallized from a slowly evaporated chlorobenzene solution and their edge-on orientation is much more obvious than for the lower molecular weight P3HTs. DSC was used to study the thermal properties of P3HTs and P3HT: PCBM blend. The χ of P3HT-PCBM was also calculated by using melting point depression method.

  17. Synthesis, Characterization and Performance of P3HT-Azide-PCBM Microgel.

    PubMed

    Wei, Guangmin; Li, Xinxin; Jia, Di; Cheng, He

    2016-06-01

    Spherical Poly(3-hexylthiophene)-azide-[6,61-phenyl-C61-butyric acid methyl ester (P3HT-azide-PCBM) microgel was synthesized by introducing an azide cross-linkable group into the conjugated polymer. Its UV-vis spectrum shifts blue as a result of the systematic disruption of planarity along the P3HT backbone and a reduction in long range conjugation. And the corresponding fluorescence spectrum also indicates that a strong intra-molecular photo-induced electron transfer is originated from the covalent linkage of PCBM moiety to the P3HT backbone via the hexyl bridge upon photoexcitation. Combined Gel Permeation Chromatography (GPC), dynamic and static light scattering (DLS and SLS) measurements prove that the resultant P3HT-azide-PCBM copolymer is a uniform spherical microgel with a hydrodynamic radius of 130 nm at room temperature. The spherical P3HT-azide-PCBM microgel can be used as electron donor or compatibilizer in bulk-heterojunction (BHJ) devices, but its introduction reduces the photovoltaic performance compared with the blend of P3HT/PCBM, because the hole mobility in the crosslinked polythiophene backbones is largely decreased. PMID:27427609

  18. Enhanced 5-hydroxytryptamine (5-HT) release from vascular adrenergic nerves in spontaneously hypertensive rats

    SciTech Connect

    Kawasaki, H.; Urabe, M.; Takasaki, K.

    1986-03-01

    The release of 5-HT from vascular adrenergic nerves was compared between normotensive Wistar Kyoto rats (WKY) and SHR. The mesenteric vascular bed isolated from WKY and SHR was perfused with Krebs solution at a constant flow rate of 5 ml/min. Periarterial nerve stimulation (PNS) was delivered at 4 to 16 Hz for 30 sec. In the SHR preparation, the pressor response to PNS, previously decreased by prazonsin (50 nM), was greatly potentiated after treatment with 5-HT(1 ..mu..M) for 15 min and a frequency-dependent pressor response to PNS reappeared, whereas the 5-HT treatment did not alter the pressor response to exogenous norepinephrine (1 nmol) previously reduced by prazonsin. The potentiation of pressor response to PNS after 5-HT treatment was small in the WKY preparation. This potentiation in both WKY and SHR did not occur in the presence of ketanserin (10 nM). In the preparation labeled with (/sup 3/H)-5-HT, PNS (4-16 Hz) evoked a frequency-dependent increase of (/sup 3/H)-efflux, which was abolished by treatment with tetrodotoxin (100 nM) or 6-hydroxydopamine (50 mg/kg i.p. x 2) and in calcium-free Krebs solution. The PNS evoked-(/sup 3/H)-efflux was much greater in SHR than WKY. These results suggest that the release of 5-HT from vascular adrenergic nerves by PNS is enhanced in the SHR preparation.

  19. Elastic constants of Si from HtN Monte Carlo simulations

    NASA Astrophysics Data System (ADS)

    Yates, Henry; Karimi, M.; Matolyak, J.; Kaplan, T.; Mostoller, M.

    1997-03-01

    A simple and efficient way of calculating the elastic constants (C_ij) of silicon as a function of temperature is still lacking. A method that has proven to be useful in the calculation of C_ij is EhN molecular dynamics (MD). EhN MD was successfully applied by Ray et al.(J. Ray, Comput. Phys. Rep. 8, 109 (1988).) to the Stillinger-Weber (SW) Si potential at three temperatures. However, the calculation of C_ij using EhN MD requires a knowledge of the second derivatives of the potential, which can be difficult to evaluate for some potential models. Another technique is HtN MD, where H is the enthalpy, t is the tension, and N is the number of particles, which has been applied with less success to Si by Ray et al.. The appeal of the HtN ensemble is that the strain fluctuations are related to the C_ij through a very simple relationship and that the second derivatives are not needed. A recent study of C_ij for a Lennard-Jones potential using HtN MC and HtN MD indicated a much faster covergence rate for HtN MC over its MD counterpart. We calculate C_ij for the SW Si potential using HtN MC with the same conditions as those used by Ray et al. in doing EhN MD and compare the convergence of the two methods.

  20. Heart rate within male crayfish: social interactions and effects of 5-HT.

    PubMed

    Listerman, L R; Deskins, J; Bradacs, H; Cooper, R L

    2000-02-01

    Behaviors, such as those that establish dominant and subordinate social status, are thought to be driven by various neuromodulators and hormones. In crustaceans, the level of serotonin (5-HT) in the hemolymph is correlated with degree of aggressiveness. The crustacean heart is neurogenic and is modulated by neural secretion of 5-HT in the hemolymph, which bathes the cardiac tissue. We discuss and present the results of measuring heart rate (HR) of crayfish during interactions, as an indication of their state of excitability. HR is the result of multiple influences: a cocktail of hormones and modulators. HR was monitored during the periods in which crayfish established aggressive and submissive social status, during sham injections, and following injections of various doses of 5-HT. Crayfish, during an interaction to establish social status, can increase HR. Both the aggressive and submissive crayfish can dampen their HR within seconds during a pause in the interaction, while still posturing in an aggressive or submissive state. Injections of 5-HT to obtain systemic levels of approximately 100 nM-10 microM increase HR substantially for hours. This suggests that aggressive interactions and the establishment of a dominant posture may not be related to large increases in the free concentrations of 5-HT within the circulating hemolymph, since a sustained HR is not observed in aggressive animals. Instead, the results may demonstrate that inhibitory cardiac regulation is present in the aggressors during interactions and that a regulator is possibly 5-HT. PMID:10825697

  1. Sensitivity of transformed (phasic to tonic) motor neurons to the neuromodulator 5-HT.

    PubMed

    Griffis, B; Bonner, P; Cooper, R L

    2000-12-01

    Long-term adaptation resulting in a 'tonic-like' state can be induced in phasic motor neurons of the crayfish, Procambarus clarkii, by daily low-frequency stimulation [Lnenicka, G.A., Atwood, H.L., 1985b. Long-term facilitation and long-term adaptation at synapses of a crayfish phasic motoneuron. J. Neurobiol. 16, 97-110]. To test the hypothesis that motor neurons undergoing adaptation show increased responses to the neuromodulator serotonin (5-HT), phasic motor neurons innervating the deep abdominal extensor muscles of crayfish were stimulated at 2.5 Hz, 2 h/day, for 7 days. One day after cessation of conditioning, contralateral control and conditioned motor neurons of the same segment were stimulated at 1 Hz and the induced excitatory post-synaptic potentials (EPSPs) were recorded from DEL(1) muscle fibers innervated by each motor neuron type. Recordings were made in saline without and with 100 nM 5-HT. EPSP amplitudes were increased by 5-HT exposure in all cases. Conditioned muscles exposed to 5-HT showed a 2-fold higher percentage of increase in EPSP amplitude than did control muscles. Thus, the conditioned motor neurons behaved like intrinsically tonic motoneurons in their response to 5-HT. While these results show that long-term adaptation (LTA) extends to 5-HT neuromodulation, no phenotype switch could be detected in the postsynaptic muscle. Protein isoform profiles, including the myosin heavy chains, do not change after 1 week of conditioning their innervating motor neurons. PMID:11154946

  2. Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT

    PubMed Central

    Descarries, Laurent; Riad, Mustaph

    2012-01-01

    Serotonin (5-HT) 5-HT1A autoreceptors (5-HT1AautoR) and the plasmalemmal 5-HT transporter (SERT) are key elements in the regulation of central 5-HT function and its responsiveness to antidepressant drugs. Previous immuno-electron microscopic studies in rats have demonstrated an internalization of 5-HT1AautoR upon acute administration of the selective agonist 8-OH-DPAT or the selective serotonin reuptake inhibitor antidepressant fluoxetine. Interestingly, it was subsequently shown in cats as well as in humans that this internalization is detectable by positron emission tomography (PET) imaging with the 5-HT1A radioligand [18F]MPPF. Further immunocytochemical studies also revealed that, after chronic fluoxetine treatment, the 5-HT1AautoR, although present in normal density on the plasma membrane of 5-HT cell bodies and dendrites, do not internalize when challenged with 8-OH-DPAT. Resensitization requires several weeks after discontinuation of the chronic fluoxetine treatment. In contrast, the SERT internalizes in both the cell bodies and axon terminals of 5-HT neurons after chronic but not acute fluoxetine treatment. Moreover, the total amount of SERT immunoreactivity is then reduced, suggesting that SERT is not only internalized, but also degraded in the course of the treatment. Ongoing and future investigations prompted by these finding are briefly outlined by way of conclusion. PMID:22826342

  3. Photoinduced charge dissociation and transport at P3HT/ITO interfaces: studied by modulated surface spectroscopy

    NASA Astrophysics Data System (ADS)

    Rujisamphan, Nopporn; Supasai, Thidarat; Dittrich, Thomas

    2016-02-01

    Results of a temperature dependence study of photoinduced charge separation across P3HT nanocrystals at P3HT/ITO interfaces have been investigated by modulated surface photovoltage (SPV) spectroscopy in a fixed capacitor arrangement. The SPV measurements were correlated with the crystalline sizes of P3HT nanocrystals determined by grazing incidence X-ray diffraction (GIXRD). The crystalline sizes of P3HT nanocrystals were varied systematically by progressive heating/cooling cycles identical for SPV and GIXRD measurements. Photovoltage signals, indication of photoinduced charge dissociation in space, at the P3HT/ITO interface were collected, and electrons were separated across the first monolayer of P3HT nanocrystals at the P3HT/ITO interface due to band bending. The activation energies for quenching of the in-phase and phase-shifted by 90° SPV signals were 0.7 and 0.6 eV, respectively. Thermal activation of the formation of P3HT nanocrystals was of the same order as the enthalpy of fusion of ideal crystals from regioregular P3HT. A schematic drawing of photoinduced charge separation at the P3HT/ITO is proposed.

  4. Target size analysis of serotonin 5-HT/sub 1/ and 5-HT/sub 2/ receptors in bovine brain membranes

    SciTech Connect

    Nishino, N.; Tanaka, C.

    1985-09-23

    Freeze-dried crude synaptic membranes prepared from bovine cerebral cortex and striatum were exposed to high energy gamma ray from the source of /sup 60/Co. The size of serotonin 5-HT/sub 1/ receptors labeled by (/sup 3/H)serotonin and that of 5-HT/sub 2/ receptors labeled by (/sup 3/H)spiperone or (/sup 3/H)ketanserin was determined by target size analyses. The values were 57,000 daltons, 145,000 daltons and 152,000 daltons for the cerebral cortex and 56,000 daltons, 141,000 daltons and 150,000 daltons for the striatum, respectively. The estimated sizes were deduced by reference to enzyme standards with known molecular masses and which were irradiated in parallel. These results demonstrate that the molecular entities in situ for 5-HT/sub 1/ receptors are distinct from those for 5-HT/sub 2/ receptors, thus supporting data on the existence of two distinct populations of serotonin receptors, hitherto evidenced physiopharmacologically.

  5. Expression of hippocampal serotonin receptors 5-HT2C and 5-HT5A in a rat model of diet-induced obesity supplemented with tryptophan.

    PubMed

    Lopez-Esparza, Sarahi; Berumen, Laura C; Padilla, Karla; Miledi, Ricardo; García-Alcocer, Guadalupe

    2015-05-01

    Food intake regulation is a complex mechanism that involves endogenous substances and central nervous system structures like hypothalamus or even hippocampus. The neurotransmitter serotonin is distinguished as food intake mediator; within its multiples receptors, the 5-HT2C type is characterized by its inhibitory appetite action but there is no information about 5-HT5A receptors involvement in obesity disease. It is also unknown if there are any changes in the receptors expression in rats hippocampus with induced obesity during development through a high energy diet (HED) supplemented with tryptophan (W). To appreciate the receptors expression pattern in the hippocampus, obesity was induced to young Sprague Dawley rats through a HED and supplemented with W. Immunocytochemical and western blot techniques were used to study the receptor distribution and quantify the protein expression. The rats with HED diet developed obesity until week 13 of treatment. The 5-HT2C receptor expression decreased in CA1, CA2, CA3 and DG of HED group; and also in CA2, CA3 and DG for HEDW group. The 5-HT5A receptor expression only decreased in DG for HED group. Variations of the two serotonin receptors subtypes support their potential role in obesity. PMID:25720309

  6. Serotonin homeostasis and serotonin receptors as actors of cortical construction: special attention to the 5-HT3A and 5-HT6 receptor subtypes

    PubMed Central

    Vitalis, Tania; Ansorge, Mark S.; Dayer, Alexandre G.

    2013-01-01

    Cortical circuits control higher-order cognitive processes and their function is highly dependent on their structure that emerges during development. The construction of cortical circuits involves the coordinated interplay between different types of cellular processes such as proliferation, migration, and differentiation of neural and glial cell subtypes. Among the multiple factors that regulate the assembly of cortical circuits, 5-HT is an important developmental signal that impacts on a broad diversity of cellular processes. 5-HT is detected at the onset of embryonic telencephalic formation and a variety of serotonergic receptors are dynamically expressed in the embryonic developing cortex in a region and cell-type specific manner. Among these receptors, the ionotropic 5-HT3A receptor and the metabotropic 5-HT6 receptor have recently been identified as novel serotonergic targets regulating different aspects of cortical construction including neuronal migration and dendritic differentiation. In this review, we focus on the developmental impact of serotonergic systems on the construction of cortical circuits and discuss their potential role in programming risk for human psychiatric disorders. PMID:23801939

  7. Individual Differences in Impulsive Action Reflect Variation in the Cortical Serotonin 5-HT2A Receptor System

    PubMed Central

    Fink, Latham HL; Anastasio, Noelle C; Fox, Robert G; Rice, Kenner C; Moeller, F Gerard; Cunningham, Kathryn A

    2015-01-01

    Impulsivity is an important feature of multiple neuropsychiatric disorders, and individual variation in the degree of inherent impulsivity could play a role in the generation or exacerbation of problematic behaviors. Serotonin (5-HT) actions at the 5-HT2AR receptor (5-HT2AR) promote and 5-HT2AR antagonists suppress impulsive action (the inability to withhold premature responses; motor impulsivity) upon systemic administration or microinfusion directly into the medial prefrontal cortex (mPFC), a node in the corticostriatal circuit that is thought to play a role in the regulation of impulsive action. We hypothesized that the functional capacity of the 5-HT2AR, which is governed by its expression, localization, and protein/protein interactions (eg, postsynaptic density 95 (PSD95)), may drive the predisposition to inherent impulsive action. Stable high-impulsive (HI) and low-impulsive (LI) phenotypes were identified from an outbred rodent population with the 1-choice serial reaction time (1-CSRT) task. HI rats exhibited a greater head-twitch response following administration of the preferential 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and were more sensitive to the effects of the selective 5-HT2AR antagonist M100907 to suppress impulsive action relative to LI rats. A positive correlation was observed between levels of premature responses and 5-HT2AR binding density in frontal cortex ([3H]-ketanserin radioligand binding). Elevated mPFC 5-HT2AR protein expression concomitant with augmented association of the 5-HT2AR with PSD95 differentiated HI from LI rats. The observed differential sensitivity of HI and LI rats to 5-HT2AR ligands and associated distinct 5-HT2AR protein profiles provide evidence that spontaneously occurring individual differences in impulsive action reflect variation in the cortical 5-HT2AR system. PMID:25666313

  8. Side effect profile