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Sample records for agonist carbachol car

  1. [Role of rennin-angiotensin system in cholinergic agonist carbachol-induced cardiovascular responses in ovine fetus].

    PubMed

    Geng, Chun-Song; Wan, Zhen; Feng, Ya-Hong; Fan, Yi-Sun

    2012-06-25

    To investigate the mechanisms underlying the cholinergic agonist carbachol-induced cardiovascular responses, changes of renin-angiotensin system were examined in fetal hormonal systems. In the ovine fetal model under stressless condition, the cardiovascular function was recorded. Blood samples were collected before (during baseline period) and after the intravenous administration of carbachol. Simultaneously, the levels of angiotensin I (Ang I), angiotensin II (Ang II) and vasopressin in the fetal plasma were detected by immunoradiological method. Also, blood gas, plasma osmolality and electrolyte concentrations were analyzed in blood samples. Results showed that in chronically prepared ovine fetus, intravenous infusion of carbachol led to a significant decrease of heart rate (P < 0.05), and a transient decrease followed by an increase of blood pressure (P < 0.05) within 30 min. After the intravenous infusion of carbachol, blood concentrations of Ang I and Ang II in near-term ovine fetus were both significantly increased (P < 0.05); however, blood concentration of vasopressin, values of blood gas, electrolytes and plasma osmolality in near-term ovine fetus were not significantly changed (P > 0.05). Blood levels of Ang I and Ang II in the atropine (M receptor antagonist) + carbachol intravenous administration group was lower than those in the carbachol group without atropine administration (P < 0.05). In conclusion, this study indicates that the near-term changes of cardiovascular system induced by intravenous administration of carbachol in ovine fetus, such as blood pressure and heart rate, are associated with the changes of hormones of circulatory renin-angiotensin system. PMID:22717634

  2. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR.

    PubMed

    Huang, Wendong; Zhang, Jun; Wei, Ping; Schrader, William T; Moore, David D

    2004-10-01

    The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans. PMID:15272053

  3. The novel β3-adrenoceptor agonist mirabegron reduces carbachol-induced contractile activity in detrusor tissue from patients with bladder outflow obstruction with or without detrusor overactivity.

    PubMed

    Svalø, Julie; Nordling, Jørgen; Bouchelouche, Kirsten; Andersson, Karl-Erik; Korstanje, Cees; Bouchelouche, Pierre

    2013-01-15

    β(3)-Adrenoceptors are major players in detrusor relaxation and have been suggested as a new putative target for the treatment of overactive bladder syndrome. We determined the effects of mirabegron (YM178), a novel β(3)-adrenoceptor agonist, on carbachol-induced tone in isolated human detrusor preparations from patients with bladder outflow obstruction (BOO) with and without detrusor overactivity (DO), and from patients with normal bladder function. We compared the effects to those of isoprenaline, a non-selective β-adrenoceptor agonist. Detrusor specimens were obtained from patients with benign prostatic hyperplasia undergoing cystoscopy and from patients undergoing radical prostatectomy/cystectomy (in total 33 donors). Detrusor contractility was evaluated by organ bath studies and strips were incubated with carbachol (1μM) to induce and enhance tension. Both mirabegron and isoprenaline reduced carbachol-induced tone in tissues from all groups. Isoprenaline decreased tension with higher potency than mirabegron in normal, BOO and BOO+DO detrusor strips with pIC(50) values of 7.49 ± 0.16 vs. 6.23 ± 0.26 (P=0.0002), 6.89 ± 0.34 vs. 6.04 ± 0.31 (P=0.01), and 6.57 ± 0.20 vs. 5.41 ± 0.08 (P<0.0001, n=4), respectively. The maximal relaxant effect of isoprenaline and mirabegron in the normal, BOO and BOO+DO detrusor was 37.7 ± 14.4% and 36.1 ± 23.3%, 14.4 ± 12.2% vs. 33.4 ± 21.0% and 18.3 ± 10.0% vs. 28.3 ± 12.2% (n=4, P>0.05), respectively. Mirabegron and isoprenaline reduced carbachol-induced tone in both normal bladders and obstructed bladder with and without DO. Isoprenaline had higher potency than mirabegron, but the efficacy of mirabegron effect was the same as that of isoprenaline. PMID:23246623

  4. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice.

    PubMed

    Wagner, Martin; Halilbasic, Emina; Marschall, Hanns-Ulrich; Zollner, Gernot; Fickert, Peter; Langner, Cord; Zatloukal, Kurt; Denk, Helmut; Trauner, Michael

    2005-08-01

    Induction of hepatic phase I/II detoxification enzymes and alternative excretory pumps may limit hepatocellular accumulation of toxic biliary compounds in cholestasis. Because the nuclear xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate involved enzymes and transporters, we aimed to induce adaptive alternative pathways with different CAR and PXR agonists in vivo. Mice were treated with the CAR agonists phenobarbital and 1,4-bis-[2-(3,5-dichlorpyridyloxy)]benzene, as well as the PXR agonists atorvastatin and pregnenolone-16alpha-carbonitrile. Hepatic bile acid and bilirubin-metabolizing/detoxifying enzymes (Cyp2b10, Cyp3a11, Ugt1a1, Sult2a1), their regulatory nuclear receptors (CAR, PXR, farnesoid X receptor), and bile acid/organic anion and lipid transporters (Ntcp, Oatp1,2,4, Bsep, Mrp2-4, Mdr2, Abcg5/8, Asbt) in the liver and kidney were analyzed via reverse-transcriptase polymerase chain reaction and Western blotting. Potential functional relevance was tested in common bile duct ligation (CBDL). CAR agonists induced Mrp2-4 and Oatp2; PXR agonists induced only Mrp3 and Oatp2. Both PXR and CAR agonists profoundly stimulated bile acid-hydroxylating/detoxifying enzymes Cyp3a11 and Cyp2b10. In addition, CAR agonists upregulated bile acid-sulfating Sult2a1 and bilirubin-glucuronidating Ugt1a1. These changes were accompanied by reduced serum levels of bilirubin and bile acids in healthy and CBDL mice and by increased levels of polyhydroxylated bile acids in serum and urine of cholestatic mice. Atorvastatin significantly increased Oatp2, Mdr2, and Asbt, while other transporters and enzymes were moderately affected. In conclusion, administration of specific CAR or PXR ligands results in coordinated stimulation of major hepatic bile acid/bilirubin metabolizing and detoxifying enzymes and hepatic key alternative efflux systems, effects that are predicted to counteract cholestasis. PMID:15986414

  5. The Use of the LanthaScreen TR-FRET CAR Coactivator Assay in the Characterization of Constitutive Androstane Receptor (CAR) Inverse Agonists.

    PubMed

    Carazo, Alejandro; Pávek, Petr

    2015-01-01

    The constitutive androstane receptor (CAR) is a critical nuclear receptor in the gene regulation of xenobiotic and endobiotic metabolism. The LanthaScreen(TM) TR-FRET CAR coactivator assay provides a simple and reliable method to analyze the affinity of a ligand to the human CAR ligand-binding domain (LBD) with no need to use cellular models. This in silico assay thus enables the study of direct CAR ligands and the ability to distinguish them from the indirect CAR activators that affect the receptor via the cell signaling-dependent phosphorylation of CAR in cells. For the current paper we characterized the pharmacodynamic interactions of three known CAR inverse agonists/antagonists-PK11195, clotrimazole and androstenol-with the prototype agonist CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3] thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) using the TR-FRET LanthaScreen(TM) assay. We have confirmed that all three compounds are inverse agonists of human CAR, with IC50 0.51, 0.005, and 0.35 μM, respectively. All the compounds also antagonize the CITCO-mediated activation of CAR, but only clotrimazole was capable to completely reverse the effect of CITCO in the tested concentrations. Thus this method allows identifying not only agonists, but also antagonists and inverse agonists for human CAR as well as to investigate the nature of the pharmacodynamic interactions of CAR ligands. PMID:25905697

  6. The Use of the LanthaScreen TR-FRET CAR Coactivator Assay in the Characterization of Constitutive Androstane Receptor (CAR) Inverse Agonists

    PubMed Central

    Carazo, Alejandro; Pávek, Petr

    2015-01-01

    The constitutive androstane receptor (CAR) is a critical nuclear receptor in the gene regulation of xenobiotic and endobiotic metabolism. The LanthaScreenTM TR-FRET CAR coactivator assay provides a simple and reliable method to analyze the affinity of a ligand to the human CAR ligand-binding domain (LBD) with no need to use cellular models. This in silico assay thus enables the study of direct CAR ligands and the ability to distinguish them from the indirect CAR activators that affect the receptor via the cell signaling-dependent phosphorylation of CAR in cells. For the current paper we characterized the pharmacodynamic interactions of three known CAR inverse agonists/antagonists—PK11195, clotrimazole and androstenol—with the prototype agonist CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) using the TR-FRET LanthaScreenTM assay. We have confirmed that all three compounds are inverse agonists of human CAR, with IC50 0.51, 0.005, and 0.35 μM, respectively. All the compounds also antagonize the CITCO-mediated activation of CAR, but only clotrimazole was capable to completely reverse the effect of CITCO in the tested concentrations. Thus this method allows identifying not only agonists, but also antagonists and inverse agonists for human CAR as well as to investigate the nature of the pharmacodynamic interactions of CAR ligands. PMID:25905697

  7. Potentiation of carbachol-induced detrusor smooth muscle contractions by β-adrenoceptor activation

    PubMed Central

    Klausner, Adam P; Rourke, Keith F; Miner, Amy S; Ratz, Paul H

    2011-01-01

    In strips of rabbit bladder free of urothelium, the β-adrenoceptor agonist, isoproterenol, significantly reduced basal detrusor smooth muscle tone and inhibited contractions produced by low concentrations of the muscarinic receptor agonist, carbachol. During a carbachol concentration-response curve, instead of inhibiting, isoproterenol strengthened contractions produced by high carbachol concentrations. Thus, the carbachol concentration-response curve was shifted by isoproterenol from a shallow, graded relationship, to a steep, switch-like relationship. The tyrosine kinase inhibitor, genistein, inhibited carbachol-induced contractions only in the presence of isoproterenol. Contraction produced by a single high carbachol concentration (1 µM) displayed 1 fast and 1 slow peak. In the presence of isoproterenol, the slow peak was not strengthened, but was delayed, and U-0126 (mitogen-activated protein kinase kinase inhibitor) selectively inhibited this delay concomitantly with inhibition of extracellular signal-regulated kinase (ERK) phosphorylation. Isoproterenol reduced ERK phosphorylation only in the absence of carbachol. These data support the concept that, by inhibiting weak contractions, potentiating strong contractions, and producing a more switch-like concentration-response curve, β-adrenoceptor stimulation enhanced the effectiveness of muscarinic receptor-induced detrusor smooth muscle contraction. Moreover, β-adrenoceptor stimulation changed the cellular mechanism by which carbachol produced contraction. The potential significance of multi-receptor and multi-cell crosstalk is discussed. PMID:19374847

  8. Carbachol-induced rhythmic slow activity (theta) in cat hippocampal formation slices.

    PubMed

    Konopacki, J; Gołebiewski, H; Eckersdorf, B

    1992-04-24

    Application of the cholinergic agonist, carbachol, produced theta-like rhythmical waveforms, recorded in the stratum moleculare of the dentate gyrus in the cat hippocampal formation slices. This effect of carbachol was antagonized by atropine but not D-tubocurarine. These results provide first direct evidence that the hippocampal formation neuronal network in the cat is capable of producing synchronized slow wave activity when isolated from pulsed rhythmic inputs of the medial septum. PMID:1511270

  9. Carbachol ameliorates lipopolysaccharide-induced intestinal epithelial tight junction damage by down-regulating NF-{kappa}{beta} and myosin light-chain kinase pathways

    SciTech Connect

    Zhang, Ying; Li, Jianguo

    2012-11-16

    Highlights: Black-Right-Pointing-Pointer Carbachol reduced the lipopolysaccharide-induced intestinal barrier breakdown. Black-Right-Pointing-Pointer Carbachol ameliorated the lipopolysaccharide-induced ileal tight junction damage. Black-Right-Pointing-Pointer Carbachol prevented the LPS-induced NF-{kappa}{beta} and myosin light-chain kinase activation. Black-Right-Pointing-Pointer Carbachol exerted its beneficial effects in an {alpha}7 nicotinic receptor-dependent manner. -- Abstract: Carbachol is a cholinergic agonist that protects the intestines after trauma or burn injury. The present study determines the beneficial effects of carbachol and the mechanisms by which it ameliorates the lipopolysaccharide (LPS)-induced intestinal barrier breakdown. Rats were injected intraperitoneally with 10 mg/kg LPS. Results showed that the gut barrier permeability was reduced, the ultrastructural disruption of tight junctions (TJs) was prevented, the redistribution of zonula occludens-1 and claudin-2 proteins was partially reversed, and the nuclear factor-kappa beta (NF-{kappa}{beta}) and myosin light-chain kinase (MLCK) activation in the intestinal epithelium were suppressed after carbachol administration in LPS-exposed rats. Pretreatment with the {alpha}7 nicotinic acetylcholine receptor ({alpha}7nAchR) antagonist {alpha}-bungarotoxin blocked the protective action of carbachol. These results suggested that carbachol treatment can protect LPS-induced intestinal barrier dysfunction. Carbachol exerts its beneficial effect on the amelioration of the TJ damage by inhibiting the NF-{kappa}{beta} and MLCK pathways in an {alpha}7nAchR-dependent manner.

  10. Carbachol promotes gastrointestinal function during oral resuscitation of burn shock

    PubMed Central

    Hu, Sen; Che, Jin-Wei; Tian, Yi-Jun; Sheng, Zhi-Yong

    2011-01-01

    AIM: To investigate the effect of carbachol on gastrointestinal function in a dog model of oral resuscitation for burn shock. METHODS: Twenty Beagle dogs with intubation of the carotid artery, jugular vein and jejunum for 24 h were subjected to 35% total body surface area full-thickness burns, and were divided into three groups: no fluid resuscitation (NR, n = 10), in which animals did not receive fluid by any means in the first 24 h post-burn; oral fluid resuscitation (OR, n = 8), in which dogs were gavaged with glucose-electrolyte solution (GES) with volume and rate consistent with the Parkland formula; and oral fluid with carbachol group (OR/CAR, n = 8), in which dogs were gavaged with GES containing carbachol (20 μg/kg), with the same volume and rate as the OR group. Twenty-four hours after burns, all animals were given intravenous fluid replacement, and 72 h after injury, they received nutritional support. Hemodynamic and gastrointestinal parameters were measured serially with animals in conscious and cooperative state. RESULTS: The mean arterial pressure, cardiac output and plasma volume dropped markedly, and gastrointestinal tissue perfusion was reduced obviously after the burn injury in all the three groups. Hemodynamic parameters and gastrointestinal tissue perfusion in the OR and OR/CAR groups were promoted to pre-injury level at 48 and 72 h, respectively, while hemodynamic parameters in the NR group did not return to pre-injury level till 72 h, and gastrointestinal tissue perfusion remained lower than pre-injury level until 120 h post-burn. CO2 of the gastric mucosa and intestinal mucosa blood flow of OR/CAR groups were 56.4 ± 4.7 mmHg and157.7 ± 17.7 blood perfusion units (BPU) at 24 h post-burn, respectively, which were significantly superior to those in the OR group (65.8 ± 5.8 mmHg and 127.7 ± 11.9 BPU, respectively, all P < 0.05). Gastric emptying and intestinal absorption rates of GES were significantly reduced to the lowest level (52.8% and

  11. Rapid activation of gluconeogenesis after intracerebroventricular carbachol.

    PubMed

    Migliorini, R H; Garofalo, M A; Roselino, J E; Kettelhut, I C

    1989-10-01

    Intracerebroventricular administration of carbachol (27 nmol in 5 microliters 0.15 M NaCl) produced marked hyperglycemia in 24-h fasted rats, despite the negligible amounts of preformed liver glycosyl residues. To investigate the possibility of a stimulation of gluconeogenesis, conscious unrestrained rats were continuously infused with [14C]bicarbonate (0.51 microliters, 0.18 muCi/min) and label incorporation into circulating glucose determined before and after intraventricular injection. The rate of 14C incorporation into blood glucose of fed rats was not affected by intraventricular injection of 0.15 M NaCl but increased significantly after carbachol administration. In both fed and 24-h fasted rats the hyperglycemia induced by intraventricular carbachol was accompanied by marked increases in plasma lactate. Previous adrenodemedullation prevented both the hyperglycemia and the hyperlactemia. Liver pyruvate kinase activity was reduced in carbachol-treated rats, when the enzyme was assayed with suboptimal concentrations of phosphoenolpyruvate and in the absence of fructose 1,6-biphosphate. Phosphoenolpyruvate carboxykinase activity was not affected. The data suggest that central chemical stimulation with cholinergic agents induces a rapid activation of liver gluconeogenesis, which probably results from an increased sympathetic outflow for epinephrine secretion by the adrenal medulla. PMID:2801933

  12. Carbachol stimulates a different phospholipid metabolism than nerve growth factor and basic fibroblast growth factor in PC12 cells.

    PubMed Central

    Pessin, M S; Altin, J G; Jarpe, M; Tansley, F; Bradshaw, R A; Raben, D M

    1991-01-01

    We have examined 1,2-diglycerides (DGs) generated in PC12 cells in response to the muscarinic agonist carbachol and compared them with those generated in response to the differentiation factors nerve growth factor and basic fibroblast growth factor. Whereas carbachol stimulates a greater release of inositol phosphates, all three agonists generate similar levels of DGs. In this report, we have analyzed the molecular species of PC12 DGs generated in response to these three agonists. Additionally, we have analyzed the molecular species of PC12 phospholipids. The data indicate that 1) after 1 min of either nerve growth factor or basic fibroblast growth factor stimulation, DGs arise primarily from phosphoinositide hydrolysis; 2) in contrast, after 1 min of carbachol stimulation, DG are generated equally by both phosphoinositide and phosphatidylcholine hydrolysis; and 3) after 15 min of stimulation by any of these agonists, DGs are generated largely by phosphatidylcholine hydrolysis, with a smaller component arising from the phosphoinositides. These results suggest that at least part of the mechanism by which PC12 cells distinguish between different agonists is via alterations in phospholipid sources and kinetics of DG generation. PMID:1892912

  13. Cars, Cars, Cars

    ERIC Educational Resources Information Center

    McIntosh, Phyllis

    2013-01-01

    Cars are the focus of this feature article, which explores such topics as the history of cars in the United States, the national highway system, safety and pollution concerns, mobility and freedom for women, classic car shows, and the road trip in American literature and film. Also included are links to the websites of Automobile in American Life…

  14. Motoneuron properties during motor inhibition produced by microinjection of carbachol into the pontine reticular formation of the decerebrate cat.

    PubMed

    Morales, F R; Engelhardt, J K; Soja, P J; Pereda, A E; Chase, M H

    1987-04-01

    It is well established that cholinergic agonists, when injected into the pontine reticular formation in cats, produce a generalized suppression of motor activity (1, 3, 6, 14, 18, 27, 33, 50). The responsible neuronal mechanisms were explored by measuring ventral root activity, the amplitude of the Ia-monosynaptic reflex, and the basic electrophysiological properties of hindlimb motoneurons before and after carbachol was microinjected into the pontine reticular formation of decerebrate cats. Intrapontine microinjections of carbachol (0.25-1.0 microliter, 16 mg/ml) resulted in the tonic suppression of ventral root activity and a decrease in the amplitude of the Ia-monosynaptic reflex. An analysis of intracellular records from lumbar motoneurons during the suppression of motor activity induced by carbachol revealed a considerable decrease in input resistance and membrane time constant as well as a reduction in motoneuron excitability, as evidenced by a nearly twofold increase in rheobase. Discrete inhibitory postsynaptic potentials were also observed following carbachol administration. The changes in motoneuron properties (rheobase, input resistance, and membrane time constant), as well as the development of discrete inhibitory postsynaptic potentials, indicate that spinal cord motoneurons were postsynaptically inhibited following the pontine administration of carbachol. In addition, the inhibitory processes that arose after carbachol administration in the decerebrate cat were remarkably similar to those that are present during active sleep in the chronic cat. These findings suggest that the microinjection of carbachol into the pontine reticular formation activates the same brain stem-spinal cord system that is responsible for the postsynaptic inhibition of alpha-motoneurons that occurs during active sleep. PMID:3585456

  15. Carbachol-induced colonic mucus formation requires transport via NKCC1, K⁺ channels and CFTR.

    PubMed

    Gustafsson, Jenny K; Lindén, Sara K; Alwan, Ala H; Scholte, Bob J; Hansson, Gunnar C; Sjövall, Henrik

    2015-07-01

    The colonic mucosa protects itself from the luminal content by secreting mucus that keeps the bacteria at a distance from the epithelium. For this barrier to be effective, the mucus has to be constantly replenished which involves exocytosis and expansion of the secreted mucins. Mechanisms involved in regulation of mucus exocytosis and expansion are poorly understood, and the aim of this study was to investigate whether epithelial anion secretion regulates mucus formation in the colon. The muscarinic agonist carbachol was used to induce parallel secretion of anions and mucus, and by using established inhibitors of ion transport, we studied how inhibition of epithelial transport affected mucus formation in mouse colon. Anion secretion and mucin exocytosis were measured by changes in membrane current and epithelial capacitance, respectively. Mucus thickness measurements were used to determine the carbachol effect on mucus growth. The results showed that the carbachol-induced increase in membrane current was dependent on NKCC1 co-transport, basolateral K(+) channels and Cftr activity. In contrast, the carbachol-induced increase in capacitance was partially dependent on NKCC1 and K(+) channel activity, but did not require Cftr activity. Carbachol also induced an increase in mucus thickness that was inhibited by the NKCC1 blocker bumetanide. However, mice that lacked a functional Cftr channel did not respond to carbachol with an increase in mucus thickness, suggesting that carbachol-induced mucin expansion requires Cftr channel activity. In conclusion, these findings suggest that colonic epithelial transport regulates mucus formation by affecting both exocytosis and expansion of the mucin molecules. PMID:25139191

  16. Carbachol-Induced Reduction in the Activity of Adult Male Zebra Finch RA Projection Neurons

    PubMed Central

    Meng, Wei; Wang, Song-Hua; Li, Dong-Feng

    2016-01-01

    Cholinergic mechanism is involved in motor behavior. In songbirds, the robust nucleus of the arcopallium (RA) is a song premotor nucleus in the pallium and receives cholinergic inputs from the basal forebrain. The activity of projection neurons in RA determines song motor behavior. Although many evidences suggest that cholinergic system is implicated in song production, the cholinergic modulation of RA is not clear until now. In the present study, the electrophysiological effects of carbachol, a nonselective cholinergic receptor agonist, were investigated on the RA projection neurons of adult male zebra finches through whole-cell patch-clamp techniques in vitro. Our results show that carbachol produced a significant decrease in the spontaneous and evoked action potential (AP) firing frequency of RA projection neurons, accompanying a hyperpolarization of the membrane potential, an increase in the evoked AP latency, afterhyperpolarization (AHP) peak amplitude, and AHP time to peak, and a decrease in the membrane input resistance, membrane time constant, and membrane capacitance. These results indicate that carbachol reduces the activity of RA projection neurons by hyperpolarizing the resting membrane potential and increasing the AHP and the membrane conductance, suggesting that the cholinergic modulation of RA may play an important role in song production. PMID:26904300

  17. Glucose and carbachol activate phospholipase C in digitonin-permeabilized islets

    SciTech Connect

    Wolf, B.A.; Florholmen, J.; Turk, J.; McDaniel, M.L.

    1987-05-01

    Stimulation of intact islets with D-glucose, the major insulin secretagogue, or with carbachol, a muscarinic agonist, results in the accumulation of inositoltrisphosphate (IP/sub 3/) suggesting that activation of phospholipase C (PLC) has a major role in stimulus-secretion coupling. Carbachol activation of PLC is an example of receptor-mediated activation in islets, whereas, the mechanism of glucose activation of PLC is controversial since a glucose receptor has not been identified. They have measured PLC activity in digitonin-permeabilized islets. Islets were labeled with /sup 3/H-inositol, permeabilized and IP/sub 3/ accumulation measured by HPLC. Carbachol, in the presence of ATP, GTP and 1 ..mu..M free Ca/sup 2 +/ released two-fold more Ins 1,3,4-P/sub 3/ than control in a time-dependent manner. Glucose, under the same conditions also significantly released more Ins 1,3,4-P/sub 3/ than control. This effect was not due to metabolism of glucose nor to an effect on the IP/sub 3/-phosphomonoesterase. Preliminary Ca/sup 2 +/-dependency studies indicate that PLC is not activated by Ca/sup 2 +/ in the submicromolar range. In conclusion, these studies show that Ca/sup 2 +/ does not activate PLC, and furthermore, that D-glucose may be recognized directly by PLC.

  18. Properties of carbachol-induced oscillatory activity in rat hippocampus.

    PubMed

    Williams, J H; Kauer, J A

    1997-11-01

    Properties of carbachol-induced oscillatory activity in rat hippocampus. J. Neurophysiol. 78: 2631-2640, 1997. The recent resurgence of interest in carbachol oscillations as an in vitro model of theta rhythm in the hippocampus prompted us to evaluate the circuit mechanisms involved. In extracellular recordings, a regularly spaced bursting pattern of field potentials was observed in both CA3 and CA1 subfields in the presence of carbachol. Removal of the CA3 region abolished oscillatory activity observed in CA1, suggesting that the oscillatory generator is located in CA3. An alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), blocked carbachol oscillations, indicating that AMPA receptor-mediated synaptic currents are necessary for the population oscillation. Moreover, the spread of oscillatory activity into CA1 required intact N-methyl--aspartate receptors. These data are more consistent with epileptiform bursting than with theta rhythm described in vivo. In the presence of carbachol, individual CA3 pyramidal cells exhibited a slow, rhythmic intrinsic oscillation that was not blocked by DNQX and that was enhanced by membrane hyperpolarization. We hypothesize that this slower oscillation is the fundamental oscillator that participates in triggering the population oscillation by exciting multiple synaptically connected CA3 neurons. gamma-aminobutyric acid-A (GABAA) receptors are not necessary for carbachol to elicit synchronous CA3 field events but are essential to the bursting pattern observed. Neither GABAB nor metabotropic glutamate receptors appear to be necessary for carbachol oscillations. However, both nicotinic and M1 and M3 muscarinic cholinergic receptors contribute to the generation of this activity. These results establish the local circuit elements and neurotransmitter receptors that contribute to carbachol-induced oscillations and indicate that carbachol-induced oscillations are

  19. Dual agonist occupancy of AT1-R–α2C-AR heterodimers results in atypical Gs-PKA signaling

    PubMed Central

    Bellot, Morgane; Galandrin, Ségolène; Boularan, Cédric; Matthies, Heinrich J; Despas, Fabien; Denis, Colette; Javitch, Jonathan; Mazères, Serge; Sanni, Samra Joke; Pons, Véronique; Seguelas, Marie-Hélène; Hansen, Jakob L; Pathak, Atul; Galli, Aurelio; Sénard, Jean-Michel; Galés, Céline

    2015-01-01

    Hypersecretion of norepinephrine (NE) and angiotensin II (AngII) is a hallmark of major prevalent cardiovascular diseases that contribute to cardiac pathophysiology and morbidity. Herein, we explore whether heterodimerization of presynaptic AngII AT1 receptor (AT1-R) and NE α2C-adrenergic receptor (α2C-AR) could underlie their functional cross-talk to control NE secretion. Multiple bioluminescence resonance energy transfer and protein complementation assays allowed us to accurately probe the structures and functions of the α2C-AR–AT1-R dimer promoted by ligand binding to individual protomers. We found that dual agonist occupancy resulted in a conformation of the heterodimer different from that induced by active individual protomers and triggered atypical Gs-cAMP–PKA signaling. This specific pharmacological signaling unit was identified in vivo to promote not only NE hypersecretion in sympathetic neurons but also sympathetic hyperactivity in mice. Thus, we uncovered a new process by which GPCR heterodimerization creates an original functional pharmacological entity and that could constitute a promising new target in cardiovascular therapeutics. PMID:25706338

  20. Aging changes agonist induced contractile responses in permeabilized rat bladder.

    PubMed

    Durlu-Kandilci, N Tugba; Denizalti, Merve; Sahin-Erdemli, Inci

    2015-08-01

    Aging alters bladder functions where a decrease in filling, storage and emptying is observed. These changes cause urinary incontinence, especially in women. The aim of this study is to examine how aging affects the intracellular calcium movements due to agonist-induced contractions in permeabilized female rat bladder. Urinary bladder isolated from young and old female Sprague-Dawley rats were used. Small detrusor strips were permeabilized with β-escin. The contractile responses induced with agonists were compared between young and old groups. Carbachol-induced contractions were decreased in permeabilized detrusor from old rats compared to young group. Heparin and ryanodine decreased carbachol-induced contractions in young rats where only heparin inhibited these contractions in olds. Caffeine-induced contractions but not inositol triphosphate (IP3)-induced contractions were decreased in old group compared to youngs. The cumulative calcium response curves (pCa 8-4) were also decreased in old rats. Carbachol-induced calcium sensitization responses did not alter by age where GTP-β-S and GF-109203X but not Y-27632 inhibited these responses. Carbachol-induced contractions decrease with aging in rat bladder detrusor. It can be postulated as IP3-induced calcium release (IICR) is primarily responsible for the contractions in older rats where the decrease in carbachol contractions in aging may be as a result of a decrease in calcium-induced calcium release (CICR), rather than carbachol-induced calcium sensitization. PMID:26153091

  1. Neocortical 40 Hz oscillations during carbachol-induced rapid eye movement sleep and cataplexy.

    PubMed

    Torterolo, Pablo; Castro-Zaballa, Santiago; Cavelli, Matías; Chase, Michael H; Falconi, Atilio

    2016-02-01

    Higher cognitive functions require the integration and coordination of large populations of neurons in cortical and subcortical regions. Oscillations in the gamma band (30-45 Hz) of the electroencephalogram (EEG) have been involved in these cognitive functions. In previous studies, we analysed the extent of functional connectivity between cortical areas employing the 'mean squared coherence' analysis of the EEG gamma band. We demonstrated that gamma coherence is maximal during alert wakefulness and is almost absent during rapid eye movement (REM) sleep. The nucleus pontis oralis (NPO) is critical for REM sleep generation. The NPO is considered to exert executive control over the initiation and maintenance of REM sleep. In the cat, depending on the previous state of the animal, a single microinjection of carbachol (a cholinergic agonist) into the NPO can produce either REM sleep [REM sleep induced by carbachol (REMc)] or a waking state with muscle atonia, i.e. cataplexy [cataplexy induced by carbachol (CA)]. In the present study, in cats that were implanted with electrodes in different cortical areas to record polysomnographic activity, we compared the degree of gamma (30-45 Hz) coherence during REMc, CA and naturally-occurring behavioural states. Gamma coherence was maximal during CA and alert wakefulness. In contrast, gamma coherence was almost absent during REMc as in naturally-occurring REM sleep. We conclude that, in spite of the presence of somatic muscle paralysis, there are remarkable differences in cortical activity between REMc and CA, which confirm that EEG gamma (≈40 Hz) coherence is a trait that differentiates wakefulness from REM sleep. PMID:26670051

  2. Activation of T84 cell chloride channels by carbachol involves a phosphoinositide-coupled muscarinic M3 receptor.

    PubMed

    Dickinson, K E; Frizzell, R A; Sekar, M C

    1992-04-10

    Muscarinic agonists stimulate Cl- secretion across monolayers of the colon tumor epithelial cell line, T84. The muscarinic receptor has been characterized in T84 cell homogenates by radioligand binding using [3H]N-methylscopolamine ([3H]NMS). [3H]NMS bound to a single population of sites at 25 degrees C in 100 mM NaCl, 20 mM HEPES, 10 mM MgCl2, pH 7.4 buffer, with calculated Kd = 278 (+/- 44) pM and Bmax = 40 (+/- 6) fmol/mg protein (n = 4). Binding was reversible (diss. t1/2 = 18 +/- 3 min) and stereoselective (dexetimide Ki = 0.3 nM) much greater than levetimide (Ki = 8300 nM). Antagonists exhibited the following rank order of potencies and Ki values (nM): atropine (0.54) greater than 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP) (0.84) greater than dicyclomine (14) = hexahydrosiladifenidol (18) greater than pirenzepine (136) greater than AF-DX 116 (3610). The same sequence was observed for inhibition of carbachol-induced 125I efflux from T84 monolayers. This is indicative of an M3 'glandular' muscarinic receptor. Coupling to second messenger systems was examined by labelling monolayers with [14C]arachidonic acid (AA) or [3H]inositol. Carbachol (0.3 mM) did not release [14C]AA from labelled lipids, but ionomycin produced a dose-dependent increase in media [14C]AA. Carbachol (0.3 mM) elevated inositol monophosphate 14-fold. The results suggest that muscarinic agonists stimulate Cl- secretion by interacting with an M3 receptor coupled to inositide lipid hydrolysis. PMID:1379932

  3. Guanine nucleotide-dependent, pertussis toxin-insensitive, stimulation of inositol phosphate formation by carbachol in a membrane preparation from astrocytoma cells

    SciTech Connect

    Hepler, J.R.; Harden, T.K.

    1986-03-05

    Formation of the inositol phosphates (InsP), InsP/sub 3/, InsP/sub 2/, and InsP/sub 1/ was increased in a concentration dependent manner (K/sub 0.5/ approx. 5 ..mu..M) by GTP..sigma..S in washed membranes prepared from /sup 3/H-inositol-prelabelled 1321N1 human astrocytoma cells. Both GTP..gamma..S and GppNHp stimulated InsP formation by 2-3 fold over control; GTP and GDP were much less efficacious and GMP had no effect. Although the muscarinic cholinergic receptor agonist carbachol had no effect in the absence of guanine nucleotide, in the presence of 10 ..mu..M GTP..gamma..S, carbachol stimulated (K/sub 0.5/ approx. 10 ..mu.. M) the formation of InsP above the level achieved with GTP..gamma..S alone. The effect of carbachol was completely blocked by atropine. The order of potency for a series of nucleotides for stimulation of InsP formation in the presence of 500 ..mu..M carbachol was GTP..gamma..S > GppNHp > GTP = GDP. Pertussis toxin, at concentrations that fully ADP-ribosylate and functionally inactivate G/sub i/, had no effect on InsP formation in the presence of GTP..gamma..S or GTP..gamma..S plus carbachol. Histamine and bradykinin also stimulated InsP formation in the presence of GTP..gamma..S in washed membranes from 1321N1 cells. These data are consistent with the idea that a guanine nucleotide regulatory protein that is not G/sub i/ is involved in receptor-mediated stimulation of InsP formation in 1321N1 human astrocytoma cells.

  4. Differences in carbachol dose, pain condition, and sex following lateral hypothalamic stimulation.

    PubMed

    Holden, J E; Wang, E; Moes, J R; Wagner, M; Maduko, A; Jeong, Y

    2014-06-13

    Lateral hypothalamic (LH) stimulation produces antinociception in female rats in acute, nociceptive pain. Whether this effect occurs in neuropathic pain or whether male-female sex differences exist is unknown. We examined the effect of LH stimulation in male and female rats using conditions of nociceptive and neuropathic pain. Neuropathic groups received chronic constriction injury (CCI) to induce thermal hyperalgesia, a sign of neuropathic pain. Nociceptive rats were naive for CCI, but received the same thermal stimulus following LH stimulation. To demonstrate that CCI ligation produced thermal hyperalgesia, males and females received either ligation or sham surgery for control. Both males and females demonstrated significant thermal hyperalgesia following CCI ligation (p<0.05), but male sham surgery rats also showed a significant left-right difference not present in female sham rats. In the second experiment, rats randomly assigned to CCI or nociceptive groups were given one of three doses of the cholinergic agonist carbachol (125, 250, or 500 nmol) or normal saline for control, microinjected into the left LH. Paw withdrawal from a thermal stimulus (paw withdrawal latency; PWL) was measured every 5 min for 45 min. Linear mixed models analysis showed that males and females in both pain conditions demonstrated significant antinociception, with the 500-nmol dose producing the greatest effect across groups compared with controls for the left paw (p<0.05). Female CCI rats showed equivalent responses to the three doses, while male CCI rats showed more variability for dose. However, nociceptive females responded only to the 500-nmol dose, while nociceptive males responded to all doses (p<0.05). For right PWL, only nociceptive males showed a significant carbachol dose response. These findings are suggestive that LH stimulation produces antinociception in male and female rats in both nociceptive and neuropathic pain, but dose response differences exist based on sex and

  5. Heart rate variability during carbachol-induced REM sleep and cataplexy.

    PubMed

    Torterolo, Pablo; Castro-Zaballa, Santiago; Cavelli, Matías; Velasquez, Noelia; Brando, Victoria; Falconi, Atilio; Chase, Michael H; Migliaro, Eduardo R

    2015-09-15

    The nucleus pontis oralis (NPO) exerts an executive control over REM sleep. Cholinergic input to the NPO is critical for REM sleep generation. In the cat, a single microinjection of carbachol (a cholinergic agonist) into the NPO produces either REM sleep (REMc) or wakefulness with muscle atonia (cataplexy, CA). In order to study the central control of the heart rate variability (HRV) during sleep, we conducted polysomnographic and electrocardiogram recordings from chronically prepared cats during REMc, CA as well as during sleep and wakefulness. Subsequently, we performed statistical and spectral analyses of the HRV. The heart rate was greater during CA compared to REMc, NREM or REM sleep. Spectral analysis revealed that the low frequency band (LF) power was significantly higher during REM sleep in comparison to REMc and CA. Furthermore, we found that during CA there was a decrease in coupling between the RR intervals plot (tachogram) and respiratory activity. In contrast, compared to natural behavioral states, during REMc and CA there were no significant differences in the HRV based upon the standard deviation of normal RR intervals (SDNN) and the mean squared difference of successive intervals (rMSSD). In conclusion, there were differences in the HRV during naturally-occurring REM sleep compared to REMc. In addition, in spite of the same muscle atonia, the HRV was different during REMc and CA. Therefore, the neuronal network that controls the HRV during REM sleep can be dissociated from the one that generates the muscle atonia during this state. PMID:25997581

  6. Involvement of inward rectifier and M-type currents in carbachol-induced epileptiform synchronization.

    PubMed

    Cataldi, Mauro; Panuccio, Gabriella; Cavaccini, Anna; D'Antuono, Margherita; Taglialatela, Maurizio; Avoli, Massimo

    2011-03-01

    Exposure to cholinergic agonists is a widely used paradigm to induce epileptogenesis in vivo and synchronous activity in brain slices maintained in vitro. However, the mechanisms underlying these effects remain unclear. Here, we used field potential recordings from the lateral entorhinal cortex in horizontal rat brain slices to explore whether two different K(+) currents regulated by muscarinic receptor activation, the inward rectifier (K(IR)) and the M-type (K(M)) currents, have a role in carbachol (CCh)-induced field activity, a prototypical model of cholinergic-dependent epileptiform synchronization. To establish whether K(IR) or K(M) blockade could replicate CCh effects, we exposed slices to blockers of these currents in the absence of CCh. K(IR) channel blockade with micromolar Ba(2+) concentrations induced interictal-like events with duration and frequency that were lower than those observed with CCh; by contrast, the K(M) blocker linopirdine was ineffective. Pre-treatment with Ba(2+) or linopirdine increased the duration of epileptiform discharges induced by subsequent application of CCh. Baclofen, a GABA(B) receptor agonist that activates K(IR), abolished CCh-induced field oscillations, an effect that was abrogated by the GABA(B) receptor antagonist CGP 55845, and prevented by Ba(2+). Finally, when applied after CCh, the K(M) activators flupirtine and retigabine shifted leftward the cumulative distribution of CCh-induced event duration; this effect was opposite to what seen during linopirdine application under similar experimental conditions. Overall, our findings suggest that K(IR) rather than K(M) plays a major regulatory role in controlling CCh-induced epileptiform synchronization. PMID:21144855

  7. Effects of aerosolized histamine and carbachol in the conscious horse.

    PubMed Central

    Mirbahar, K B; McDonell, W N; Bignell, W; Eyre, P

    1985-01-01

    Pulmonary function tests were performed in seven conscious, standing horses. Changes in pulmonary mechanics and ventilation volumes were measured after inhalation challenge with saline (baseline), histamine (1% w/v solution for 5 min) and carbachol (0.5% w/v solution for 3 min). Comparisons between baseline and posthistamine values revealed a significant (P less than 0.05) increase in nonelastic work of breathing (Wb), maximum change in transpulmonary pressure (max delta Ppl), and pulmonary resistance (RL), while dynamic compliance (Cdyn) decreased (P less than 0.05). Tripelennamine completely abolished these histamine induced changes suggesting the involvement of H1 receptors. A nonsignificant increase occurred in functional residual capacity. However, the amount of nitrogen retained in the lung at the end of a nitrogen washout test was significantly (P less than 0.05) greater after histamine when compared to baseline values. The effect of carbachol was qualitatively similar to that of histamine, Wb and max delta Ppl increased while Cdyn decreased (P less than 0.05). The increase in lower RL reached statistical significance (P less than 0.05) only at the beginning of expiration (/ 25% VT). The present investigation demonstrates that the physiological measurements of lung function could be carried out in conscious, unsedated horses and that the pulmonary function test methods could be used as a tool for study of drug induced changes in pulmonary mechanics. PMID:4016587

  8. MECHANISMS UNDERLYING ALC13 INHIBITION OF AGONIST-STIMULATED INOSITOL PHOSPHATE ACCUMULATION

    EPA Science Inventory

    Possible mechanisms of AlC13-induced inhibition of agonist-stimulated inositol phosphate (IP) accumulation were investigated using rat brain cortex slices, synaptosomes or homogenates. nder conditions in which AlC13 inhibits carbachol (CARB) stimulated IP accumulation (Gp-mediate...

  9. Renshaw cells are inactive during motor inhibition elicited by the pontine microinjection of carbachol.

    PubMed

    Morales, F R; Engelhardt, J K; Pereda, A E; Yamuy, J; Chase, M H

    1988-04-12

    The present study was undertaken to determine whether the postsynaptic inhibition of motoneurons that occurs following the pontine microinjection of carbachol in the decerebrate cat is due to the activity of Renshaw cells. Thirty-two out of 37 Renshaw cells (86%) were spontaneously active prior to the administration of carbachol, whereas only 2 out of 13 Renshaw cells (15%) discharged during carbachol-induced motor inhibition. In addition, discrete inhibitory synaptic potentials were observed in 33% of the Renshaw cells from which intracellular recordings were obtained after carbachol administration, indicating that these cells were actively inhibited. The finding that a population of Renshaw cells, which inhibit motoneurons, were themselves inhibited during a period of profound motoneuron inhibition was quite unexpected. These results support the conclusion that Renshaw cells are not the inhibitory interneurons that are responsible for the powerful inhibition of motoneurons that occurs following the pontine microinjection of carbachol. PMID:3380320

  10. Car Art.

    ERIC Educational Resources Information Center

    Meilach, Dona Z.

    2002-01-01

    Discusses car art and its appeal to boys and girls. Describes the popularity of customizing cars, focusing on this as a future career for students. Includes a list of project ideas that focuses on car art. (CMK)

  11. Modeling carbachol-induced hippocampal network synchronization using hidden Markov models

    NASA Astrophysics Data System (ADS)

    Dragomir, Andrei; Akay, Yasemin M.; Akay, Metin

    2010-10-01

    In this work we studied the neural state transitions undergone by the hippocampal neural network using a hidden Markov model (HMM) framework. We first employed a measure based on the Lempel-Ziv (LZ) estimator to characterize the changes in the hippocampal oscillation patterns in terms of their complexity. These oscillations correspond to different modes of hippocampal network synchronization induced by the cholinergic agonist carbachol in the CA1 region of mice hippocampus. HMMs are then used to model the dynamics of the LZ-derived complexity signals as first-order Markov chains. Consequently, the signals corresponding to our oscillation recordings can be segmented into a sequence of statistically discriminated hidden states. The segmentation is used for detecting transitions in neural synchronization modes in data recorded from wild-type and triple transgenic mice models (3xTG) of Alzheimer's disease (AD). Our data suggest that transition from low-frequency (delta range) continuous oscillation mode into high-frequency (theta range) oscillation, exhibiting repeated burst-type patterns, occurs always through a mode resembling a mixture of the two patterns, continuous with burst. The relatively random patterns of oscillation during this mode may reflect the fact that the neuronal network undergoes re-organization. Further insight into the time durations of these modes (retrieved via the HMM segmentation of the LZ-derived signals) reveals that the mixed mode lasts significantly longer (p < 10-4) in 3xTG AD mice. These findings, coupled with the documented cholinergic neurotransmission deficits in the 3xTG mice model, may be highly relevant for the case of AD.

  12. Effect of morphine and morphine-like drugs on carbachol-induced fighting in cats.

    PubMed

    Krstić, S K; Stefanović-Denić, K; Beleslin, D B

    1982-08-01

    In the present experiments, morphine, methadone or pethidine was injected into the cerebral ventricle of the unanesthetized cat after fighting was induced with carbachol injected previously. The fighting evoked by carbachol was sensitive to the depressant action of morphine or pethidine but not to the depressant effect of methadone. The most likely explanation of the depressant effects of the former compounds is that they act on the postsynaptic receptors of central cholinergic neurons. PMID:6890210

  13. Endothelial-dependent relaxant actions of carbachol and substance P in arterial smooth muscle.

    PubMed

    Bolton, T B; Clapp, L H

    1986-04-01

    In helical strips cut from the small mesenteric artery of guinea-pig (GPSMA) (0.3-0.6 mm o.d.) relaxations induced by substance P were more susceptible to damage of the endothelium by rubbing than were relaxations evoked by carbachol. Relaxations induced by 2-nicotin-amidoethyl nitrate (SG75) were unaffected by this procedure. Relaxations evoked by the calcium ionophore A23187 persisted when those to substance P had been abolished by rubbing the endothelium in GPSMA, rabbit mesenteric and rabbit ear arteries. In guinea-pig pulmonary artery and aorta relaxations to A23187 were lost after this treatment. Carbachol and SG75 were more effective in inhibiting phasic than tonic tension induced by noradrenaline in GPSMA, but substance P was more effective against tonic tension. In the GPSMA, carbachol and substance P inhibited tension produced by noradrenaline to similar extents. However, carbachol was less, and substance P much less effective in inhibiting tension evoked by high-potassium solution than by noradrenaline. Susceptibility of relaxations to blockade by haemoglobin in GPSMA was: substance P greater than carbachol greater than ATP greater than SG75. The membrane potential of smooth muscle cells in the media of the GPSMA was recorded by microelectrode. Carbachol, but not substance P, hyperpolarized the cells both in the presence and absence of noradrenaline at concentrations which relaxed the muscle. These results suggest a heterogeneity in the mechanisms of endothelial-dependent relaxations induced by various vascular relaxants. PMID:2423170

  14. Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms.

    PubMed

    Randáková, Alena; Dolejší, Eva; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; El-Fakahany, Esam E; Jakubík, Jan

    2015-07-01

    We mutated key amino acids of the human variant of the M1 muscarinic receptor that target ligand binding, receptor activation, and receptor-G protein interaction. We compared the effects of these mutations on the action of two atypical M1 functionally preferring agonists (N-desmethylclozapine and xanomeline) and two classical non-selective orthosteric agonists (carbachol and oxotremorine). Mutations of D105 in the orthosteric binding site and mutation of D99 located out of the orthosteric binding site decreased affinity of all tested agonists that was translated as a decrease in potency in accumulation of inositol phosphates and intracellular calcium mobilization. Mutation of D105 decreased the potency of the atypical agonist xanomeline more than that of the classical agonists carbachol and oxotremorine. Mutation of the residues involved in receptor activation (D71) and coupling to G-proteins (R123) completely abolished the functional responses to both classical and atypical agonists. Our data show that both classical and atypical agonists activate hM1 receptors by the same molecular switch that involves D71 in the second transmembrane helix. The principal difference among the studied agonists is rather in the way they interact with D105 in the orthosteric binding site. Furthermore, our data demonstrate a key role of D105 in xanomeline wash-resistant binding and persistent activation of hM1 by wash-resistant xanomeline. PMID:25882246

  15. Changes in electrophysiological properties of cat hypoglossal motoneurons during carbachol-induced motor inhibition.

    PubMed

    Fung, S J; Yamuy, J; Xi, M C; Engelhardt, J K; Morales, F R; Chase, M H

    2000-12-01

    The control of hypoglossal motoneurons during sleep is important from a basic science perspective as well as to understand the bases for pharyngeal occlusion which results in the obstructive sleep apnea syndrome. In the present work, we used intracellular recording techniques to determine changes in membrane properties in adult cats in which atonia was produced by the injection of carbachol into the pontine tegmentum (AS-carbachol). During AS-carbachol, 86% of the recorded hypoglossal motoneurons were found to be postsynaptically inhibited on the basis of analyses of their electrical properties; the electrical properties of the remaining 14% were similar to motoneurons recorded during control conditions. Those cells that exhibited changes in their electrical properties during AS-carbachol also displayed large-amplitude inhibitory synaptic potentials. Following sciatic nerve stimulation, hypoglossal motoneurons which responded with a depolarizing potential during control conditions exhibited a hyperpolarizing potential during AS-carbachol. Both spontaneous and evoked inhibitory potentials recorded during AS-carbachol were comparable to those that have been previously observed in trigeminal and spinal cord motoneurons under similar experimental conditions as well as during naturally occurring active sleep. Calculations based on modeling the changes that we found in input resistance and membrane time constant with a three-compartment neuron model suggest that shunts are present in all three compartments of the hypoglossal motoneuron model. Taken together, these data indicate that postsynaptic inhibitory drives are widely distributed on the soma-dendritic tree of hypoglossal motoneurons during AS-carbachol. These postsynaptic inhibitory actions are likely to be involved in the pathophysiology of obstructive sleep apnea. PMID:11102580

  16. Phosphoinositides metabolism in primary culture of dog thyroid cells: Effects of thyrotropin and carbachol

    SciTech Connect

    Taguchi, M.; Field, J.B. )

    1990-04-01

    Thyrotropin (TSH) and carbachol stimulated in a dose-dependent manner the accumulation of 3H-glycerophosphoinositol (GPI), 3H-inositol monophosphate (IP1), 3H-inositol bisphosphate (IP2) and 3H-inositol trisphosphate (IP3) in primary cultures of dog thyroid cells prelabeled with myo-(2-3H)inositol. TSH, 250 mU/mL, stimulated 3H-IP3 level after a 10-minute incubation while 10 mU/mL TSH increased it during a 60-minute incubation. The effect of carbachol was more rapid and greater than that of TSH. Carbachol, 100 mumol/L, elevated 3H-IP3 after a 2-minute incubation and 3H-IP3 formation was increased by as little as 1 mumol/L carbachol. TSH stimulation was observed only if the cells were deprived of TSH for 5 days before being labeled with 3H-inositol. Prolongation of the labeling period or addition of TSH, (Bu)2cAMP or carbachol during the labeling increased 3H-inositol incorporation into polyphoinositides (PIPs). When the cells were labeled without any other addition, control and TSH-stimulated 3H-IP3 levels increased in parallel with 3H-PIP levels. However, TSH or carbachol-stimulated 3H-IP3 levels did not increase in proportion to 3H-PIPs level when the cells were labeled with TSH or (Bu)2cAMP. Thus, the ratio of 3H-IP3/3H-PIPs (both control and TSH or carbachol-stimulated) decreased in the cells labeled with TSH or (Bu)2cAMP, which might reflect TSH stimulation of 3H-inositol incorporation into PIPs pool(s) that do not participate in hormone-induced hydrolysis of PIPs.

  17. Voltage dependence of agonist effectiveness at the frog neuromuscular junction: resolution of a paradox.

    PubMed Central

    Dionne, V E; Stevens, C F

    1975-01-01

    1. End-plate currents produced by nerve-released acetylcholine and iontophoretically applied acetylcholine and carbachol have been recorded from voltage-clamped frog cutaneous pectoris neuromuscular junctions made visible with Nomarski differential interference contrast optics. 2. The effectiveness of agonists - that is, the end-plate conductance change produced by a given dose-has been determined as a function of post-junctional membrane potential. 3. As the post-junctional membrane potential is made more negative, nerve-released acetylcholine becomes less effective whereas iontophoretically-applied agonists become more effective. 4. This voltage dependence of agonist effectiveness is mediated neither by end-plate current iontophoresis of agonist into the cleft nor through electric field effects on the esterase. 5. Influences of membrane potential on the opening and closing of end-plate channel gates can account quantitatively for the voltage-dependent effectiveness of both nerve-released and iontophoretically applied agonist. PMID:1081139

  18. Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons.

    PubMed Central

    Kelly, J F; Furukawa, K; Barger, S W; Rengen, M R; Mark, R J; Blanc, E M; Roth, G S; Mattson, M P

    1996-01-01

    Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C, resulting in the liberation of inositol trisphosphate and Ca2+ release from intracellular stores. We now report that amyloid beta-peptide (Abeta), which forms plaques in the brain in AD, impairs muscarinic receptor activation of G proteins in cultured rat cortical neurons. Exposure of rodent fetal cortical neurons to Abeta25-35 and Abeta1-40 resulted in a concentration and time-dependent attenuation of carbachol-induced GTPase activity without affecting muscarinic receptor ligand binding parameters. Downstream events in the signal transduction cascade were similarly attenuated by Abeta. Carbachol-induced accumulation of inositol phosphates (IP, IP2, IP3, and IP4) was decreased and calcium imaging studies revealed that carbachol-induced release of calcium was severely impaired in neurons pretreated with Abeta. Muscarinic cholinergic signal transduction was disrupted with subtoxic levels of exposure to AP. The effects of Abeta on carbachol-induced GTPase activity and calcium release were attenuated by antioxidants, implicating free radicals in the mechanism whereby Abeta induced uncoupling of muscarinic receptors. These data demonstrate that Abeta disrupts muscarinic receptor coupling to G proteins that mediate induction of phosphoinositide accumulation and calcium release, findings that implicate Abeta in the impairment of cholinergic transmission that occurs in AD. PMID:8692890

  19. Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons.

    PubMed

    Kelly, J F; Furukawa, K; Barger, S W; Rengen, M R; Mark, R J; Blanc, E M; Roth, G S; Mattson, M P

    1996-06-25

    Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C, resulting in the liberation of inositol trisphosphate and Ca2+ release from intracellular stores. We now report that amyloid beta-peptide (Abeta), which forms plaques in the brain in AD, impairs muscarinic receptor activation of G proteins in cultured rat cortical neurons. Exposure of rodent fetal cortical neurons to Abeta25-35 and Abeta1-40 resulted in a concentration and time-dependent attenuation of carbachol-induced GTPase activity without affecting muscarinic receptor ligand binding parameters. Downstream events in the signal transduction cascade were similarly attenuated by Abeta. Carbachol-induced accumulation of inositol phosphates (IP, IP2, IP3, and IP4) was decreased and calcium imaging studies revealed that carbachol-induced release of calcium was severely impaired in neurons pretreated with Abeta. Muscarinic cholinergic signal transduction was disrupted with subtoxic levels of exposure to AP. The effects of Abeta on carbachol-induced GTPase activity and calcium release were attenuated by antioxidants, implicating free radicals in the mechanism whereby Abeta induced uncoupling of muscarinic receptors. These data demonstrate that Abeta disrupts muscarinic receptor coupling to G proteins that mediate induction of phosphoinositide accumulation and calcium release, findings that implicate Abeta in the impairment of cholinergic transmission that occurs in AD. PMID:8692890

  20. Interaction of IFN-γ with Cholinergic Agonists to Modulate Rat and Human Goblet Cell Function

    PubMed Central

    García-Posadas, L; Hodges, RR; Li, D; Shatos, MA; Storr-Paulsen, T; Diebold, Y; Dartt, DA

    2015-01-01

    Goblet cells populate wet-surfaced mucosa including the conjunctiva of the eye, intestine, and nose, among others. These cells function as part of the innate immune system by secreting high molecular weight mucins that interact with environmental constituents including pathogens, allergens, and particulate pollutants. Herein we determined whether IFN-γ, a Th1 cytokine increased in dry eye, alters goblet cell function. Goblet cells from rat and human conjunctiva were cultured. Changes in intracellular [Ca2+] ([Ca2+]i), high molecular weight glycoconjugate secretion, and proliferation were measured after stimulation with IFN-γ with or without the cholinergic agonist carbachol. IFN-γ itself increased [Ca2+]i in rat and human goblet cells and prevented the increase in [Ca2+]i caused by carbachol. Carbachol prevented IFN-γ-mediated increase in [Ca2+]i. This cross-talk between IFN-γ and muscarinic receptors may be partially due to use of the same Ca2+i reservoirs, but also from interaction of signaling pathways proximal to the increase in [Ca2+]i. IFN-γ blocked carbachol-induced high molecular weight glycoconjugate secretion and reduced goblet cell proliferation. We conclude that increased levels of IFN-γ in dry eye disease could explain the lack of goblet cells and mucin deficiency typically found in this pathology. IFN-γ could also function similarly in respiratory and gastrointestinal tracts. PMID:26129651

  1. From synapse to gene product: Prolonged expression of c-fos induced by a single microinjection of carbachol in the pontomesencephalic tegmentum

    PubMed Central

    Quattrochi, James J.; Bazalakova, Mihaela; Hobson, J. Allan

    2006-01-01

    It is not known how the brain modifies its regulatory systems in response to the application of a drug, especially over the long term of weeks and months. We have developed a model system approach to this question by manipulating cholinergic cell groups of the laterodorsal and pedunculopontine tegmental (LDT/PPT) nuclei in the pontomesencephalic tegmentum (PMT), which are known to be actively involved in the timing and quantity of rapid eye movement (REM) sleep. In a freely moving feline model, a single microinjection of the cholinergic agonist carbachol conjugated to a latex nanosphere delivery system into the caudolateral PMT elicits a long-term enhancement of one distinguishing phasic event of REM sleep, ponto-geniculo-occipital (PGO) waves, lasting 5 days but without any significant change in REM sleep or other behavioral state. Here, we test the hypothesis that cholinergic activation within the caudolateral PMT alters the postsynaptic excitability of the PGO network, stimulating the prolonged expression of c-fos that underlies this long-term PGO enhancement (LTPE) effect. Using quantitative Fos immunohistochemistry, we found that the number of Fos-immunoreactive (Fos-IR) neurons surrounding the caudolateral PMT injection site decreased sharply by postcarbachol day 03, while the number of Fos-IR neurons in the more rostral LDT/PPT increased >30-fold and remained at a high level following the course of LTPE. These results demonstrate a sustained c-fos expression in response to pharmacological stimulation of the brain and suggest that carbachol's acute effects induce LTPE via cholinergic receptors, with subsequent transsynaptic activation of the LDT/PPT maintaining the LTPE effect. PMID:15893601

  2. Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats

    PubMed Central

    Lu, Jackie W; Fenik, Victor B; Branconi, Jennifer L; Mann, Graziella L; Rukhadze, Irma; Kubin, Leszek

    2007-01-01

    Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABAA receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABAA receptor antagonist, bicuculline (20 nl, 1 mm), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABAA receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABAA receptor-expressing PF neurones may cause narcolepsy/cataplexy. PMID:17495048

  3. Flying Cars

    NASA Technical Reports Server (NTRS)

    Crow, Steven

    1996-01-01

    Flying cars have nearly mythical appeal to nonpilots, a group that includes almost the whole human race. The appeal resides in the perceived utility of flying cars, vehicles that offer portal-to-portal transportation, yet break the bonds of road and traffic and travel freely through the sky at the drivers will. Part of the appeal is an assumption that flying cars can be as easy to fly as to drive. Flying cars have been part of the dream of aviation since the dawn of powered flight. Glenn Curtiss built, displayed, and maybe even flew a flying car in 1917, the Curtiss Autoplane. Many roadable airplanes were built in the 1930's, like the Waterman Arrowbile and the Fulton Airphibian. Two flying cars came close to production in the early 1950's. Ted Hall built a series of flying cars culminating in the Convaircar, sponsored by Consolidated Vultee, General Motors, and Hertz. Molt Taylor built and certified his Aerocar, and Ford came close to producing them. Three Aerocars are still flyable, two in museums in Seattle and Oshkosh, and the third owned and flown by Ed Sweeny. Flying cars do have problems, which so far have prevented commercial success. An obvious problem is complexity of the vehicle, the infrastructure, or both. Another is the difficulty of matching low power for normal driving with high power in flight. An automobile uses only about 20 hp at traffic speeds, while a personal airplane needs about 160 hp at speeds typical of flight. Many automobile engines can deliver 160 hp, but not for very long. A more subtle issue involves the drag of automobiles and airplanes. A good personal airplane can fly 30 miles per gallon of fuel at 200 mph. A good sports car would need 660 hp at the same speed and would travel only 3 miles per gallon. The difference is drag area, about 4.5 sq ft for the automobile and 1.4 sq ft for the airplane. A flying car better have the drag area of the airplane, not the car!

  4. Effects of nitric acid on carbachol reactivity of the airways in normal and allergic sheep

    SciTech Connect

    Abraham, W.M.; Kim, C.S.; King, M.M.; Oliver, W. Jr.; Yerger, L.

    1982-01-01

    The airway effects of a 4-hr exposure (via a Plexiglas hood) to 1.6 ppm nitric acid vapor were evaluated in seven normal and seven allergic sheep, i.e., animals that have a history of reacting with bronchospasm to inhalation challenge with Ascaris suum antigen. The nitric acid vapor was generated by ultrasonic nebulization of a 2% nitric acid solution. Airway effects were assessed by measuring the change in specific pulmonary flow resistance before and after a standard inhalation challenge with 2.5% carbachol aerosol. Nitric acid exposure did not produce bronchoconstriction in either group. Pre-exposure increases in specific pulmonary flow resistance after carbachol inhalation were 68% (SD+/- 13%) and 82% (SD+/- 35%) for the normal and allergic sheep, respectively. Within 24 hr, the largest post-exposure increases in specific pulmonary flow resistance for the normal and allergic sheep were 108% (SD+/- 51%(P<.06)) and 175% (SD+/- 87% (p<.02)), respectively. We conclude that a short-term exposure to nitric acid vapor at levels below the industrial threshold limit (2 ppm), produces airway hyperreactivity to aerosolized carbachol in allergic sheep.

  5. Antinociception and behavioral changes induced by carbachol microinjected into identified sites of the rat brain.

    PubMed

    Klamt, J G; Prado, W A

    1991-05-17

    The sites of the rat brain in which intracerebral administration of carbachol (0.4 microgram/0.5 microliter) elevates the nociceptive threshold to thermic (tail-flick test) and mechanical (calibrated-pinch test) noxious stimuli were examined. An extensive mapping (510 sites) ranging from AP + 10.5 to AP-0.1 mm revealed that antinociception was obtained from 119 sites (23%) widely scattered in the brain, and reached structures distant from, or within the immediate vicinity of the ventricular system. The effects from most placement were demonstrated using the tail-flick test, whereas a smaller proportion (approximately 13%) of sites was effective in reducing the response to mechanical stimuli only. Structures containing sensitive sites include the dorsal raphe nucleus, lateral border of the superior cerebellar peduncle, caudal portion of the superior colliculus, medial geniculate body, habenular complex, amygdala, temporal pole of the ventral hippocampus, rostral aspect of the dorsal hippocampus, lateral septal area, and triangular nucleus of the septum. Analysis of the distribution of responsive sites indicated that they are poorly superposed to the known distribution of opiate-sensitive areas. Most of the structures found to be responsive to carbachol are also known to possess cholinergic receptors and to evoke antinociception following focal electrical stimulation. In various placements, particularly in limbic structures, microinjection of carbachol evoked jumping to mechanical noxious stimulation, hyperexcitability to non-noxious stimuli, convulsive reactions, and other less frequent reactions. On few occasions, however, these changes were accompanied by antinociception. PMID:1893255

  6. Basolateral K channel activated by carbachol in the epithelial cell line T84.

    PubMed

    Tabcharani, J A; Harris, R A; Boucher, A; Eng, J W; Hanrahan, J W

    1994-11-01

    Cholinergic stimulation of chloride secretion involves the activation of a basolateral membrane potassium conductance, which maintains the electrical gradient favoring apical Cl efflux and allows K to recycle at the basolateral membrane. We have used transepithelial short-circuit current (Isc), fluorescence imaging, and patch clamp studies to identify and characterize the K channel that mediates this response in T84 cells. Carbachol had little effect on Isc when added alone but produced large, transient currents if added to monolayers prestimulated with cAMP. cAMP also enhanced the subsequent Isc response to calcium ionophores. Carbachol (100 microM) transiently elevated intracellular free calcium ([Ca2+]i) by approximately 3-fold in confluent cells cultured on glass coverslips with a time course resembling the Isc response of confluent monolayers that had been grown on porous supports. In parallel patch clamp experiments, carbachol activated an inwardly rectifying potassium channel on the basolateral aspect of polarized monolayers which had been dissected from porous culture supports. The same channel was transiently activated on the surface of subconfluent monolayers during stimulation by carbachol. Activation was more prolonged when cells were exposed to calcium ionophores. The conductance of the inward rectifier in cell-attached patches was 55 pS near the resting membrane potential (-54 mV) with pipette solution containing 150 mM KCl (37 degrees C). This rectification persisted when patches were bathed in symmetrical 150 mM KCl solutions. The selectivity sequence was 1 K > 0.88 Rb > 0.18 Na > Cs based on permeability ratios under bi-ionic conditions. The channel exhibited fast block by external sodium ions, was weakly inhibited by external TEA, was relatively insensitive to charybdotoxin, kaliotoxin, 4-aminopyridine and quinidine, and was unaffected by external 10 mM barium. It is referred to as the KBIC channel based on its most distinctive properties (Ba

  7. Car sick.

    PubMed

    Renner, M G

    1988-01-01

    The automobile is currently seen as the most desirable mode of transportation. However, this view needs to be changed since the proliferation of the automobile worldwide is leading to the poisoning of the environment and people. In the US the number of passenger cars grew 51% between 1971-86 and in the noncommunist industrialized community that figure is 71%. The gasoline and diesel fuel used to power the overwhelming majority of cars creates a variety of problems. The pollution is estimated to have a hidden cost of US $.80/gallon. Others estimate that the pollution causes 30,000 premature deaths annually just in the US. 75% of the carbon monoxide (CO), 48% of nitrogen oxides (NO2), 13% of particulates (P), and 3% of sulfur (S) emissions come from cars in the countries of the Organization for Economic Cooperation and Development (OECD), which includes the US, Canada, Western Europe, Japan, Australia, and New Zealand. 17% of all worldwide carbon dioxide (CO2) emission comes from the production and use of fossil fuels for cars. The single biggest problem associated with cars is the photochemical smog they create in urban areas. In 1986 75 million Americans lived in areas that failed to meet national air quality standards for CO, P, and ozone (03). The only area of major improvement has been the removal of lead from gasoline. It was known to cause problems from the beginning of its use in the 1920s, but remained for 50 years because of auto and oil company pressure. Ground 03 is estimated by the US government to cost US $4 billion in annual losses, just for corn, wheat, soybeans, and peanuts. Acid rain is the other major problem associated with cars, and its damage is estimated at US $5 billion annually. Both these problems are shortterm, their effects occur immediately; the longterm disadvantage is the build up of CO2 and its contribution to the greenhouse effect. While the US is at the forefront of regulation and many other countries are modeling their emission

  8. Mechanism of carbachol-evoked contractions of guinea-pig ileal smooth muscle close to freezing point.

    PubMed

    Blackwood, A M; Bolton, T B

    1993-08-01

    1. The effect of lowering the temperature to near freezing-point upon the contractions and [3H]-inositol phosphate responses to carbachol were investigated in longitudinal smooth muscle from the guinea-pig ileum. 2. The peak amplitude of the contraction to a single application of 100 microM carbachol was the same at 37 degrees C and temperatures near freezing-point. However, the sensitivity to carbachol was reduced upon lowering the temperature and the time to peak contraction was increased from 5-10 s to 2-10 min. Even when the temperature was maintained near freezing-point, washing off carbachol produced a relaxation and eventual return of tension to basal levels. 3. Incubating the tissue in 140 mM K+, calcium-free solution or in calcium channel antagonists significantly reduced the carbachol-induced contraction to 10-30% of the control at 37 degrees C and also at 3 degrees C. Thus the majority of the activator calcium required for contraction entered the tissue via voltage-dependent calcium channels (VDCs) at both 37 degrees C and 3 degrees C. 4. The contractions produced by high potassium solutions were less at temperatures close to freezing-point than those at 37 degrees C suggesting that voltage-dependent calcium entry was inhibited as the temperature was lowered. 5. A small part of the contractile response to 100 microM carbachol was resistant to the removal of extracellular calcium at both 37 degrees C and 3 degrees C and this component was increased under depolarizing conditions. This suggests that the release of stored calcium contributes to a minor degree to contraction at both 37 degrees C and 3 degrees C.6. Although 100 microM carbachol produced a statistically significant rise in several [3H]-inositol phosphate isomers at both 37 degrees C and 3 degrees C, the production of [3H]-inositol phosphates was less at 3 degrees C than at 37 degrees C and the increase in their production caused by carbachol was much slower.7. These results suggest that the

  9. Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors.

    PubMed

    Jakubík, J; Bacáková, L; El-Fakahany, E E; Tucek, S

    1997-07-01

    It is well known that allosteric modulators of muscarinic acetylcholine receptors can both diminish and increase the affinity of receptors for their antagonists. We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Allosterically induced changes in the affinities for agonists were computed from changes in the ability of a fixed concentration of each agonist to compete with [3H]N-methylscopolamine for the binding to the receptors in the absence and the presence of varying concentrations of allosteric modulators. The effects of allosteric modulators varied greatly depending on the agonists and the subtypes of receptors. The affinity for acetylcholine was augmented by (-)-eburnamonine on the M2 and M4 receptors and by brucine on the M1 and M3 receptors. Brucine also enhanced the affinities for carbachol, bethanechol, furmethide, methylfurmethide, pilocarpine, 3-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1- methylpyridine (pentylthio-TZTP), oxotremorine-M, and McN-A-343 on the M1, M3, and M4 receptors, for pentylthio-TZTP on the M2 receptors, and for arecoline on the M3 receptors. (-)-Eburnamonine enhanced the affinities for carbachol, bethanechol, furmethide, methylfurmethide, pentylthio-TZTP, pilocarpine, oxotremorine and oxotremorine-M on the M2 receptors and for pilocarpine on the M4 receptors. Vincamine, strychnine, and alcuronium displayed fewer positive allosteric interactions with the agonists, but each allosteric modulator displayed positive cooperativity with at least one agonist on at least one muscarinic receptor subtype. The highest degrees of positive cooperativity were observed between (-)-eburnamonine and pilocarpine and (-)-eburnamonine and oxotremorine-M on the M2 receptors (25- and 7-fold increases in

  10. C-fos expression in the pons and medulla of the cat during carbachol-induced active sleep.

    PubMed

    Yamuy, J; Mancillas, J R; Morales, F R; Chase, M H

    1993-06-01

    Microinjection of carbachol into the rostral pontine tegmentum of the cat induces a state that is comparable to naturally occurring active (REM, rapid eye movement) sleep. We sought to determine, during this pharmacologically induced behavioral state, which we refer to as active sleep-carbachol, the distribution of activated neuron within the pons and medulla using c-fos immunocytochemistry as a functional marker. Compared with control cats, which were injected with saline, active sleep-carbachol cats exhibited higher numbers of c-fos-expressing neurons in (1) the medial and portions of the lateral reticular formation of the pons and medulla, (2) nuclei in the dorsolateral rostral pons, (3) various raphe nuclei, including the dorsal, central superior, magnus, pallidus, and obscurus, (4) the medial and lateral vestibular, prepositus hypoglossi, and intercalatus nuclei, and (5) the abducens nuclei. On the other hand, the mean number of c-fos-expressing neurons found in the masseter, facial, and hypoglossal nuclei was lower in carbachol-injected than in control cats. The data indicate that c-fos expression can be employed as a marker of state-dependent neuronal activity. The specific sites in which there were greater numbers of c-fos-expressing neurons during active sleep-carbachol are discussed in relation to the state of active sleep, as well as the functional role that these sites play in generating the various physiological patterns of activity that occur during this state. PMID:8501533

  11. Voltage-current relationship of a carbachol-induced potassium-ion pathway in Aplysia neurones.

    PubMed Central

    Ginsborg, B L; Kado, R T

    1975-01-01

    1. The electrical characteristics of a potassium ion selective pathway produced by the action of carbachol on Aplysia neurones (Kehoe, 1972b) has been studied. 2. The relationship between current and voltage has been found to be non-linear, the conductance increasing with depolarization and decreasing with hyperpolarization. The degree of rectification was reduced when the external potassium was raised to 50 mM from its normal value of 10 mM. 3. The direction of the rectification and the effect of increased potassium are as predicted by the 'constant field' theory, but the degree of rectification is somewhat larger. PMID:1142225

  12. Nitric oxide donor beta2-agonists: furoxan derivatives containing the fenoterol moiety and related furazans.

    PubMed

    Buonsanti, M Federica; Bertinaria, Massimo; Stilo, Antonella Di; Cena, Clara; Fruttero, Roberta; Gasco, Alberto

    2007-10-01

    The structure of fenoterol, a beta2-adrenoceptor agonist used in therapy, has been joined with furoxan NO-donor moieties to give new NO-donor beta2-agonists. The furazan analogues, devoid of the property to release NO, were also synthesized for comparison. All the compounds retained beta2-agonistic activity at micromolar or submicromolar concentration when tested on guinea pig tracheal rings precontracted with carbachol. Among the furoxan derivatives, the NO contribution to trachea relaxation was evident with product 15b at micromolar concentrations. All the new NO-donor hybrids were able to dilate rat aortic strips precontracted with phenylephrine. Both furoxan and furazan derivatives displayed antioxidant activity greater than that of fenoterol. PMID:17845020

  13. Hydrogen sulphide inhibits carbachol-induced contractile responses in β-escin permeabilized guinea-pig taenia caecum.

    PubMed

    Denizalti, Merve; Durlu-Kandilci, N Tugba; Bozkurt, T Emrah; Sahin-Erdemli, Inci

    2011-05-11

    Hydrogen sulphide (H(2)S) is an endogenous mediator producing a potent relaxation response in vascular and non-vascular smooth muscles. While ATP-sensitive potassium channels are mainly involved in this relaxant effect in vascular smooth muscle, the mechanism in other smooth muscles has not been revealed yet. In the present study, we investigated how H(2)S relaxes non-vascular smooth muscle by using intact and β-escin permeabilized guinea-pig taenia caecum. In intact tissues, concentration-dependent relaxation response to H(2)S donor NaHS in carbachol-precontracted preparations did not change in the presence of a K(ATP) channel blocker glibenclamide, adenylate cyclase inhibitor SQ-22536, guanylate cyclase inhibitor ODQ, protein kinase A inhibitor KT-5720, protein kinase C inhibitor H-7, tetrodotoxin, apamin/charybdotoxin, NOS inhibitor L-NAME and cyclooxygenase inhibitor indomethacin. We then studied how H(2)S affected carbachol- or Ca(2+)-induced contractions in permeabilized tissues. When Ca(2+) was clamped to a constant value (pCa6), a further contraction could be elicited by carbachol that was decreased by NaHS. This decrease in contraction was reversed by catalase but not by superoxide dismutase or N-acetyl cysteine. The sarcoplasmic reticulum Ca(2+)-ATPase pump inhibitor, cyclopiazonic acid, also decreased the carbachol-induced contraction that was further inhibited by NaHS. Mitochondrial proton pump inhibitor carbonyl cyanide p-trifluromethoxyphenylhydrazone also decreased the carbachol-induced contraction but this was not additionally changed by NaHS. The carbachol-induced Ca(2+) sensitization, calcium concentration-response curves, IP(3)- and caffeine-induced contractions were not affected by NaHS. In conclusion, we propose that hydrogen peroxide and mitochondria may have a role in H(2)S-induced relaxation response in taenia caecum. PMID:21371473

  14. Mechanism of carbachol-evoked contractions of guinea-pig ileal smooth muscle close to freezing point.

    PubMed Central

    Blackwood, A. M.; Bolton, T. B.

    1993-01-01

    1. The effect of lowering the temperature to near freezing-point upon the contractions and [3H]-inositol phosphate responses to carbachol were investigated in longitudinal smooth muscle from the guinea-pig ileum. 2. The peak amplitude of the contraction to a single application of 100 microM carbachol was the same at 37 degrees C and temperatures near freezing-point. However, the sensitivity to carbachol was reduced upon lowering the temperature and the time to peak contraction was increased from 5-10 s to 2-10 min. Even when the temperature was maintained near freezing-point, washing off carbachol produced a relaxation and eventual return of tension to basal levels. 3. Incubating the tissue in 140 mM K+, calcium-free solution or in calcium channel antagonists significantly reduced the carbachol-induced contraction to 10-30% of the control at 37 degrees C and also at 3 degrees C. Thus the majority of the activator calcium required for contraction entered the tissue via voltage-dependent calcium channels (VDCs) at both 37 degrees C and 3 degrees C. 4. The contractions produced by high potassium solutions were less at temperatures close to freezing-point than those at 37 degrees C suggesting that voltage-dependent calcium entry was inhibited as the temperature was lowered. 5. A small part of the contractile response to 100 microM carbachol was resistant to the removal of extracellular calcium at both 37 degrees C and 3 degrees C and this component was increased under depolarizing conditions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8401915

  15. In vitro effect of nicorandil on the carbachol-induced contraction of the lower esophageal sphincter of the rat.

    PubMed

    Shimbo, Tomonori; Adachi, Takeshi; Fujisawa, Susumu; Hongoh, Mai; Ohba, Takayoshi; Ono, Kyoichi

    2016-08-01

    The lower esophageal sphincter (LES) is a specialized region of the esophageal smooth muscle that allows the passage of a swallowed bolus into the stomach. Nitric oxide (NO) plays a major role in LES relaxation. Nicorandil possesses dual properties of a NO donor and an ATP-sensitive potassium channel (KATP channel) agonist, and is expected to reduce LES tone. This study investigated the mechanisms underlying the effects of nicorandil on the LES. Rat LES tissues were placed in an organ bath, and activities were recorded using an isometric force transducer. Carbachol-induced LES contraction was significantly inhibited by KATP channel agonists in a concentration-dependent manner; pinacidil > nicorandil ≈ diazoxide. Nicorandil-induced relaxation of the LES was prevented by pretreatment with glibenclamide, whereas N(G)-nitro-l-arginine methyl ester (l-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and iberiotoxin were ineffective at preventing nicorandil-induced LES relaxation. Furthermore, nicorandil did not affect high K(+)-induced LES contraction. Reverse-transcription polymerase chain reaction analysis and immunohistochemistry revealed expression of KCNJ8 (Kir6.1), KCNJ11 (Kir6.2), ABCC8 (SUR1) and ABCC9 (SUR2) subunits of the KATP channel in the rat lower esophagus. These findings indicate that nicorandil causes LES relaxation chiefly by activating the KATP channel, and that it may provide an additional pharmacological tool for the treatment of spastic esophageal motility disorders. PMID:27562702

  16. Nigramide J is a novel potent inverse agonist of the human constitutive androstane receptor.

    PubMed

    Kanno, Yuichiro; Tanuma, Nobuaki; Yatsu, Tomofumi; Li, Wei; Koike, Kazuo; Inouye, Yoshio

    2014-02-01

    The constitutive androstane receptor (CAR, NR1I3) is very important for drug development and for understanding pharmacokinetic drug-drug interactions. We screened by mammalian one hybrid assay among natural compounds to discover novel ligands of human constitutive androstane receptor (hCAR). hCAR transcriptional activity was measured by luciferase assay and mRNA levels of CYP2B6 and CYP3A4 in HepTR-hCAR cells and human primary hepatocytes were measured by real-time RT-PCR. Nigramide J (NJ) whose efficacy is comparable to those of hitherto known inverse agonists such as clotrimazole, PK11195, and ethinylestradiol. NJ is a naturally occurring cyclohexane-type amide alkaloid that was isolated from the roots of Piper nigrum. The suppressive effect of NJ on the CAR-dependent transcriptional activity was found to be species specific, in the descending order of hCAR, rat CAR, and mouse CAR. The unliganded hCAR-dependent transactivation of reporter and endogenous genes was suppressed by NJ at concentrations higher than 5 μmol/L. The ligand-binding cavity of hCAR was shared by NJ and CITCO, because they were competitive in the binding to hCAR. NJ interfered with the interaction of hCAR with coactivator SRC-1, but not with its interaction with the corepressor NCoR1. Furthermore, NJ is agonist of human pregnane X receptor (hPXR). NJ is a dual ligand of hCAR and hPXR, being an agonist of hPXR and an inverse agonist of hCAR. PMID:25505573

  17. GABAergic neurons of the cat dorsal raphe nucleus express c-fos during carbachol-induced active sleep.

    PubMed

    Torterolo, P; Yamuy, J; Sampogna, S; Morales, F R; Chase, M H

    2000-11-24

    Serotonergic neurons of the dorsal raphe nucleus (DRN) cease firing during active sleep (AS, also called rapid-eye-movement sleep). This cessation of electrical activity is believed to play a 'permissive' role in the generation of AS. In the present study we explored the possibility that GABAergic cells in the DRN are involved in the suppression of serotonergic activity during AS. Accordingly, we examined whether immunocytochemically identified GABAergic neurons in the DRN were activated, as indicated by their expression of c-fos, during carbachol-induced AS (AS-carbachol). Three chronically-prepared cats were euthanized after prolonged episodes of AS that was induced by microinjections of carbachol into the nucleus pontis oralis. Another four cats (controls) were maintained 2 h in quiet wakefulness before being euthanized. Thereafter, immunocytochemical studies were performed on brainstem sections utilizing antibodies against Fos, GABA and serotonin. When compared with identically prepared tissue from awake cats, the number of Fos+ neurons was larger in the DRN during AS-carbachol (35.9+/-5.6 vs. 13.9+/-4.4, P<0.05). Furthermore, a larger number of GABA+ Fos+ neurons were observed during AS-carbachol than during wakefulness (24.8+/-3.3 vs. 4.0+/-1.0, P<0.001). These GABA+ Fos+ neurons were distributed asymmetrically with a larger number located ipsilaterally to the site of injection. There was no significant difference between control and experimental animals in the number of non-GABAergic neurons that expressed c-fos in the DRN. We therefore suggest that activated GABAergic neurons of the DRN are responsible for the inhibition of serotonergic neurons that occurs during natural AS. PMID:11082488

  18. Population synaptic potentials evoked in lumbar motoneurons following stimulation of the nucleus reticularis gigantocellularis during carbachol-induced atonia.

    PubMed

    Yamuy, J; Jiménez, I; Morales, F; Rudomin, P; Chase, M

    1994-03-14

    The effect of electrical stimulation of the medullary nucleus reticularis gigantocellularis (NRGc) on lumbar spinal cord motoneurons was studied in the decerebrate cat using sucrose-gap recordings from ventral roots. The NRGc was stimulated ipsi- and contralaterally before and during atonia elicited by the microinjection of carbachol into the pontine reticular formation. Prior to carbachol administration, the NRGc-induced response recorded from the sucrose-gap consisted of two consecutive excitatory population synaptic potentials followed by a long-lasting, small amplitude inhibitory population synaptic potential. Following carbachol injection, the same NRGc stimulus evoked a distinct, large amplitude inhibitory population synaptic potential, whereas the excitatory population synaptic potentials decreased in amplitude. In addition, after carbachol administration, the amplitude of the monosynaptic excitatory population synaptic potential, which was evoked by stimulation of group Ia afferents in hindlimb nerves, was reduced by 18 to 43%. When evoked at the peak of the NRGc-induced inhibitory response, this potential was further decreased in amplitude. Systemic strychnine administration (0.07-0.1 mg/kg, i.v.) blocked the NRGc-induced inhibitory population synaptic potential and promoted an increase in the amplitude of the excitatory population synaptic potentials induced by stimulation of the NRGc and group Ia afferents. These data indicate that during the state of carbachol-induced atonia, the NRGc effects on ipsi- and contralateral spinal cord motoneurons are predominantly inhibitory and that glycine is likely to be involved in this inhibitory process. These results support the hypothesis that the nucleus reticularis gigantocellularis is part of the system responsible for state-dependent somatomotor inhibition that occurs during active sleep. PMID:8205484

  19. Carbachol induces a rapid and sustained hydrolysis of polyphosphoinositide in bovine tracheal smooth muscle measurements of the mass of polyphosphoinositides, 1,2-diacylglycerol, and phosphatidic acid

    SciTech Connect

    Takuwa, Y.; Takuwa, N.; Rasmussen, H.

    1986-11-05

    The effects of carbachol on polyphosphoinositides and 1,2-diacylglycerol metabolism were investigated in bovine tracheal smooth muscle by measuring both lipid mass and the turnover of (/sup 3/H)inositol-labeled phosphoinositides. Carbachol induces a rapid reduction in the mass of phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-monophosphate and a rapid increase in the mass of 1,2-diacylglycerol and phosphatidic acid. These changes in lipid mass are sustained for at least 60 min. The level of phosphatidylinositol shows a delayed and progressive decrease during a 60-min period of carbachol stimulation. The addition of atropine reverses these responses completely. Carbachol stimulates a rapid loss in (/sup 3/H)inositol radioactivity from phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-monophosphate associated with production of (/sup 3/H)inositol trisphosphate. The carbachol-induced change in the mass of phosphoinositides and phosphatidic acid is not affected by removal of extracellular Ca/sup 2 +/ and does not appear to be secondary to an increase in intracellular Ca/sup 2 +/. These results indicate that carbachol causes phospholipase C-mediated polyphosphoinositide breakdown, resulting in the production of inositol trisphosphate and a sustained increase in the actual content of 1,2-diacylglycerol. These results strongly suggest that carbachol-induced contraction is mediated by the hydrolysis of polyphosphoinositides with the resulting generation of two messengers: inositol 1,4,5-trisphosphate and 1,2-diacylglycerol.

  20. Subclassification of muscarinic receptors in the heart, urinary bladder and sympathetic ganglia in the pithed rat. Selectivity of some classical agonists.

    PubMed

    van Charldorp, K J; de Jonge, A; Thoolen, M J; van Zwieten, P A

    1985-12-01

    In pithed normotensive rats muscarinic receptors were characterized in heart, urinary bladder and sympathetic ganglia; the selectivity of some classical muscarinic agents for these subtypes was investigated. The potencies in decreasing heart rate, increasing bladder pressure and increasing diastolic blood pressure were measured for the following, intraarterially administered cholinergic agonists: McN-A-343 ([4-m-chlorophenylcarbamoyloxy]-2-butynyltrimethylammonium), pilocarpine, carbachol, oxotremorine, arecoline, acetyl-beta-methylcholine and acetylcholine. The selective M1-antagonist pirenzepine, the mixed M1/M2-antagonist dexetimide and the cardioselective M2-antagonist gallamine were used as tools for identification of the receptors. All data were obtained after intravenous pretreatment with a high dose of atenolol to eliminate tachycardia induced by stimulating sympathetic ganglionic muscarinic receptors. Dexetimide strongly antagonized the bradycardia as well as the increase in bladder pressure induced by pilocarpine, carbachol, oxotremorine, arecoline, acetyl-beta-methylcholine and acetylcholine, whereas pirenzepine was much less effective. Gallamine antagonized the bradycardia, whereas no influence was found on the bladder contraction. Pilocarpine acted as a partial agonist in reducing heart rate as well as in increasing bladder pressure, whereas McN-A-343 was almost ineffective in doses up to 1 mg/kg. The hypertensive response to pilocarpine and carbachol was less pronounced than that produced by McN-A-343. Pirenzepine and dexetimide significantly antagonized the hypertensive response to McN-A-343 and pilocarpine, whereas gallamine was much less effective. The hypertensive response induced by carbachol was totally blocked by hexamethonium. The other agonists used in this study did not produce a significant increase in diastolic blood pressure in doses that produced a maximal effect on heart rate and urinary bladder pressure.(ABSTRACT TRUNCATED AT 250 WORDS

  1. Electrophysiological properties of lumbar motoneurons in the alpha-chloralose-anesthetized cat during carbachol-induced motor inhibition.

    PubMed

    Xi, M C; Liu, R H; Yamuy, J; Morales, F R; Chase, M H

    1997-07-01

    The present study was undertaken 1) to examine the neuronal mechanisms responsible for the inhibition of spinal cord motoneurons that occurs in alpha-chloralose-anesthetized cats following the microinjection of carbachol into the nucleus pontis oralis (NPO), and 2) to determine whether the inhibitory mechanisms are the same as those that are responsible for the postsynaptic inhibition of motoneurons that is present during naturally occurring active sleep. Accordingly, the basic electrophysiological properties of lumbar motoneurons were examined, with the use of intracellular recording techniques, in cats anesthetized with alpha-chloralose and compared with those present during naturally occurring active sleep. The intrapontine administration of carbachol resulted in a sustained reduction in the amplitude of the spinal cord Ia monosynaptic reflex. Discrete large-amplitude inhibitory postsynaptic potentials (IPSPs), which are only present during the state of active sleep in the chronic cat, were also observed in high-gain recordings from lumbar motoneurons after the injection of carbachol. During carbachol-induced motor inhibition, lumbar motoneurons exhibited a statistically significant decrease in input resistance, membrane time constant and a reduction in the amplitude of the action potential's afterhyperpolarization. In addition, there was a statistically significant increase in rheobase and in the delay between the initial-segment (IS) and somadendritic (SD) portions of the action potential (IS-SD delay). There was a significant increase in the mean motoneuron resting membrane potential (i.e., hyperpolarization). The preceding changes in the electrophysiological properties of motoneurons, as well as the development of discrete IPSPs, indicate that lumbar motoneurons are postsynaptically inhibited after the intrapontine administration of carbachol in cats that are anesthetized with alpha-chloralose. These changes in the electrophysiological properties of lumbar

  2. Axonal transport of muscarinic cholinergic receptors in rat vagus nerve: high and low affinity agonist receptors move in opposite directions and differ in nucleotide sensitivity

    SciTech Connect

    Zarbin, M.A.; Wamsley, J.K.; Kuhar, M.J.

    1982-07-01

    The presence and transport of muscarinic cholinergic binding sites have been detected in the rat vagus nerve. These binding sites accumulate both proximal and distal to ligatures in a time-dependent manner. The results of double ligature and colchicine experiments are compatible with the notion that the anterogradely transported binding sites move by fast transport. Most of the sites accumulating proximal to ligatures bind the agonist carbachol with high affinity, while most of the sites accumulating distally bind carbachol with a low affinity. Also, the receptors transported in the anterograde direction are affected by a guanine nucleotide analogue (GppNHp), while those transported in the retrograde direction are less, or not, affected. The bulk of the sites along the unligated nerve trunk bind carbachol with a low affinity and are less sensitive to GppNHp modulation than the anterogradely transported sites. These results suggest that some receptors in the vagus may undergo axonal transport in association with regulatory proteins and that receptor molecules undergo changes in their binding and regulatory properties during their life cycle. These data also support the notion that the high and low affinity agonist form of the muscarinic receptor represent different modulated forms of a single receptor molecule.

  3. Muscarinic receptors mediate negative and positive inotropic effects in mammalian ventricular myocardium: differentiation by agonists.

    PubMed Central

    Korth, M.; Kühlkamp, V.

    1987-01-01

    The concentration-dependence of the negative and positive inotropic effect of choline esters and of oxotremorine was studied in isometrically contracting papillary muscles of the guinea-pig. The preparations were obtained from reserpine-pretreated animals and were electrically driven at a frequency of 0.2 Hz. In the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methyl xanthine (IBMX, 100 mumol l-1), choline esters and oxotremorine produced concentration-dependent negative inotropic effects. Oxotremorine exhibited the highest negative inotropic potency (with a half-maximal effective concentration, EC50, of 20 nmol l-1) followed by carbachol (139 nmol l-1), methacholine (490 nmol l-1), acetylcholine in the presence of 10 mumol l-1 physostigmine (1.36 mumol l-1) and bethanechol (10 mumol l-1). Atropine was a competitive antagonist of the negative inotropic effects. Carbachol and oxotremorine decreased Vmax, overshoot and duration of slow Ca2+-dependent action potentials which had been elicited in the presence of 100 mumol l-1 IBMX. Choline esters produced a concentration-dependent positive inotropic effect. With an EC50 of 32 mumol l-1, carbachol was the most potent compound, followed by methacholine (35 mumol l-1), acetylcholine in the presence of 10 mumol l-1 physostigmine (46 mumol l-1) and bethanechol (142 mumol l-1). Compared to carbachol and methacholine which increased force by 100% of control, the increase induced by acetylcholine and bethanechol was only 64 and 58%, respectively. Atropine shifted the concentration-effect curves of all choline esters to higher concentrations. Choline esters caused intracellular Na+ activity to increase in the quiescent papillary muscle. This effect was reversed by atropine. Oxotremorine produced a small concentration-dependent positive inotropic effect (about 30% of the maximal effect of carbachol) which was resistant to atropine. Oxotremorine was a potent inhibitor of the positive inotropic effect of choline esters

  4. c-fos Expression in mesopontine noradrenergic and cholinergic neurons of the cat during carbachol-induced active sleep: a double-labeling study.

    PubMed

    Yamuy, J; Sampogna, S; Morales, F R; Chase, M H

    1998-01-01

    The interaction of cholinergic and catecholaminergic mechanisms in the mesopontine region has been hypothesized as being critical for the generation and maintenance of active (REM) sleep. To further examine this hypothesis, we sought to determine the pattern of neuronal activation (via c-fos expression) of catecholaminergic and cholinergic neurons in this region during active sleep induced by the pontine microapplication of carbachol (designated as active sleep-carbachol). Accordingly, we used two sets of double-labeling techniques; the first to identify tyrosine hydroxylase-containing neurons (putative catecholaminergic cells) which also express the c-fos protein product Fos, and the second to reveal choline acetyltransferase-containing neurons (putative cholinergic cells) which also express Fos. Compared to control cats, active sleep-carbachol cats exhibited a significantly greater number of Fos-expressing neurons in the dorsolateral region of the pons, which encompasses the locus coeruleus, the lateral pontine reticular formation, the peribrachial nuclei and the latero-dorsal and pedunculo-pontine tegmental nuclei. However, both control and active sleep-carbachol cats exhibited a similar number of catecholaminergic and cholinergic neurons in those regions that expressed Fos (i.e., double-labeled cells). A large number of c-fos-expressing neurons in the active sleep-carbachol cats whose neurotransmitter phenotype was not identified suggests that non-catecholaminergic, non-cholinergic neuronal populations in mesopontine regions are involved in the generation and maintenance of active sleep. The lack of increased c-fos expression in catecholaminergic neurons during active sleep-carbachol confirms and extends previous data that indicate that these cells are silent during active sleep-carbachol and naturally-occurring active sleep. The finding that cholinergic neurons of the dorsolateral pons were not activated either during wakefulness or active sleep-carbachol

  5. Carbachol increases basolateral K+ conductance in T84 cells. Simultaneous measurements of cell [Ca] and gK explore calcium's role.

    PubMed

    Wong, S M; Tesfaye, A; DeBell, M C; Chase, H S

    1990-12-01

    To explore the role of calcium in mediating the action of carbachol in chloride-secreting epithelia, we simultaneously measured intracellular free [Ca] ([Ca]i) and the potassium conductance (gK) of the basolateral membrane in T84 cells grown on collagen-coated filters. [Ca]i was measured with fura-2 and fluorescence microscopy and expressed as a relative value ([Ca]'i) normalized to control. To assess changes in basolateral gK, we measured the short circuit current (Isc) in the presence of luminal amphotericin and a transepithelial mucosa-to-serosa K+ gradient (Germann, W. J., M. E. Lowy, S. A. Ernst, and D. C. Dawson. 1986. J. Gen. Physiol. 88:237-251). Treatment of the monolayers with carbachol resulted in a parallel increase and then decrease in [Ca]'i and gK. The carbachol-induced changes in gK appeared to be dependent on the increase in [Ca]i because stimulation of gK was significantly diminished when the hormone-induced increase in [Ca]'i was blunted, either by loading the cells with BAPTA or by reducing the extracellular [Ca]. The carbachol-stimulated increase in gK appeared to be the direct result of the increase in steady-state [Ca]'i. The changes in gK and [Ca]'i after stimulation with carbachol were correlated and ionomycin also increased gK and [Ca]'i in a parallel manner. The carbachol-induced delta gK per delta[Ca]'i, however, was greater than that after ionomycin. Because ionomycin and carbachol appear to open the same channel, a conclusion based on inhibitor and selectivity experiments, carbachol may have a second action that amplifies the effect of calcium on gK. PMID:2126802

  6. Naloxone reduces the amplitude of IPSPs evoked in lumbar motoneurons by reticular stimulation during carbachol-induced motor inhibition.

    PubMed

    Xi, M C; Liu, R H; Yamuy, J; Morales, F R; Chase, M H

    1999-02-20

    During active sleep or carbachol-induced motor inhibition, electrical stimulation of the medullary nucleus reticularis gigantocellularis (NRGc) evoked large amplitude, glycinergic inhibitory postsynaptic potentials (IPSPs) in cat motoneurons. The present study was directed to determine whether these IPSPs, that are specific to the state of active sleep, are modulated by opioid peptides. Accordingly, intracellular recordings were obtained from lumbar motoneurons of acute decerebrate cats during carbachol-induced motor inhibition while an opiate receptor antagonist, naloxone, was microiontophoretically released next to the recorded cells. Naloxone reversibly reduced by 26% the mean amplitude of NRGc-evoked IPSPs (1.9+/-0.2 mV (S.E.M.) vs. 1.4+/-0.2 mV; n=11, control and naloxone, respectively, p<0.05), but had no effect on the other waveform parameters of these IPSPs (e.g., latency-to-onset, latency-to-peak, duration, etc.). The mean resting membrane potential, input resistance and membrane time constant of motoneurons following naloxone ejection were not statistically different from those of the control. These data indicate that opioid peptides have a modulatory effect on NRGc-evoked IPSPs during carbachol-induced motor inhibition. We therefore suggest that endogenous opioid peptides may act as neuromodulators to regulate inhibitory glycinergic synaptic transmission at motoneurons during active sleep. PMID:10082872

  7. Effects of papaverine on carbachol- and high K+-induced contraction in the bovine abomasum

    PubMed Central

    KANEDA, Takeharu; SAITO, Erika; KANDA, Hidenori; URAKAWA, Norimoto; SHIMIZU, Kazumasa

    2015-01-01

    The effects of papaverine on carbachol (CCh) -and high K+- induced contraction in the bovine abomasum were investigated. Papaverine inhibited CCh (1 µM) -and KCl (65 mM) -induced contractions in a concentration-dependent manner. Forskolin or sodium nitroprusside inhibited CCh-induced contractions in a concentration-dependent manner in association with increases in the cAMP or cGMP contents, whereas papaverine increased cGMP contents only at 30 µM. Changes in the extracellular Ca2+ from 1.5 mM to 7.5 mM reduced verapamil-induced relaxation in high K+-depolarized muscles, but papaverine-induced relaxation did not change. Futhermore, papaverine (30 µM) and NaCN (300 µM) decreased the creatine phosphate contents. These results suggest that the relaxing effects of papaverine on the bovine abomasum are mainly due to the inhibition of aerobic energy metabolism. PMID:26018357

  8. The mechanism of agonist induced Ca2+ signalling in intact endothelial cells studied confocally in in situ arteries.

    PubMed

    Mumtaz, S; Burdyga, G; Borisova, L; Wray, Susan; Burdyga, T

    2011-01-01

    In endothelial cells there remain uncertainties in the details of how Ca(2+) signals are generated and maintained, especially in intact preparations. In particular the role of the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), in contributing to the components of agonist-induced signals is unclear. The aim of this work was to increase understanding of the detailed mechanism of Ca(2+) signalling in endothelial cells using real time confocal imaging of Fluo-4 loaded intact rat tail arteries in response to muscarinic stimulation. In particular we have focused on the role of SERCA, and its interplay with capacitative Ca(2+) entry (CCE) and ER Ca(2+) release and uptake. We have determined its contribution to the Ca(2+) signal and how it varies with different physiological stimuli, including single and repeated carbachol applications and brief and prolonged exposures. In agreement with previous work, carbachol stimulated a rise in intracellular Ca(2+) in the endothelial cells, consisting of a rapid initial phase, then a plateau upon which oscillations of Ca(2+) were superimposed, followed by a decline to basal Ca(2+) levels upon carbachol removal. Our data support the following conclusions: (i) the size (amplitude and duration) of the Ca(2+) spike and early oscillations are limited by SERCA activity, thus both are increased if SERCA is inhibited. (ii) SERCA activity is such that brief applications of carbachol do not trigger CCE, presumably because the fall in luminal Ca(2+) is not sufficient to trigger it. However, longer applications sufficient to deplete the ER or even partial SERCA inhibition stimulate CCE. (iii) Ca(2+) entry occurs via STIM-mediated CCE and SERCA contributes to the cessation of CCE. In conclusion our data show how SERCA function is crucial to shaping endothelial cell Ca signals and its dynamic interplay with both CCE and ER Ca releases. PMID:21176847

  9. 17. CABLE CAR #22, VIEW SHOWING CAR ROUNDING CORNER IN ...

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

    17. CABLE CAR #22, VIEW SHOWING CAR ROUNDING CORNER IN LOADING AREA NEXT TO CAR DUMP AND CAR DUMP BUILDING - Pennsylvania Railroad, Canton Coal Pier, Clinton Street at Keith Avenue (Canton area), Baltimore, Independent City, MD

  10. Cars, Cycles, and Consumers.

    ERIC Educational Resources Information Center

    Idleman, Hillis K. Ed.

    The purpose of this consumer education module is to provide information and skills, and the ability to raise questions and find answers, while seeking the best automobile or motorcycle buy available for the money. The module may be used for a full or part semester course. The five sections (cars and the consumer, renting and leasing cars, cars and…

  11. Involvement of cyclooxygenase-2 in carbachol-induced positive inotropic response in mouse isolated left atrium.

    PubMed

    Hara, Yukio; Ike, Asako; Tanida, Riyo; Okada, Muneyoshi; Yamawaki, Hideyuki

    2009-12-01

    The mouse heart is expected to have characteristic contractile properties. However, basic information on the function of the mouse heart has not been accumulated sufficiently. In this study, the involvement of cyclooxygenase (COX)-2 in carbachol (CCh)-induced inotropic response was investigated in mouse isolated left atrium. Influences of CCh and their mechanisms of action on developed tension elicited by electrical stimulation were examined pharmacologically. The presence of COX-2 in atrium was examined by Western blotting and immunohistochemical analysis. CCh (3 microM for 15 min) produced a biphasic inotropic response: a transient decrease in contractile force followed by a late increase. Atropine suppressed the biphasic inotropic response to CCh. A muscarinic M(3) receptor antagonist, 4-diphenyl-acetoxy-N-methlpiperidine, inhibited the late positive inotropic action. Blockade of prostaglandin (PG) E(2) or F(2alpha) receptor by 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) or 9alpha, 15R-dihydroxy-11beta-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta 5Z, 13E-dien-1-oic acid (AL8810), respectively, significantly suppressed the positive inotropic response to CCh. A nonselective COX inhibitor, indomethacin, and a selective COX-2 inhibitor, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398) inhibited the positive response. A COX-1 inhibitor, valeroyl salicylate, did not affect the positive response. The positive response was almost completely abolished in the endocardial endothelium-deprived atria. Existence of COX-2 in endocardial endothelium was confirmed by Western blotting and immunohistochemical analysis. The present study indicated that the CCh-induced positive inotropic response was mediated by PGs, possibly PGE(2) and PGF(2alpha), released in part from endocardial endothelium. Furthermore, for the first time, we demonstrated that the production of PGs depended in part on COX-2 in endocardial endothelium through the

  12. Electric car arrives - again

    SciTech Connect

    Dunn, S.

    1997-03-01

    The first mass-produced electric cars in modern times are here, although they are expensive, limited in capability and unfamiliar to most prospective consumers. This article presents a brief history of the reintroduction of the modern electric car as well as discussions of the limitations of development, alternative routes to both producing and selling electric cars or some modified version of electric cars, economic incentives and governmental policies, and finally a snapshot description of the future for electric cars. 6 refs., 1 tab.

  13. Fos and serotonin immunoreactivity in the raphe nuclei of the cat during carbachol-induced active sleep: a double-labeling study.

    PubMed

    Yamuy, J; Sampogna, S; López-Rodríguez, F; Luppi, P H; Morales, F R; Chase, M H

    1995-07-01

    The microinjection of carbachol into the nucleus pontis oralis produces a state which is polygraphically and behaviorally similar to active sleep (rapid eye movement sleep). In the present study, using double-labeling techniques for serotonin and the protein product of c-fos (Fos), we sought to examine whether immunocytochemically identified serotonergic neurons of the raphe nuclei of the cat were activated, as indicated by their expression of c-fos, during this pharmacologically-induced behavioral state (active sleep-carbachol). Compared with control cats, which were injected with saline, active sleep-carbachol cats exhibited a significantly greater number of c-fos-expressing neurons in the raphe dorsalis, magnus and pallidus. Whereas most of the c-fos-expressing neurons in the raphe dorsalis were small, those in the raphe magnus were medium-sized and in the raphe pallidus they were small and medium-sized. The mean number of serotonergic neurons that expressed c-fos (i.e. double-labeled cells) was similar in control and active sleep-carbachol cats. These data indicate that there is an increased number of non-serotonergic, c-fos-expressing neurons in the raphe dorsalis, magnus and pallidus during the carbachol-induced state.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7477901

  14. Agonists and allosteric modulators of the calcium-sensing receptor and their therapeutic applications.

    PubMed

    Saidak, Zuzana; Brazier, Michel; Kamel, Saïd; Mentaverri, Romuald

    2009-12-01

    The calcium-sensing receptor (CaR) belongs to the G protein-coupled receptor superfamily, with a characteristic structure consisting of seven transmembrane helices, an intracellular C-terminal and an extracellular N terminal domain. The primary physiological function of the CaR is the maintenance of constant blood Ca2+ levels, as a result of its ability to sense very small changes in extracellular Ca2+ (Ca2+(o)). Nevertheless, in addition to being expressed in tissues involved in Ca2+(o) homeostasis, the CaR is also expressed in tissues not involved in mineral homeostasis, suggestive of additional physiological functions. Numerous agonists and modulators of the CaR are now known in addition to Ca2+(o), including various divalent and trivalent cations, aromatic l-amino acids, polyamines, and aminoglycoside antibiotics. The signaling of the CaR is also regulated by extracellular pH and ionic strength. The activated CaR couples mainly to the phospholipase Cbeta and extracellular signal-regulated kinase 1/2 signaling pathways, and it decreases intracellular cAMP levels, leading to various physiological effects. The recent identification of synthetic allosteric modulators of the CaR has opened up a new field of research possibilities. Calcimimetics and calcilytics, which increase and decrease agonist signaling via the CaR, respectively, may facilitate the manipulation of the CaR and thus aid in further investigations of its precise signaling. These allosteric modulators, as well as strontium, have been demonstrated to have therapeutic potential for the treatment of disorders involving the CaR. This review discusses the various agonists and modulators of the CaR, differences in their binding and signaling, and their roles as therapeutics in various diseases. PMID:19779033

  15. Rational Quantitative Structure-Activity Relationship (RQSAR) Screen for PXR and CAR Isoform-Specific Nuclear Receptor Ligands

    PubMed Central

    Dring, Ann M.; Anderson, Linnea E.; Qamar, Saima; Stoner, Matthew A.

    2010-01-01

    Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related orphan nuclear receptor proteins that share several ligands and target overlapping sets of genes involved in homeostasis and all phases of drug metabolism. CAR and PXR are involved in the development of certain diseases, including diabetes, metabolic syndrome and obesity. Ligand screens for these receptors so far have typically focused on steroid hormone analogs with pharmacophore-based approaches, only to find relatively few new hits. Multiple CAR isoforms have been detected in human liver, with the most abundant being the constitutively active reference, CAR1, and the ligand-dependent isoform CAR3. It has been assumed that any compound that binds CAR1 should also activate CAR3, and so CAR3 can be used as a ligand-activated surrogate for CAR1 studies. The possibility of CAR3-specific ligands has not, so far, been addressed. To investigate the differences between CAR1, CAR3 and PXR, and to look for more CAR ligands that may be of use in quantitative structure-activity relationship (QSAR) studies, we performed a luciferase transactivation assay screen of 60 mostly non-steroid compounds. Known active compounds with different core chemistries were chosen as starting points and structural variants were rationally selected for screening. Distinct differences in agonist versus inverse agonist/antagonist effects were seen in 49 compounds that had some ligand effect on at least one receptor and 18 that had effects on all three receptors; eight were CAR1 ligands only, three were CAR3 only ligands and four affected PXR only. This work provides evidence for new CAR ligands, some of which have CAR3-specific effects, and provides observational data on CAR and PXR ligands with which to inform in silico strategies. Compounds that demonstrated unique activity on any one receptor are potentially valuable diagnostic tools for the investigation of in vivo molecular targets. PMID:20869355

  16. Microfluidic CARS cytometry

    PubMed Central

    Wang, Han-Wei; Bao, Ning; Le, Thuc T.; Lu, Chang; Cheng, Ji-Xin

    2009-01-01

    Coherent anti-stokes Raman scattering (CARS) flow cytometry was demonstrated by combining a laser-scanning CARS microscope with a polydimethylsiloxane (PDMS) based microfluidic device. Line-scanning across the hydrodynamically focused core stream was performed for detection of flowing objects. Parameters were optimized by utilizing polystyrene beads as flowing particles. Population measurements of adipocytes isolated from mouse fat tissues demonstrated the viability of microfluidic CARS cytometry for quantitation of adipocyte size distribution. CARS cytometry could be a new modality for quantitative analysis with vibrational selectivity. PMID:18542688

  17. GABAergic neurons of the laterodorsal and pedunculopontine tegmental nuclei of the cat express c-fos during carbachol-induced active sleep.

    PubMed

    Torterolo, P; Yamuy, J; Sampogna, S; Morales, F R; Chase, M H

    2001-02-23

    The laterodorsal and pedunculopontine tegmental nuclei (LDT-PPT) are involved in the generation of active sleep (AS; also called REM or rapid eye movement sleep). Although the LDT-PPT are composed principally of cholinergic neurons that participate in the control of sleep and waking states, the function of the large number of GABAergic neurons that are also located in the LDT-PPT is unknown. Consequently, we sought to determine if these neurons are activated (as indicated by their c-fos expression) during active sleep induced by the microinjection of carbachol into the rostro-dorsal pons (AS-carbachol). Accordingly, immunocytochemical double-labeling techniques were used to identify GABA and Fos protein, as well as choline acetyltransferase (ChAT), in histological sections of the LDT-PPT. Compared to control awake cats, there was a larger number of GABAergic neurons that expressed c-fos during AS-carbachol (31.5+/-6.1 vs. 112+/-15.2, P<0.005). This increase in the number of GABA+Fos+ neurons occurred on the ipsilateral side relative to the injection site; there was a small decrease in GABA+Fos+ cells in the contralateral LDT-PPT. However, the LDT-PPT neurons that exhibited the largest increase in c-fos expression during AS-carbachol were neither GABA+ nor ChAT+ (47+/-22.5 vs. 228.7+/-14.0, P<0.0005). The number of cholinergic neurons that expressed c-fos during AS-carbachol was not significantly different compared to wakefulness. These data demonstrate that, during AS-carbachol, GABAergic as well as an unidentified population of neurons are activated in the LDT-PPT. We propose that these non-cholinergic LDT-PPT neurons may participate in the regulation of active sleep. PMID:11172778

  18. The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction.

    PubMed

    Maglich, Jodi M; Watson, Joe; McMillen, Patrick J; Goodwin, Bryan; Willson, Timothy M; Moore, John T

    2004-05-01

    The orphan nuclear receptor CAR (NR1I3) has been characterized as a central component in the coordinate response to xenobiotic and endobiotic stress. In this study, we demonstrate that CAR plays a pivotal function in energy homeostasis and establish an unanticipated metabolic role for this nuclear receptor. Wild-type mice treated with the synthetic CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) exhibited decreased serum concentration of the thyroid hormone (TH) thyroxine (T(4)). However, treatment of Car(-/-) mice with TCPOBOP failed to elicit these changes. To examine whether CAR played a role in the regulation of TH levels under physiological conditions, wild-type and Car(-/-) mice were fasted for 24 h, a process known to alter TH metabolism in mammals. As expected, the serum triiodothyronine and T(4) concentrations decreased in wild-type mice. However, triiodothyronine and T(4) levels in fasted Car(-/-) mice remained significantly higher than those in fasted wild-type animals. Concomitant with the changes in serum TH levels, both CAR agonist treatment and fasting induced the expression of CAR target genes (notably, Cyp2b10, Ugt1a1, Sultn, Sult1a1, and Sult2a1) in a receptor-dependent manner. Importantly, the Ugt1a1, Sultn, Sult1a1, and Sult2a1 genes encode enzymes that are capable of metabolizing TH. An attenuated reduction in TH levels during fasting, as observed in Car(-/-) mice, would be predicted to increase weight loss during caloric restriction. Indeed, when Car(-/-) animals were placed on a 40% caloric restriction diet for 12 weeks, Car(-/-) animals lost over twice as much weight as their wild-type littermates. Thus, CAR participates in the molecular mechanisms contributing to homeostatic resistance to weight loss. These data imply that CAR represents a novel therapeutic target to uncouple metabolic rate from food intake and has implications in obesity and its associated disorders. PMID:15004031

  19. 2. VAL CAMERA CAR, VIEW OF CAMERA CAR AND TRACK ...

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

    2. VAL CAMERA CAR, VIEW OF CAMERA CAR AND TRACK WITH CAMERA STATION ABOVE LOOKING WEST TAKEN FROM RESERVOIR. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  20. 3. VAL CAMERA CAR, VIEW OF CAMERA CAR AND TRACK ...

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

    3. VAL CAMERA CAR, VIEW OF CAMERA CAR AND TRACK WITH THE VAL TO THE RIGHT, LOOKING NORTHEAST. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  1. 18. CABLE CAR #21, DETAIL OF CAR COMING OUT OF ...

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

    18. CABLE CAR #21, DETAIL OF CAR COMING OUT OF LOADING AREA OF CAR DUMP BUILDING - Pennsylvania Railroad, Canton Coal Pier, Clinton Street at Keith Avenue (Canton area), Baltimore, Independent City, MD

  2. Sleep attacks in patients taking dopamine agonists: review

    PubMed Central

    Homann, Carl Nikolaus; Wenzel, Karoline; Suppan, Klaudia; Ivanic, Gerd; Kriechbaum, Norbert; Crevenna, Richard; Ott, Erwin

    2002-01-01

    Objectives To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. Design Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinson's disease. Results 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. Conclusion Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinson's disease. Prospective population based studies are needed to provide this information. What is already known on this topicCar crashes in patients with Parkinson's disease have been associated with sleep attacks caused by the dopamine agonists pramipexole and ropiniroleWhether sleep attacks exist, their connection with certain agonists, prevention or treatment, and the justification of legal actions are controversialWhat this study addsSleep attacks as a phenomenon distinct from normal somnolence really do existThey are a class effect of all dopamine drugsEffective prevention and treatment

  3. The Electric Cars Challenge

    ERIC Educational Resources Information Center

    Roman, Harry T.

    2011-01-01

    Over 100 years ago, the great inventor Thomas Edison warned that gasoline cars would pollute the environment and lead to gasoline shortages. He preferred the use of clean electric vehicles. He also put his money where his mouth was and developed an entirely new alkaline storage battery system for his beloved cars, the nickel-iron storage battery.…

  4. Muscarinic agonists and phorbol esters increase tyrosine phosphorylation of a 40-kilodalton protein in hippocampal slices

    SciTech Connect

    Stratton, K.R.; Worley, P.F.; Huganir, R.L.; Baraban, J.M. )

    1989-04-01

    The authors have used the hippocampal slice preparation to investigate the regulation of protein tyrosine phosphorylation in brain. After pharmacological treatment of intact slices, proteins were separated by electrophoresis, and levels of protein tyrosine phosphorylation were assessed by immunoblotting with specific anti-phosphotyrosine antibodies. Phorbol esters, activators of the serine- and threonine-phosphorylating enzyme protein kinase C, selectively increase tyrosine phosphorylation of a soluble protein with an apparent molecular mass of approximately 40 kilodaltons. Muscarinic agonists such as carbachol and oxotremorine M that strongly activate the inositol phospholipid system also increase tyrosine phosphorylation of this protein. Neurotransmitter activation of the inositol phospholipid system and protein kinase C appears to trigger a cascade leading to increased tyrosine phosphorylation.

  5. Shuttle car loading system

    NASA Technical Reports Server (NTRS)

    Collins, E. R., Jr. (Inventor)

    1985-01-01

    A system is described for loading newly mined material such as coal, into a shuttle car, at a location near the mine face where there is only a limited height available for a loading system. The system includes a storage bin having several telescoping bin sections and a shuttle car having a bottom wall that can move under the bin. With the bin in an extended position and filled with coal the bin sections can be telescoped to allow the coal to drop out of the bin sections and into the shuttle car, to quickly load the car. The bin sections can then be extended, so they can be slowly filled with more while waiting another shuttle car.

  6. Synthetic drugs and natural products as modulators of constitutive androstane receptor (CAR) and pregnane X receptor (PXR).

    PubMed

    Chang, Thomas K H; Waxman, David J

    2006-01-01

    Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are members of the nuclear receptor superfamily. These transcription factors are predominantly expressed in the liver, where they are activated by structurally diverse compounds, including many drugs and endogenous substances. CAR and PXR regulate the expression of a broad range of genes, which contribute to transcellular transport, bioactivation, and detoxification of numerous xenochemicals and endogenous substances. This article discusses the importance of these receptors for pharmacology and toxicology, emphasizing the role of individual drugs and natural products as agonists, indirect activators, inverse agonists, and antagonists of CAR and PXR. PMID:16684648

  7. Beta-Adrenergic Agonists

    PubMed Central

    Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito

    2010-01-01

    Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.

  8. Electrophysiological characterization of neurons in the dorsolateral pontine REM sleep induction zone of the rat: intrinsic membrane properties and responses to carbachol and orexins

    PubMed Central

    Brown§, Ritchie E.; Winston, Stuart; Basheer, Radhika; Thakkar, Mahesh M; McCarley, Robert W.

    2006-01-01

    Pharmacological, lesion and single-unit recording techniques in several animal species have identified a region of the pontine reticular formation (Subcoeruleus, SubC) just ventral to the locus coeruleus as critically involved in the generation of rapid-eye-movement (REM) sleep. However, the intrinsic membrane properties and responses of SubC neurons to neurotransmitters important in REM sleep control, such as acetylcholine and orexins/hypocretins, have not previously been examined in any animal species and thus were targeted in this study. We obtained whole-cell patch-clamp recordings from visually identified SubC neurons in rat brain slices in vitro. Two groups of large neurons (mean diameter 30 and 27μm) were tentatively identified as cholinergic (rostral SubC) and noradrenergic (caudal SubC) neurons. SubC reticular neurons (non-cholinergic, non-noradrenergic) showed a medium-sized depolarizing sag during hyperpolarizing current pulses and often had a rebound depolarization (low-threshold spike, LTS). During depolarizing current pulses they exhibited little adaptation and fired maximally at 30–90 Hz. Those SubC reticular neurons excited by carbachol (n=27) fired spontaneously at 6 Hz, often exhibited a moderately sized LTS, and varied widely in size (17–42 μm). Carbachol-inhibited SubC reticular neurons were medium-sized (15–25 μm) and constituted two groups. The larger group (n=22) was silent at rest and possessed a prominent LTS and associated 1–4 action potentials. The second, smaller group (n=8) had a delayed return to baseline at the offset of hyperpolarizing pulses. Orexins excited both carbachol excited and carbachol inhibited SubC reticular neurons. SubC reticular neurons had intrinsic membrane properties and responses to carbachol similar to those described for other reticular neurons but a larger number of carbachol inhibited neurons were found (> 50 %), the majority of which demonstrated a prominent LTS and may correspond to PGO-on neurons

  9. Modeling the Mousetrap Car

    NASA Astrophysics Data System (ADS)

    Jumper, William D.

    2012-03-01

    Many high school and introductory college physics courses make use of mousetrap car projects and competitions as a way of providing an engaging hands-on learning experience incorporating Newton's laws, conversion of potential to kinetic energy, dissipative forces, and rotational mechanics. Presented here is a simple analytical and finite element spreadsheet model for a typical mousetrap car, as shown in Fig. 1. It is hoped that the model will provide students with a tool for designing or modifying the designs of their cars, provide instructors with a means to insure students close the loop between physical principles and an understanding of their car's speed and distance performance, and, third, stimulate in students at an early stage an appreciation for the merits of computer modeling as an aid in understanding and tackling otherwise analytically intractable problems so common in today's professional world.

  10. The Electric Car Challenge.

    ERIC Educational Resources Information Center

    Diehl, Brian E.

    1997-01-01

    Describes the Electric Car Challenge during which students applied methods of construction to build lightweight, strong vehicles that were powered by electricity. The activity required problem solving, sheet metal work, electricity, design, and construction skills. (JOW)

  11. Aerodynamics of Race Cars

    NASA Astrophysics Data System (ADS)

    Katz, Joseph

    2006-01-01

    Race car performance depends on elements such as the engine, tires, suspension, road, aerodynamics, and of course the driver. In recent years, however, vehicle aerodynamics gained increased attention, mainly due to the utilization of the negative lift (downforce) principle, yielding several important performance improvements. This review briefly explains the significance of the aerodynamic downforce and how it improves race car performance. After this short introduction various methods to generate downforce such as inverted wings, diffusers, and vortex generators are discussed. Due to the complex geometry of these vehicles, the aerodynamic interaction between the various body components is significant, resulting in vortex flows and lifting surface shapes unlike traditional airplane wings. Typical design tools such as wind tunnel testing, computational fluid dynamics, and track testing, and their relevance to race car development, are discussed as well. In spite of the tremendous progress of these design tools (due to better instrumentation, communication, and computational power), the fluid dynamic phenomenon is still highly nonlinear, and predicting the effect of a particular modification is not always trouble free. Several examples covering a wide range of vehicle shapes (e.g., from stock cars to open-wheel race cars) are presented to demonstrate this nonlinear nature of the flow field.

  12. Mechanisms underlying activation of transient BK current in rabbit urethral smooth muscle cells and its modulation by IP3-generating agonists

    PubMed Central

    Kyle, Barry D.; Bradley, Eamonn; Large, Roddy; Sergeant, Gerard P.; McHale, Noel G.; Thornbury, Keith D.

    2013-01-01

    We used the perforated patch-clamp technique at 37°C to investigate the mechanisms underlying the activation of a transient large-conductance K+ (tBK) current in rabbit urethral smooth muscle cells. The tBK current required an elevation of intracellular Ca2+, resulting from ryanodine receptor (RyR) activation via Ca2+-induced Ca2+ release, triggered by Ca2+ influx through L-type Ca2+ (CaV) channels. Carbachol inhibited tBK current by reducing Ca2+ influx and Ca2+ release and altered the shape of spike complexes recorded under current-clamp conditions. The tBK currents were blocked by iberiotoxin and penitrem A (300 and 100 nM, respectively) and were also inhibited when external Ca2+ was removed or the CaV channel inhibitors nifedipine (10 μM) and Cd2+ (100 μM) were applied. The tBK current was inhibited by caffeine (10 mM), ryanodine (30 μM), and tetracaine (100 μM), suggesting that RyR-mediated Ca2+ release contributed to the activation of the tBK current. When IP3 receptors (IP3Rs) were blocked with 2-aminoethoxydiphenyl borate (2-APB, 100 μM), the amplitude of the tBK current was not reduced. However, when Ca2+ release via IP3Rs was evoked with phenylephrine (1 μM) or carbachol (1 μM), the tBK current was inhibited. The effect of carbachol was abolished when IP3Rs were blocked with 2-APB or by inhibition of muscarinic receptors with the M3 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (1 μM). Under current-clamp conditions, bursts of action potentials could be evoked with depolarizing current injection. Carbachol reduced the number and amplitude of spikes in each burst, and these effects were reduced in the presence of 2-APB. In the presence of ryanodine, the number and amplitude of spikes were also reduced, and carbachol was without further effect. These data suggest that IP3-generating agonists can modulate the electrical activity of rabbit urethral smooth muscle cells and may contribute to the effects of neurotransmitters on

  13. 1. VARIABLEANGLE LAUNCHER CAMERA CAR, VIEW OF CAMERA CAR AND ...

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

    1. VARIABLE-ANGLE LAUNCHER CAMERA CAR, VIEW OF CAMERA CAR AND TRACK WITH CAMERA STATION ABOVE LOOKING NORTH TAKEN FROM RESERVOIR. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  14. Modeling the Mousetrap Car

    ERIC Educational Resources Information Center

    Jumper, William D.

    2012-01-01

    Many high school and introductory college physics courses make use of mousetrap car projects and competitions as a way of providing an engaging hands-on learning experience incorporating Newton's laws, conversion of potential to kinetic energy, dissipative forces, and rotational mechanics. Presented here is a simple analytical and finite element…

  15. 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

  16. Changes in the contractile responses to carbachol and in the inhibitory effects of verapamil and nitrendipine on isolated smooth muscle preparations from rats subchronically exposed to Pb2+ and Zn2+.

    PubMed

    Vassilev, P P; Venkova, K; Pencheva, N; Radomirov, R; Staneva-Stoytcheva, D

    1994-01-01

    Male Wistar rats were exposed to Pb2+ or Zn2+ and to Pb2+ + Zn2+, receiving Pb(CH3COO)2 or/and ZnSO4 with drinking water for 30 days. Cumulative concentration-effect curves for carbachol were obtained in ileum and trachea isolated from control and heavy metal-treated rats. The effect of the Ca2+ channel blockers on the carbachol-induced contractions was studied by addition of increasing concentrations of verapamil or nitrendipine to the bath solution 20 min. prior to carbachol. The results showed that exposure of rats to heavy metals in doses which did not change the body weight and behaviour, altered the contractile responses to carbachol. The sensitivity to carbachol was higher in preparations from the ileum of Zn(2+)-exposed rats as compared to controls, while a tendency towards decreasing this sensitivity was observed in ileal preparations from Pb(2+)-treated animals. The concentration-effect curves for carbachol in ileal preparations from Pb2+ + Zn(2+)-treated rats did not differ from those in the preparations from untreated rats. The inhibitory effect of the Ca2+ channel blockers on the contractility of ileal and tracheal preparations from treated rats was weaker as compared to that in controls. PMID:7800652

  17. Carbachol-induced MUC17 endocytosis is concomitant with NHE3 internalization and CFTR membrane recruitment in enterocytes.

    PubMed

    Pelaseyed, Thaher; Gustafsson, Jenny K; Gustafsson, Ida J; Ermund, Anna; Hansson, Gunnar C

    2013-08-15

    We have reported that transmembrane mucin MUC17 binds PDZ protein PDZK1, which retains MUC17 apically in enterocytes. MUC17 and transmembrane mucins MUC3 and MUC12 are suggested to build the enterocyte apical glycocalyx. Carbachol (CCh) stimulation of the small intestine results in gel-forming mucin secretion from goblet cells, something that requires adjacent enterocytes to secrete chloride and bicarbonate for proper mucin formation. Surface labeling and confocal imaging demonstrated that apically expressed MUC17 in Caco-2 cells and Muc3(17) in murine enterocytes were endocytosed upon stimulation with CCh. Relocation of MUC17 in response to CCh was specific as MUC3 and MUC12 did not relocate following CCh stimulation. MUC17 colocalized with PDZK1 under basal conditions, while MUC17 relocated to the terminal web and into early endosomes after CCh stimulation. CCh stimulation concomitantly internalized the Na(+/)H(+) exchanger 3 (NHE3) and recruited cystic fibrosis transmembrane conductance regulator (CFTR) to the apical membranes, a process that was important for CFTR-mediated bicarbonate secretion necessary for proper gel-forming mucin unfolding. The reason for the specific internalization of MUC17 is not understood, but it could limit the diffusion barrier for ion secretion caused by the apical enterocyte glycocalyx or alternatively act to sample luminal bacteria. Our results reveal well-orchestrated mucus secretion and trafficking of ion channels and the MUC17 mucin. PMID:23784542

  18. Role of CAR and PXR in Xenobiotic Sensing and Metabolism

    PubMed Central

    Wang, Yue-Ming; Ong, Su Sien; Chai, Sergio C.; Chen, Taosheng

    2013-01-01

    Introduction The xenobiotic detoxification system, which protects the human body from external chemicals, comprises drug-metabolizing enzymes and transporters whose expressions are regulated by pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). The progress made in a large number of recent studies calls for a timely review to summarize and highlight these key discoveries. Areas covered This review summarizes recent advances in elucidating the roles of PXR and CAR in the xenobiotic detoxification system and highlights the progress in understanding the regulation of PXR and CAR activity at the post-translational levels, as well as the structural basis for the regulation of these two xenobiotic sensors. Expert opinion Future efforts are needed to discover novel agonists and antagonists with species and isoform selectivity, to systematically understand the regulation of PXR and CAR at multiple levels (transcriptional, post-transcriptional, and post-translational levels) in response to xenobiotics exposure, and to solve the structures of the full-length receptors, which will be enabled by improved protein expression and purification techniques and approaches. In addition, more efforts will be needed to validate PXR and CAR as disease-related therapeutic targets and thus expand their roles as master xenobiotic sensors. PMID:22554043

  19. Characterization and agonist regulation of muscarinic ([3H]N-methyl scopolamine) receptors in isolated ventricular myocytes from rat.

    PubMed

    Horackova, M; Robinson, B; Wilkinson, M

    1990-11-01

    Cell surface muscarinic cholinergic receptors have been characterized and quantified for the first time, in intact, isolated adult rat cardiomyocytes. The cells were previously established as functionally fully compatible with cellular responses in intact cardiac tissue. The specific binding of the hydrophilic radioligand, [3H]-NMS, (N-methyl-[3H]-scopolamine methylchloride) was found to be stereo-specific, saturable, reversible and of high affinity. Binding of [3H]-NMS demonstrated appropriate drug specificity and was positively correlated with increasing cell concentrations. Bmax for [3H]-NMS binding to ventricular myocytes, enzymatically dissociated from adult male rats, was 15.8 +/- 1.03 fmol/25 x 10(3) cells (at 4 degrees C) and KD was 0.27 +/- 0.05 nM (n = 14). Binding assays performed at a higher incubation temperature (30 degrees C) yielded a higher Bmax value (22.1 +/- 1.6 fmol/25 x 10(3) cells; n = 11; P less than 0.005 vs. Bmax at 4 degrees C) but an unchanged KD (0.23 +/- 0.06 nM). Pretreatment of myocytes with the muscarinic agonist carbachol (1 mM) at 37 degrees C resulted in a reduction (down-regulation) in specific binding of the hydrophilic ligand [3H]-NMS. The magnitude of this reduction and its rate of recovery were dependent on the time of the exposure to carbachol. Exposures of 30-60 min elicited down-regulated by 35% (Bmax = 14.29 +/- 1.66 changed to 9.5 +/- 1.79 fmol/25 x 10(3) cells, without change in KD P less than 0.01, n = 4). The down-regulation of the muscarinic receptors by carbachol was insensitive to application of bacitracin - an inhibitor of endocytosis. On the other hand preincubation with 10(-9)M atropine, a muscarinic antagonist, hindered the agonist-induced receptor "loss" from the cell surface confirming the muscarinic nature of these receptors. We conclude that our preparation of intact, isolated ventricular cardiomyocytes is ideally suited for the study of cell surface muscarinic receptor regulation under physiological and

  20. New developments in clinical CARS

    NASA Astrophysics Data System (ADS)

    Weinigel, Martin; Breunig, Hans Georg; Kellner-Höfer, Marcel; Bückle, Rainer; Darvin, Maxim; Lademann, Juergen; König, Karsten

    2013-02-01

    We combined two-photon fluorescence and coherent anti-Stokes Raman scattering (CARS) imaging in a clinical hybrid multiphoton tomograph for in vivo imaging of human skin. The clinically approved TPEF/CARS system provides simultaneous imaging of endogenous fluorophores and non-fluorescent lipids. The Stokes laser for the two-beam configuration of CARS is based on spectral broadening of femtosecond laser pulses in a photonic crystal fiber (PCF). We report on the highly flexible medical TPEF/CARS tomograph MPTflex®-CARS with an articulated arm and first in vivo measurements on human skin.

  1. Girls, Cars, and Science

    NASA Astrophysics Data System (ADS)

    Parks, Beth

    2005-03-01

    For the past two summers, I have run an NSF-funded residential camp for girls ages 14-17. This camp is designed to stimulate girls' interest in science by building on their interest in automobiles. The girls spend half the day in hands-on work with cars at Morrisville State College. The other half of the day is dedicated to laboratory exercises at Colgate University that have been designed to help girls learn the science behind the operation of cars. While it is impossible to assess the long-range impact of this program after only two years, the results seem promising. I will discuss the camp program, with particular emphasis on the laboratory experiments that have been developed, which could easily be incorporated into standard high school or college laboratories.

  2. All purpose railroad car

    SciTech Connect

    Terlecky, B.S.

    1987-01-13

    An all purpose railroad car is described for transporting wheeled trailers and containers, the car comprising an elongated frame supported by wheel trucks, combined hitch and bolster means adjacent one end of the frame for selectively receiving and releasably retaining a trailer king pin and one end of a container. A means is spaced from the combined hitch and bolster means for selectively receiving and supporting the wheels of a wheeled trailer and the other end of a container. The combined hitch and bolster means is an integral rigid structure with the hitch fixed in spaced relationship to the bolster with both the hitch and the bolster permanently disposed in operative position to respectively receive and retain a trailer king pin and a container.

  3. Usability of car stereo.

    PubMed

    Razza, Bruno Montanari; Paschoarelli, Luis Carlos

    2012-01-01

    Automotive sound systems vary widely in terms of functions and way of use between different brands and models what can bring difficulties and lack of consistency to the user. This study aimed to analyze the usability of car stereo commonly found in the market. Four products were analyzed by task analysis and after use reports and the results indicate serious usability issues with respect to the form of operation, organization, clarity and quality of information, visibility and readability, among others. PMID:22317617

  4. Hydraulic motor for cars

    SciTech Connect

    Gagnon, D.C.

    1986-09-02

    A hydraulic motor for a car is described comprising, in combination, an automotive vehicle engine for travel self-propulsion, including a block, a plurality of cylinders in the block, a piston slidable in each cylinder, a crankshaft in the block, a piston rod connected between the crankshaft and each of the pistons, a power take-off gear on the crankshaft for the travel self-propulsion, and the engine including a hydraulic means for driving the pistons in the cylinders.

  5. Scrap car recycling in Taiwan

    SciTech Connect

    Lee, C.H.; Tai, H.S.; Fan, R.K.S.

    1997-12-31

    The official figure of registered automobiles released by the Ministry of Transportation of Taiwan, R.O.C. as of the end of April 1996, is approximately 4.8 millions. Among them, 18% of the cars are between seven and ten years old and 15% of the cars are old than ten years. The result of this large number of old cars is the problem of abandoned cars on the street of Taiwan. This phenomena not only hinders traffic flow but also undermines the living quality in the cities. To minimize these negative effects, EPA has promulgated a Scrap Motor Vehicles Management Regulation to enforce the scrap car recycling in Taiwan. Under this regulation, a buyer of a new vehicle has to pay the Scrap Motor Vehicle Disposal fee (NT$ 3000, or US$ 110 for a car; and NT$ 700, or US$ 25 for a motorcycle). This paper presents the current status of scrap car recycling in Taiwan.

  6. Dual-CARS microscopy

    NASA Astrophysics Data System (ADS)

    Enejder, Annika; Brackmann, Christian; Burkacky, Ondrej; Åkeson, Madeleine

    2007-02-01

    We present a new Coherent Anti-Stokes Raman Scattering (CARS) microscopy technique for label-free imaging of biomolecules in living cells; dual-CARS microscopy. The use of three synchronized laser pulses in a dual-pump/dualdetection configuration enables imaging of two species with different molecular vibrations simultaneously, as well as acquisition of images free of non-resonant background. We show the power of the method by imaging deuterated nonadecane slowly diffusing into a suspension of living yeast cells in medium, clearly distinguishing the medium and the lipid droplets in the cells by probing the CH II vibration from the D-nonadecane by probing the CD vibration. In addition, images of lipid stores in living C. elegans nematodes free of non-resonant background are shown. This results in a significant enhancement of the image contrast, allowing the visualization of emerging, low-density lipid stores in a dauer larva, difficult to distinguish in conventional CARS microscopy. The separation of the non-resonant background is shown to be beneficial also when monitoring molecules with weak vibrational modes. The improved sensitivity obtained is illustrated by probing the C=C vibration in polyunsaturated lipids extracted from fish. This enables the monitoring of the degree of unsaturation of lipids, a high value of which is reported in foods known to have positive effects on human health.

  7. Mechanisms involved in carbachol-induced Ca2+ sensitization of contractile elements in rat proximal and distal colon

    PubMed Central

    Takeuchi, Tadayoshi; Kushida, Masahiko; Hirayama, Nobue; Kitayama, Muneyoshi; Fujita, Akikazu; Hata, Fumiaki

    2004-01-01

    Mechanisms involved in Ca2+ sensitization of contractile elements induced by the activation of muscarinic receptors in membrane-permeabilized preparations of the rat proximal and distal colon were studied. In α-toxin-permeabilized preparations from the rat proximal and distal colon, Ca2+ induced a rapid phasic and subsequent tonic component. After Ca2+-induced contraction reached a plateau, guanosine 5′-triphosphate (GTP) and carbachol (CCh) in the presence of GTP further contracted preparations of both the proximal and distal colon (Ca2+ sensitization). Y-27632, a rho-kinase inhibitor, inhibited GTP plus CCh-induced Ca2+ sensitization more significantly in the proximal colon than in the distal colon. Y-27632 at 10 μM had no effect on Ca2+-induced contraction or slightly inhibited phorbol-12,13-dibutyrate-induced Ca2+ sensitization in either proximal or distal colon. Chelerythrine, a protein kinase C inhibitor, inhibited GTP plus CCh-induced Ca2+ sensitization in the distal colon, but not in the proximal colon. The component of Ca2+ sensitization that persisted after the chelerythrine treatment was completely inhibited by Y-27632. In β-escin-permeabilized preparations of the proximal colon, C3 exoenzyme completely inhibited GTP plus CCh-induced Ca2+ sensitization, but PKC(19–31) did not. In the distal colon, C3 exoenzyme abolished GTP-induced Ca2+ sensitization. It inhibited CCh-induced sensitization by 50 % and the remaining component was inhibited by PKC(19–31). These results suggest that both protein kinase C and rho pathways in parallel mediate the Ca2+ sensitization coupled to activation of muscarinic receptors in the rat distal colon, whereas the rho pathway alone mediates this action in the proximal colon. PMID:15159278

  8. Diminished agonist-stimulated inositol trisphosphate generation blocks stimulus-secretion coupling in mouse pancreatic acini during diet-induced experimental pancreatitis

    SciTech Connect

    Powers, R.E.; Saluja, A.K.; Houlihan, M.J.; Steer, M.L.

    1986-05-01

    Young female mice fed a choline-deficient, ethionine-supplemented (CDE) diet rapidly develop acute hemorrhagic pancreatitis. We have observed that pancreatic acini prepared from these mice are unable to secrete amylase in response to addition of the cholinergic agonist carbachol, although they retain the ability to secrete amylase in response to the Ca2+ ionophore A23187. The CDE diet does not alter the binding characteristics (Kd or the maximal number of binding sites) for muscarinic cholinergic receptors as tested using the antagonist (/sup 3/H)N-methylscopolamine nor the competition for this binding by carbachol. Addition of carbachol to acini prepared from mice fed the CDE diet does not result in as marked an increase in cytosolic free Ca2+ levels as that noted in control samples (evaluated using quin2 fluorescence). These observations indicate that the CDE diet interferes with stimulus-secretion coupling in mouse pancreatic acini at a step subsequent to hormone-receptor binding and prior to Ca2+ release. This conclusion is confirmed by our finding that the hormone-stimulated generation of (/sup 3/H)inositol phosphates (inositol trisphosphate, inositol bisphosphate, and inositol monophosphate) from acini labeled with (/sup 3/H)myoinositol is markedly reduced in acini prepared from mice fed the CDE diet. This reduction is not due to a decrease in phosphatidylinositol-4,5-bisphosphate. This communication represents the first report of a system in which a blockade of inositol phosphate generation can be related to a physiologic defect and pathologic lesion.

  9. Calcium-mediated agonists activate an inwardly rectified K+ channel in colonic secretory cells.

    PubMed

    Devor, D C; Frizzell, R A

    1993-11-01

    Single-channel recording techniques were used to identify and characterize the K+ channel activated by Ca(2+)-mediated secretory agonists in T84 cells. Carbachol (CCh; 100 microM) and taurodeoxycholate (TDC; 0.75 mM) stimulated oscillatory outward K+ currents. With K gluconate in bath and pipette, cell-attached single-channel K+ currents stimulated by CCh and ionomycin (2 microM) were inwardly rectified and reversed at 0 mV. The single-channel chord conductance was 32 pS at -90 mV and 14 pS at +90 mV. Similar properties were observed in excised inside-out patches in symmetric K+, permitting further characterization of channel properties. Partial substitution of bath or pipette K+ with Na+ gave a K(+)-to-Na+ selectivity ratio of 5.5:1. Channel activity increased with increasing bath Ca2+ concentration in the physiological range of 50-800 nM. Maximal channel activity occurred at intracellular pH 7.2 and decreased at more acidic or alkaline pH values. Extracellular charybdotoxin (CTX; 50 nM) blocked inward but not outward currents. Extracellular tetraethylammonium (TEA; 10 mM) reduced single-channel amplitude at all voltages. No apparent block of the channel was observed with extracellular Ba2+ (1 mM), apamin (1 microM), 4-aminopyridine (4-AP; 4 mM), quinine (500 microM), or glyburide (10 microM). Cytosolic quinine and 4-AP blocked both inward and outward currents, whereas Ba2+ blocked only outward currents. Apamin, CTX, TEA, and glyburide did not affect channel activity. The agonist activation and pharmacological profile of this inwardly rectified K+ channel indicate that it is responsible for the increase in basolateral K+ conductance stimulated by Ca(2+)-mediated agonists in T84 cells. PMID:7694492

  10. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs. PMID:19275609

  11. Lighting innovations in concept cars

    NASA Astrophysics Data System (ADS)

    Berlitz, Stephan; Huhn, Wolfgang

    2005-02-01

    Concept cars have their own styling process. Because of the big media interest they give a big opportunity to bring newest technology with styling ideas to different fairgrounds. The LED technology in the concept cars Audi Pikes Peak, Nuvolari and Le Mans will be explained. Further outlook for the Audi LED strategy starting with LED Daytime Running Lamp will be given. The close work between styling and technical engineers results in those concept cars and further technical innovations based on LED technologies.

  12. 54. VAL COUNTERWEIGHT CAR DURING CONSTRUCTION SHOWING CAR FRAME, WHEEL ...

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

    54. VAL COUNTERWEIGHT CAR DURING CONSTRUCTION SHOWING CAR FRAME, WHEEL ASSEMBLIES AND METAL REINFORCING, December 19, 1947. (Original photograph in possession of Dave Willis, San Diego, California.) - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  13. 49 CFR 174.615 - Cleaning cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 2 2014-10-01 2014-10-01 false Cleaning cars. 174.615 Section 174.615... Requirements for Division 6.1 (Poisonous) Materials § 174.615 Cleaning cars. (a) (b) After Division 6.1 (poisonous) materials are unloaded from a rail car, that car must be thoroughly cleaned unless the car...

  14. 49 CFR 174.615 - Cleaning cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 2 2013-10-01 2013-10-01 false Cleaning cars. 174.615 Section 174.615... Requirements for Division 6.1 (Poisonous) Materials § 174.615 Cleaning cars. (a) (b) After Division 6.1 (poisonous) materials are unloaded from a rail car, that car must be thoroughly cleaned unless the car...

  15. 49 CFR 174.615 - Cleaning cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 2 2012-10-01 2012-10-01 false Cleaning cars. 174.615 Section 174.615... Requirements for Division 6.1 (Poisonous) Materials § 174.615 Cleaning cars. (a) (b) After Division 6.1 (poisonous) materials are unloaded from a rail car, that car must be thoroughly cleaned unless the car...

  16. 49 CFR 174.615 - Cleaning cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 2 2011-10-01 2011-10-01 false Cleaning cars. 174.615 Section 174.615... Requirements for Division 6.1 (Poisonous) Materials § 174.615 Cleaning cars. (a) (b) After Division 6.1 (poisonous) materials are unloaded from a rail car, that car must be thoroughly cleaned unless the car...

  17. Acute Aerobic Swimming Exercise Induces Distinct Effects in the Contractile Reactivity of Rat Ileum to KCl and Carbachol

    PubMed Central

    Araujo, Layanne C. da Cunha; de Souza, Iara L. L.; Vasconcelos, Luiz H. C.; Brito, Aline de Freitas; Queiroga, Fernando R.; Silva, Alexandre S.; da Silva, Patrícia M.; Cavalcante, Fabiana de Andrade; da Silva, Bagnólia A.

    2016-01-01

    Aerobic exercise promotes short-term physiological changes in the intestinal smooth muscle associated to the ischemia-reperfusion process; however, few studies have demonstrated its effect on the intestinal contractile function. Thus, this work describes our observations regarding the influence of acute aerobic swimming exercise in the contractile reactivity, oxidative stress, and morphology of rat ileum. Wistar rats were divided into sedentary (SED) and acutely exercised (EX-AC) groups. Animals were acclimated by 10, 10, and 30 min of swimming exercise in intercalated days 1 week before exercise. Then they were submitted to forced swimming for 1 h with a metal of 3% of their body weight attached to their body. Animals were euthanized immediately after the exercise section and the ileum was suspended in organ baths for monitoring isotonic contractions. The analysis of lipid peroxidation was performed in order to determinate the malondialdehyde (MDA) levels as a marker of oxidative stress, and intestinal smooth muscle morphology by histological staining. Cumulative concentration-response curves to KCl were altered in the EX-AC with an increase in both its efficacy and potency (Emax = 153.2 ± 2.8%, EC50 = 1.3 ± 0.1 × 10−2 M) compared to the SED group (Emax = 100%, EC50 = 1.8 ± 0.1 × 10−2 M). Interestingly, carbachol had its efficacy and potency reduced in the EX-AC (Emax = 67.1 ± 1.4%, EC50 = 9.8 ± 1.4 × 10−7 M) compared to the SED group (Emax = 100%, EC50 = 2.0 ± 0.2 × 10−7 M). The exercise did not alter the MDA levels in the ileum (5.4 ± 0.6 μ mol/mL) in the EX-AC compared to the SED group (8.4 ± 1.7 μ mol/mL). Moreover, neither the circular nor the longitudinal smooth muscle layers thickness were modified by the exercise (66.2 ± 6.0 and 40.2 ± 2.6 μm, respectively), compared to the SED group (61.6 ± 6.4 and 34.8 ± 3.7 μm, respectively). Therefore, the ileum sensitivity to contractile agents is differentially altered by the acute aerobic

  18. PASSENGER CAR HYDROCARBON EMISSIONS SPECIATION

    EPA Science Inventory

    Emission factors for over 60 individual hydrocarbon compounds were determined for four passenger cars. The cars included a 1963 Chevrolet, a 1977 Mustang, and 1978 Monarch, and 1979 LTD II. The speciation data is reported for both tailpipe and evaporative emissions. The tailpipe ...

  19. Car versus bicycle: conclusion.

    PubMed

    Ross, David W; Wichman, Carol; Mackinnon, Mike

    2009-01-01

    A 58-year-old man was riding his bicycle and was struck by a car. He was ejected and landed on his back on the pavement of the roadway. He complained of severe pain in his lower back and sacral area. Ground emergency medical services (EMS) arrived to find a pale, diaphoretic man who was alert but in distress. His medical history was negative, and he was taking no medications. The initial heart rate was 130 beats/minute, and the blood pressure was 70 mmHg by palpation. A helicopter air ambulance was requested from the rural scene location to transport the patient to a trauma center. The physical examination by the flight crew demonstrated the patient had not changed from the original EMS assessment, despite the administration of 1 L normal saline intravenously. There were no apparent injuries to his head, neck, chest, or extremities. PMID:19896575

  20. Changes in the contractile responses to carbachol and in the inhibitory effects of verapamil and nitrendipine on isolated smooth muscle preparations from rats subchronically exposed to Co2+ and Ni2+.

    PubMed

    Vassilev, P P; Venkova, K; Pencheva, N; Staneva-Stoytcheva, D

    1993-01-01

    Male Wistar rats were exposed to subtoxic doses of Co2+ or Ni2+, receiving Co(NO3)2 or NiSO4 with drinking water for 30 days. No significant differences in the body weight and no visible changes in the behaviour of the controls and experimental animals were established. Cumulative concentration-effect curves for carbachol were obtained in ileum and trachea isolated from control and Co(2+)- or Ni(2+)-treated rats. The effect of the Ca2+ antagonists on the carbachol-induced contractions was studied by adding increasing concentrations of verapamil or nitrendipine to the bath solution 20 min prior to carbachol. The results showed that exposure of rats to subtoxic doses of Co(NO3)2 or NiSO4 altered the contractile responses to carbachol. The changes in the pD2 values and the shift to the left of the concentration-effect curves suggest a higher sensitivity to carbachol in preparations from the ileum of Co(2+)- or Ni(2+)-exposed rats. The tracheal strips isolated from control and heavy metal-treated rats showed a less potent sensitiveness to carbachol as compared to the ileal segments. An opposite tendency for decreased cholinergic reactivity was observed in tracheal strips from Co(2+)- and Ni(2+)-treated animals. The inhibitory effect of the Ca(2+)-antagonists on the contractility of ileal preparations from Co(2+)-treated rats increased at all concentrations of verapamil and at the highest concentration of nitrendipine, but decreased at lower concentrations of nitrendipine. The effect of verapamil on the preparations from Ni(2+)-exposed rats was unchanged or even decreased at higher verapamil concentrations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8368943

  1. 49 CFR 1247.1 - Annual Report of Cars Loaded and Cars Terminated.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 9 2012-10-01 2012-10-01 false Annual Report of Cars Loaded and Cars Terminated... TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION (CONTINUED) ACCOUNTS, RECORDS AND REPORTS REPORT OF CARS LOADED AND CARS TERMINATED § 1247.1 Annual Report of Cars Loaded and Cars Terminated. Beginning with...

  2. 49 CFR 1247.1 - Annual Report of Cars Loaded and Cars Terminated.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 9 2013-10-01 2013-10-01 false Annual Report of Cars Loaded and Cars Terminated... TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION (CONTINUED) ACCOUNTS, RECORDS AND REPORTS REPORT OF CARS LOADED AND CARS TERMINATED § 1247.1 Annual Report of Cars Loaded and Cars Terminated. Beginning with...

  3. 49 CFR 1247.1 - Annual Report of Cars Loaded and Cars Terminated.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 9 2014-10-01 2014-10-01 false Annual Report of Cars Loaded and Cars Terminated... TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION (CONTINUED) ACCOUNTS, RECORDS AND REPORTS REPORT OF CARS LOADED AND CARS TERMINATED § 1247.1 Annual Report of Cars Loaded and Cars Terminated. Beginning with...

  4. 49 CFR 1247.1 - Annual Report of Cars Loaded and Cars Terminated.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 9 2011-10-01 2011-10-01 false Annual Report of Cars Loaded and Cars Terminated... TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION (CONTINUED) ACCOUNTS, RECORDS AND REPORTS REPORT OF CARS LOADED AND CARS TERMINATED § 1247.1 Annual Report of Cars Loaded and Cars Terminated. Beginning with...

  5. Car insurance and the risk of car crash injury.

    PubMed

    Blows, Stephanie; Ivers, Rebecca Q; Connor, Jennie; Ameratunga, Shanthi; Norton, Robyn

    2003-11-01

    Despite speculation about the role of vehicle insurance in road traffic accidents, there is little research estimating the direction or extent of the risk relationship. Data from the Auckland Car Crash Injury Study (1998-1999) were used to examine the association between driving an uninsured motor vehicle and car crash injury. Cases were all cars involved in crashes in which at least one occupant was hospitalized or killed anywhere in the Auckland region. Controls were 588 drivers of randomly selected cars on Auckland roads. Participants completed a structured interview. Uninsured drivers had significantly greater odds of car crash injury compared to insured drivers after adjustment for age, sex, level of education, and driving exposure (odds ratio 4.77, 95% confidence interval 2.94-7.75). The causal mechanism for insurance and car crash injury is not easily determined. Although we examined the effects of multiple potential confounders in our analysis including socioeconomic status and risk-taking behaviours, both of which have been previously observed to be associated with both insurance status and car crash injury, residual confounding may partly explain this association. The estimated proportion of drivers who are uninsured is between 5 and 15% in developed countries, representing a significant public health problem worthy of further investigation. PMID:12971933

  6. Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver

    PubMed Central

    Chen, Wei-Dong; Fu, Xianghui; Dong, Bingning; Wang, Yan-Dong; Shiah, Steven; Moore, David D.; Huang, Wendong

    2012-01-01

    Aberrant epigenetic alterations during development may result in long-term epigenetic memory and have a permanent effect on the health of subjects. Constitutive androstane receptor (CAR; NR1I3) is a central regulator of drug/xenobiotic metabolism. Here, we report that transient neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism. CAR activation by neonatal exposure to a CAR-specific ligand, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) led to persistently induced expression of the CAR target genes Cyp2B10 and Cyp2C37 throughout the life of exposed mice. These mice showed a permanent reduction in sensitivity to zoxazolamine treatment as adults. Compared with control groups, the induction of Cyp2B10 and Cyp2C37 in hepatocytes isolated from these mice was more sensitive to low concentrations of the CAR agonist TCPOBOP. Accordingly, neonatal activation of CAR led to a permanent increase of histone 3 lysine 4 (H3K4) mono-, di- and trimethylation and decrease of H3K9 trimethylation within the Cyp2B10 locus. Transcriptional coactivator ASC-2 and histone demethylase JMJD2d participated in this CAR-dependent epigenetic switch. Conclusion Neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism. PMID:22488010

  7. Pervasive Adaptation in Car Crowds

    NASA Astrophysics Data System (ADS)

    Ferscha, Alois; Riener, Andreas

    Advances in the miniaturization and embedding of electronics for microcomputing, communication and sensor/actuator systems, have fertilized the pervasion of technology into literally everything. Pervasive computing technology is particularly flourishing in the automotive domain, exceling the “smart car”, embodying intelligent control mechanics, intelligent driver assistance, safety and comfort systems, navigation, tolling, fleet management and car-to-car interaction systems, as one of the outstanding success stories of pervasive computing. This paper raises the issue of the socio-technical phenomena emerging from the reciprocal interrelationship between drivers and smart cars, particularly in car crowds. A driver-vehicle co-model (DVC-model) is proposed, expressing the complex interactions between the human driver and the in-car and on-car technologies. Both explicit (steering, shifting, overtaking), as well as implicit (body posture, respiration) interactions are considered, and related to the drivers vital state (attentive, fatigue, distracted, aggressive). DVC-models are considered as building blocks in large scale simulation experiments, aiming to analyze and understand adaptation phenomena rooted in the feed-back loops among individual driver behavior and car crowds.

  8. Clinical multiphoton and CARS microscopy

    NASA Astrophysics Data System (ADS)

    Breunig, H. G.; Weinigel, M.; Darvin, M. E.; Lademann, J.; König, K.

    2012-03-01

    We report on clinical CARS imaging of human skin in vivo with the certified hybrid multiphoton tomograph CARSDermaInspect. The CARS-DermaInspect provides simultaneous imaging of non-fluorescent intradermal lipid and water as well as imaging of two-photon excited fluorescence from intrinsic molecules. Two different excitation schemes for CARS imaging have been realized: In the first setup, a combination of fs oscillator and optical parametric oscillator provided fs-CARS pump and Stokes pulses, respectively. In the second setup a fs oscillator was combined with a photonic crystal fiber which provided a broadband spectrum. A spectral range out of the broadband-spectrum was selected and used for CARS excitation in combination with the residual fs-oscillator output. In both setups, in addition to CARS, single-beam excitation was used for imaging of two-photon excited fluorescence and second harmonic generation signals. Both CARS-excitation systems were successfully used for imaging of lipids inside the skin in vivo.

  9. Inhibition of Rho-associated kinase blocks agonist-induced Ca2+ sensitization of myosin phosphorylation and force in guinea-pig ileum

    PubMed Central

    Swärd, Karl; Dreja, Karl; Susnjar, Marija; Hellstrand, Per; Hartshorne, David J; Walsh, Michael P

    2000-01-01

    Ca2+ sensitization of smooth muscle contraction involves the small GTPase RhoA, inhibition of myosin light chain phosphatase (MLCP) and enhanced myosin regulatory light chain (LC20) phosphorylation. A potential effector of RhoA is Rho-associated kinase (ROK).The role of ROK in Ca2+ sensitization was investigated in guinea-pig ileum.Contraction of permeabilized muscle strips induced by GTPγS at pCa 6.5 was inhibited by the kinase inhibitors Y-27632, HA1077 and H-7 with IC50 values that correlated with the known Ki values for inhibition of ROK. GTPγS also increased LC20 phosphorylation and this was prevented by HA1077. Contraction and LC20 phosphorylation elicited at pCa 5.75 were, however, unaffected by HA1077.Pre-treatment of intact tissue strips with HA1077 abolished the tonic component of carbachol-induced contraction and the sustained elevation of LC20 phosphorylation, but had no effect on the transient or sustained increase in [Ca2+]i induced by carbachol.LC20 phosphorylation and contraction dynamics suggest that the ROK-mediated increase in LC20 phosphorylation is due to MLCP inhibition, not myosin light chain kinase activation.In the absence of Ca2+, GTPγS stimulated 35S incorporation from [35S]ATPγS into the myosin targeting subunit of MLCP (MYPT). The enhanced thiophosphorylation was inhibited by HA1077. No thiophosphorylation of LC20 was detected.These results indicate that ROK mediates agonist-induced increases in myosin phosphorylation and force by inhibiting MLCP activity through phosphorylation of MYPT. Under Ca2+-free conditions, ROK does not appear to phosphorylate LC20in situ, in contrast to its ability to phosphorylate myosin in vitro. In particular, ROK activation is essential for the tonic phase of agonist-induced contraction. PMID:10618150

  10. The role of TRPP2 in agonist-induced gallbladder smooth muscle contraction.

    PubMed

    Zhong, Xingguo; Fu, Jie; Song, Kai; Xue, Nairui; Gong, Renhua; Sun, Dengqun; Luo, Huilai; He, Wenzhu; Pan, Xiang; Shen, Bing; Du, Juan

    2016-04-01

    TRPP2 channel protein belongs to the superfamily of transient receptor potential (TRP) channels and is widely expressed in various tissues, including smooth muscle in digestive gut. Accumulating evidence has demonstrated that TRPP2 can mediate Ca(2+) release from Ca(2+) stores. However, the functional role of TRPP2 in gallbladder smooth muscle contraction still remains unclear. In this study, we used Ca(2+) imaging and tension measurements to test agonist-induced intracellular Ca(2+) concentration increase and smooth muscle contraction of guinea pig gallbladder, respectively. When TRPP2 protein was knocked down in gallbladder muscle strips from guinea pig, carbachol (CCh)-evoked Ca(2+) release and extracellular Ca(2+) influx were reduced significantly, and gallbladder contractions induced by endothelin 1 and cholecystokinin were suppressed markedly as well. CCh-induced gallbladder contraction was markedly suppressed by pretreatment with U73122, which inhibits phospholipase C to terminate inositol 1,4,5-trisphosphate receptor (IP3) production, and 2-aminoethoxydiphenyl borate (2APB), which inhibits IP3 recepor (IP3R) to abolish IP3R-mediated Ca(2+) release. To confirm the role of Ca(2+) release in CCh-induced gallbladder contraction, we used thapsigargin (TG)-to deplete Ca(2+) stores via inhibiting sarco/endoplasmic reticulum Ca(2+)-ATPase and eliminate the role of store-operated Ca(2+) entry on the CCh-induced gallbladder contraction. Preincubation with 2 μmol L(-1) TG significantly decreased the CCh-induced gallbladder contraction. In addition, pretreatments with U73122, 2APB or TG abolished the difference of the CCh-induced gallbladder contraction between TRPP2 knockdown and control groups. We conclude that TRPP2 mediates Ca(2+) release from intracellular Ca(2+) stores, and has an essential role in agonist-induced gallbladder muscle contraction. PMID:26660312

  11. Involvement rate in two-car crashes versus driver age and car mass of each involved car.

    PubMed

    Evans, L

    1985-04-01

    This work was performed to investigate how the likelihood of a two-car crash depends on the driver age and car mass for each of the two involved cars, and also to examine the special case of cars of similar mass crashing into each other. Data on 108 044 cars involved in police reported two-car crashes occurring in New York State in 1971 and 1972 were fitted to a function of the driver age and car mass for each of the two involved cars. Car registrations are used to estimate exposure. The special case of crashes between cars of similar mass is considered because of prior results on driver injuries in such crashes. It is found that "small-small" crashes (defined as a 900 kg car crashing into another 900 kg car) are about 0.3 times as likely as "big-big" crashes (an 1800 kg car crashing into another 1800 kg car), assuming equal numbers of cars driven by drivers of the same age. Combining the present results with earlier findings of increased injury risk in small-small crashes gives that such crashes injure about 70% as many drivers as big-big crashes when normalized for numbers of cars and driver age. That is, it is concluded that small-small crashes produce 30% fewer injuries than do big-big crashes. PMID:4096783

  12. Synergistic acceleration of thyroid hormone degradation by phenobarbital and the PPAR{alpha} agonist WY14643 in rat hepatocytes

    SciTech Connect

    Wieneke, N.; Neuschaefer-Rube, F.; Bode, L.M.; Kuna, M.; Andres, J.; Carnevali, L.C.; Hirsch-Ernst, K.I.; Pueschel, G.P.

    2009-10-01

    Energy balance is maintained by controlling both energy intake and energy expenditure. Thyroid hormones play a crucial role in regulating energy expenditure. Their levels are adjusted by a tight feedback-controlled regulation of thyroid hormone production/incretion and by their hepatic metabolism. Thyroid hormone degradation has previously been shown to be enhanced by treatment with phenobarbital or other antiepileptic drugs due to a CAR-dependent induction of phase II enzymes of xenobiotic metabolism. We have recently shown, that PPAR{alpha} agonists synergize with phenobarbital to induce another prototypical CAR target gene, CYP2B1. Therefore, it was tested whether a PPAR{alpha} agonist could enhance the phenobarbital-dependent acceleration of thyroid hormone elimination. In primary cultures of rat hepatocytes the apparent half-life of T3 was reduced after induction with a combination of phenobarbital and the PPAR{alpha} agonist WY14643 to a larger extent than after induction with either compound alone. The synergistic reduction of the half-life could be attributed to a synergistic induction of CAR and the CAR target genes that code for enzymes and transporters involved in the hepatic elimination of T3, such as OATP1A1, OATP1A3, UGT1A3 and UGT1A10. The PPAR{alpha}-dependent CAR induction and the subsequent induction of T3-eliminating enzymes might be of physiological significance for the fasting-induced reduction in energy expenditure by fatty acids as natural PPAR{alpha} ligands. The synergism of the PPAR{alpha} agonist WY14643 and phenobarbital in inducing thyroid hormone breakdown might serve as a paradigm for the synergistic disruption of endocrine control by other combinations of xenobiotics.

  13. Plastic cars for developing nations

    SciTech Connect

    Ashley, S.

    1997-11-01

    Plastic automobiles may have passed a milestone on the long road to commercial reality with the development of Composite Concept Vehicle (CCV) from Chrysler Corp. in Auburn Hills, Mich. This basic compact car--so basic it could be called bare bones--is built by attaching an injection-molded thermoplastic polyester body onto a tubular steel chassis. The 1,200-pound CCV, which is expected to require one-third the labor and investment needed to build a conventional small car, was designed for new buyers in the emerging economies of China, India, and Southeast Asia. If commercialized, the car would likely cost about $6,000--halfway between a motorcycle and an entry-level auto. The small car was unveiled in September 1996 at the Frankfurt Auto Show in Germany.

  14. Car Safety for Special Children.

    ERIC Educational Resources Information Center

    Holland, Suzanne Hauser

    1983-01-01

    Various car seats, harnesses, and vests that can be used with handicapped children are described. Suggestions are also made for improvment when existing equipment is not appropriate. A list of resources on the topic is also provided. (CL)

  15. CARS applications to combustion diagnostics

    NASA Astrophysics Data System (ADS)

    Eckbreth, Alan C.

    1986-01-01

    Attention is given to broadband or multiplex CARS of combustion processes, using pulsed lasers whose intensity is sufficiently great for instantaneous measurement of medium properties. This permits probability density functions to be assembled from a series of single-pulse measurements, on the basis of which the true parameter average and the magnitude of the turbulent fluctuations can be ascertained. CARS measurements have been conducted along these lines in diesel engines, gas turbine combustors, scramjets, and solid rocket propellants.

  16. Getting More Mileage out of Mousetrap Cars

    ERIC Educational Resources Information Center

    Rutherford, Sandra; Wylo, Bonnie

    2004-01-01

    Building and racing mousetrap cars is a common activity in many eighth- and ninth-grade physical science classrooms. However, once students have raced their cars, most mousetrap assignments come to an end. In this article, the authors developed a project to help teachers get more mileage out of mousetrap cars. The Mousetrap Car Project addresses…

  17. 49 CFR 215.203 - Restricted cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Restricted cars. 215.203 Section 215.203..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Restricted Equipment § 215.203 Restricted cars. (a) This section restricts the operation of any railroad freight car that is— (1) More than...

  18. 49 CFR 215.203 - Restricted cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Restricted cars. 215.203 Section 215.203..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Restricted Equipment § 215.203 Restricted cars. (a) This section restricts the operation of any railroad freight car that is— (1) More than...

  19. 49 CFR 231.6 - Flat cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Flat cars. 231.6 Section 231.6 Transportation... TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.6 Flat cars. (Cars with sides 12 inches or less above the floor may be equipped the same as flat cars.) (a) Hand brakes—(1) Number. Same as specified...

  20. 49 CFR 1037.2 - Cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 8 2012-10-01 2012-10-01 false Cars. 1037.2 Section 1037.2 Transportation Other... GENERAL RULES AND REGULATIONS BULK GRAIN AND GRAIN PRODUCTS-LOSS AND DAMAGE CLAIMS § 1037.2 Cars. A car is... railroad-leased cars....

  1. 49 CFR 231.6 - Flat cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Flat cars. 231.6 Section 231.6 Transportation... TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.6 Flat cars. (Cars with sides 12 inches or less above the floor may be equipped the same as flat cars.) (a) Hand brakes—(1) Number. Same as specified...

  2. 49 CFR 231.6 - Flat cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Flat cars. 231.6 Section 231.6 Transportation... TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.6 Flat cars. (Cars with sides 12 inches or less above the floor may be equipped the same as flat cars.) (a) Hand brakes—(1) Number. Same as specified...

  3. 49 CFR 215.203 - Restricted cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Restricted cars. 215.203 Section 215.203..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Restricted Equipment § 215.203 Restricted cars. (a) This section restricts the operation of any railroad freight car that is— (1) More than...

  4. 49 CFR 1037.2 - Cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 8 2013-10-01 2013-10-01 false Cars. 1037.2 Section 1037.2 Transportation Other... GENERAL RULES AND REGULATIONS BULK GRAIN AND GRAIN PRODUCTS-LOSS AND DAMAGE CLAIMS § 1037.2 Cars. A car is... railroad-leased cars....

  5. 49 CFR 1037.2 - Cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 8 2014-10-01 2014-10-01 false Cars. 1037.2 Section 1037.2 Transportation Other... GENERAL RULES AND REGULATIONS BULK GRAIN AND GRAIN PRODUCTS-LOSS AND DAMAGE CLAIMS § 1037.2 Cars. A car is... railroad-leased cars....

  6. Art Cars: Transformations of the Mundane

    ERIC Educational Resources Information Center

    Stienecker, Dawn

    2010-01-01

    The automobile itself is often understood as an extension of oneself, where individuals may manipulate the interior and exterior of cars and trucks, decorating them through detailing, stickers, custom colors, and so on. Others go further and change their cars into unique works of art called art cars. Such cars break away from the banality of mass…

  7. 49 CFR 231.6 - Flat cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Flat cars. 231.6 Section 231.6 Transportation... TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.6 Flat cars. (Cars with sides 12 inches or less above the floor may be equipped the same as flat cars.) (a) Hand brakes—(1) Number. Same as specified...

  8. 49 CFR 215.203 - Restricted cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Restricted cars. 215.203 Section 215.203..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Restricted Equipment § 215.203 Restricted cars. (a) This section restricts the operation of any railroad freight car that is— (1) More than...

  9. 49 CFR 1037.2 - Cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 8 2011-10-01 2011-10-01 false Cars. 1037.2 Section 1037.2 Transportation Other... GENERAL RULES AND REGULATIONS BULK GRAIN AND GRAIN PRODUCTS-LOSS AND DAMAGE CLAIMS § 1037.2 Cars. A car is... railroad-leased cars....

  10. The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation.

    PubMed

    Larsson, Olivia J; Manson, Martijn L; Starkhammar, Magnus; Fuchs, Barbara; Adner, Mikael; Kumlien Georén, Susanna; Cardell, Lars-Olaf

    2016-06-01

    Toll-like receptor (TLR) 7 agonists are known to reduce allergic airway inflammation. Their recently reported ability to rapidly relax airways has further increased their interest in the treatment of pulmonary disease. However, the mechanisms behind this effect are not fully understood. The present study, therefore, aimed to determine whether airway smooth muscle (ASM)-dependent mechanisms could be identified. TLR7 agonists were added to guinea pig airways following precontraction with carbachol in vitro or histamine in vivo. Pharmacological inhibitors were used to dissect conventional pathways of bronchodilation; tetrodotoxin was used or bilateral vagotomy was performed to assess neuronal involvement. Human ASM cells (HASMCs) were employed to determine the effect of TLR7 agonists on intracellular Ca(2+) ([Ca(2+)]i) mobilization. The well-established TLR7 agonist imiquimod rapidly relaxed precontracted airways in vitro and in vivo. This relaxation was demonstrated to be independent of nitric oxide, carbon monoxide, and cAMP signaling, as well as neuronal activity. A limited role for prostanoids could be detected. Imiquimod induced [Ca(2+)]i release from endoplasmic reticulum stores in HASMCs, inhibiting histamine-induced [Ca(2+)]i The TLR7 antagonist IRS661 failed to inhibit relaxation, and the structurally dissimilar agonist CL264 did not relax airways or inhibit [Ca(2+)]i This study shows that imiquimod acts directly on ASM to induce bronchorelaxation, via a TLR7-independent release of [Ca(2+)]i The effect is paralleled by other bronchorelaxant compounds, like chloroquine, which, like imiquimod, but unlike CL264, contains the chemical structure quinoline. Compounds with quinoline moieties may be of interest in the development of multifunctional drugs to treat pulmonary disease. PMID:27084847

  11. SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism

    PubMed Central

    Chen, Tenghui; Chen, Qiang; Xu, Yixiang; Zhou, Qiling; Zhu, Jingwei; Zhang, Hao; Wu, Qiao; Xu, Jianming; Yu, Chundong

    2011-01-01

    Background & Aims Nuclear receptors such as pregnane X receptor and constitutive androstane receptor (CAR) are important regulators of drug-metabolizing systems such as P450s enzymes and modulate xenobiotic metabolism as well as hepatocellular proliferation. Binding of CAR to NR response elements alone is not sufficient to activate gene expression. Here we investigate the role of steroid receptor coactivator (SRC) family members in CAR-mediated hepatocyte proliferation and drug metabolism. Methods The role of SRCs in CAR activation was assessed in cell-based transfection assays and protein-protein interaction assays. The in vivo role of SRCs in CAR-mediated hepatocyte proliferation and drug metabolism was examined by using mice deficient in SRCs. Results SRC-3 displayed the highest coactivating activity to CAR compared with SRC-1 and SRC-2 in a cell-based reporter assay. Knockout of SRC-3 in mice attenuated hepatic hyperplasia induced by a CAR agonist 1,4-bis-[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), which was associated with a reduced expression of c-Myc and Foxm-1. In contrast, knockout of SRC-1 or SRC-2 in mice did not affect TCPOBOP-induced hepatic hyperplasia. SRC-3-deficient mice were hypersensitive to zoxazolamine-induced paralysis, but were resistant to acetaminophen hepatotoxicity induced by TCPOBOP, whereas mutant mice deficient in SRC-1 or SRC-2 exhibited severe acetaminophen hepatotoxicity similar to wild-type controls. Accordingly, deficiency in SRC-3, but not SRC-1 or SRC-2, resulted in a reduced CAR-mediated expression of drug metabolism-related genes in the liver. Conclusions Our study demonstrates that SRC-3 is the predominant transcriptional coactivator among the three SRC family members for CAR activation to promote hepatocyte proliferation and drug metabolism. PMID:21827731

  12. Phase dependency of long-term potentiation induction during the intermittent bursts of carbachol-induced β oscillation in rat hippocampal slices

    PubMed Central

    Nishimura, Motoshi; Nakatsuka, Hiroki; Natsume, Kiyohisa

    2012-01-01

    The rodent hippocampus possesses theta (θ) and beta (β) rhythms, which occur intermittently as bursts. Both rhythms are related to spatial memory processing in a novel environment. θ rhythm is related to spatial memory encoding process. β rhythm is related to the match/mismatch process. In the match/mismatch process, rodent hippocampus detects a representation matching sensory inputs of the current place among the retrieved internal representations of places. Long-term synaptic potentiation (LTP) is induced in both processes. The cholinergic agent carbachol induces intermittent θ and β oscillations in in vitro slices similar to in vivo bursts. LTP is facilitated during the generation of θ oscillation, suggesting that the facilitation of LTP is dependent upon the phases of intermittent burst (burst phases) of the oscillation. However, whether this is the case for β oscillation has not yet been studied. In the present study, LTP-inducing θ-burst stimulation was administered at the different burst phases of carbachol-induced β oscillations (CIBO), and the synaptic changes were measured at CA3-CA3 pyramidal cell synapses (CA3 synapse) and at CA3-CA1 pyramidal cell synapses (CA1 synapse). At the CA3 synapse, the largest magnitude of LTP was induced at the late burst phases of CIBO. At the CA1 synapse, LTP was induced only at the late burst phases. Modulation of LTP was suppressed when CIBO was blocked by the application of atropine at both synapses. The results suggest that the bursts of hippocampal β rhythm can determine the optimal temporal period for completing with the match/mismatch process.

  13. Role of orexin-2 receptors in the nucleus accumbens in antinociception induced by carbachol stimulation of the lateral hypothalamus in formalin test.

    PubMed

    Yazdi, Fatemeh; Jahangirvand, Mahboubeh; Ezzatpanah, Somayeh; Haghparast, Abbas

    2016-08-01

    Orexins, which are mainly produced by orexin-expressing neurons in the lateral hypothalamus (LH), play an important role in pain modulation. Previously, it has been established that the nucleus accumbens (NAc) is involved in the modulation of formalin-induced nociceptive responses, a model of tonic pain. In this study, the role of intra-accumbal orexin-2 receptors (OX2rs) in the mediation of formalin-induced pain was investigated. A volume of 0.5 μl of 10, 20, and 40 nmol/l solutions of TCS OX2 29, an OX2r antagonist, were unilaterally microinjected into the NAc 5 min before an intra-LH carbachol microinjection (0.5 μl of 250 nmol/l solution). After 5 min, animals received a subcutaneous injection of formalin 2.5% (50 μl) into the hind paw. Pain-related behaviors were assessed at 5 min intervals during a 60-min test period. The findings showed that TCS OX2 29 administration dose dependently blocked carbachol-induced antinociception during both phases of formalin-induced pain. The antianalgesic effect of TCS OX2 29 was greater during the late phase compared with the early phase. These observations suggest that the NAc, as a part of a descending pain-modulatory circuitry, partially mediates LH-induced analgesia in the formalin test through recruitment of OX2rs. This makes the orexinergic system a good potential therapeutic target in the control of persistent inflammatory pain. PMID:26871404

  14. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  15. Seatbelts in CAR therapy: How Safe Are CARS?

    PubMed Central

    Minagawa, Kentaro; Zhou, Xiaoou; Mineishi, Shin; Di Stasi, Antonio

    2015-01-01

    T-cells genetically redirected with a chimeric antigen receptor (CAR) to recognize tumor antigens and kill tumor cells have been infused in several phase 1 clinical trials with success. Due to safety concerns related to on-target/off-tumor effects or cytokine release syndrome, however, strategies to prevent or abate serious adverse events are required. Pharmacologic therapies; suicide genes; or novel strategies to limit the cytotoxic effect only to malignant cells are under active investigations. In this review, we summarize results and toxicities of investigations employing CAR redirected T-cells, with a focus on published strategies to grant safety of this promising cellular application. PMID:26110321

  16. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  17. Method for loading coal into railroad cars

    SciTech Connect

    Moon, J.L.; Tompkins, J.C.

    1984-07-17

    A system for loading coal or other particles into railroad cars wherein every other railroad car is designated an EVEN railroad car and the remaining every other railroad cars are designated ODD railroad cars. Each EVEN railroad car is weighed after being filled with coal and before the initiation of the loading of coal into the next EVEN railroad car to determine a filled weight. The filled weight of each EVEN railroad car is compared to a predetermined control weight and, in response to this determination, the termination of the loading of coal into the next EVEN railroad car controllably is varied to bring the filled weight closer to control weight. In a like manner, each ODD railroad car is weighed after being filled with coal and before the initiation of the loading of coal into the next ODD railroad car to determine a filled weight. The filled weight of each ODD railroad car is compared to the predetermined control weight and, in response to this determination, the termination of the loading of coal into the next ODD railroad car controllably is varied to bring the filled weight closer to the control weight.

  18. Symmetry in the Car Park

    ERIC Educational Resources Information Center

    Hancock, Karen

    2007-01-01

    In this article, the author presents a lesson on rotational symmetry which she developed for her students. The aim of the lesson was "to identify objects with rotational symmetry in the staff car park" and the success criteria were "pictures or sketches of at least six objects with different orders of rotation". After finding examples of…

  19. Restoring a Classic Electric Car

    ERIC Educational Resources Information Center

    Kraft, Thomas E.

    2012-01-01

    One hundred years ago, automobiles were powered by steam, electricity, or internal combustion. Female drivers favored electric cars because, unlike early internal-combustion vehicles, they did not require a crank for starting. Nonetheless, internal-combustion vehicles came to dominate the industry and it's only in recent years that the electrics…

  20. The Speeding Car Design Challenge

    ERIC Educational Resources Information Center

    Roman, Harry T.

    2009-01-01

    All too often, one reads about high-speed police chases in pursuit of stolen cars that result in death and injury to people and innocent bystanders. Isn't there another way to accomplish the apprehension of the thieves that does not put people at such great risk? This article presents a classroom challenge to use technology to remotely shutdown…

  1. Car Hits Boy on Bicycle

    ERIC Educational Resources Information Center

    Ruiz, Michael J.

    2005-01-01

    In this article we present the fascinating reconstruction of an accident where a car hit a boy riding his bicycle. The boy dramatically flew several metres through the air after the collision and was injured, but made a swift and complete recovery from the accident with no long-term after-effects. Students are challenged to determine the speed of…

  2. Automated Car Park Management System

    NASA Astrophysics Data System (ADS)

    Fabros, J. P.; Tabañag, D.; Espra, A.; Gerasta, O. J.

    2015-06-01

    This study aims to develop a prototype for an Automated Car Park Management System that will increase the quality of service of parking lots through the integration of a smart system that assists motorist in finding vacant parking lot. The research was based on implementing an operating system and a monitoring system for parking system without the use of manpower. This will include Parking Guidance and Information System concept which will efficiently assist motorists and ensures the safety of the vehicles and the valuables inside the vehicle. For monitoring, Optical Character Recognition was employed to monitor and put into list all the cars entering the parking area. All parking events in this system are visible via MATLAB GUI which contain time-in, time-out, time consumed information and also the lot number where the car parks. To put into reality, this system has a payment method, and it comes via a coin slot operation to control the exit gate. The Automated Car Park Management System was successfully built by utilizing microcontrollers specifically one PIC18f4550 and two PIC16F84s and one PIC16F628A.

  3. Power unit for electric cars

    SciTech Connect

    Ishikawa, Masami; Minezawa, Yukihiro.

    1993-07-06

    A power unit for mounting on the body of an electric car is described, comprising: a sensor for detecting a running condition of the car; a first power supply mounted on the electric car body; a second power supply module; means for detachably mounting different, interchangeable types of the second power supply module on the electric car body; a motor control circuit, including a computer, connected to the first power supply and the second power supply module for feeding a current to a motor as commanded by the computer; the computer including control means for determining (1) whether the second power supply module is mounted or not and (2) for determining the type of second power supply module mounted; setting means for connecting the first power supply and the second power supply module with the motor control circuit, in parallel or in series, responsive to the detected running condition; and the computer controlling the motor control circuit according to determinations of the control means.

  4. Physics Fun with Toy Cars

    ERIC Educational Resources Information Center

    Herald, Christine

    2010-01-01

    According to the National Science Education Standards, students should be able to describe an object by its position, direction of motion, and speed (NRC 1996). During a unit on motion, the author decided to use Hot Wheels cars as the object students would describe. The first two activities are used to introduce students to the equipment and the…

  5. Friction in a Moving Car

    ERIC Educational Resources Information Center

    Goldberg, Fred M.

    1975-01-01

    Describes an out-of-doors, partially unstructured experiment to determine the coefficient of friction for a moving car. Presents the equation which relates the coefficient of friction to initial velocity, distance, and time and gives sample computed values as a function of initial speed and tire pressure. (GS)

  6. AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer’s Disease.

    PubMed

    Fisher, Abraham; Bezprozvanny, Ilya; Wu, Lili; Ryskamp, Daniel A; Bar-Ner, Nira; Natan, Niva; Brandeis, Rachel; Elkon, Hanoch; Nahum, Victoria; Gershonov, Eitan; LaFerla, Frank M; Medeiros, Rodrigo

    2016-01-01

    We previously developed orthosteric M1 muscarinic agonists (e.g. AF102B, AF267B and AF292), which act as cognitive enhancers and potential disease modifiers. We now report on a novel compound, AF710B, a highly potent and selective allosteric M1 muscarinic and σ1 receptor agonist. AF710B exhibits an allosteric agonistic profile on the M1 muscarinic receptor; very low concentrations of AF710B significantly potentiated the binding and efficacy of carbachol on M1 receptors and their downstream effects (p-ERK1/2, p-CREB). AF710B (1-30 µg/kg, p.o.) was a potent and safe cognitive enhancer in rats treated with the M1 antagonist trihexyphenidyl (passive avoidance impairment). These effects of AF710B involve σ1 receptor activation. In agreement with its antiamnesic properties, AF710B (at 30 nM), via activation of M1 and a possible involvement of σ1 receptors, rescued mushroom synapse loss in PS1-KI and APP-KI neuronal cultures, while AF267B (1 µM) was less potent in PS1-KI and ineffective in APP-KI models, respectively. In female 3xTg-AD mice, AF710B (10 µg/kg, i.p./daily/2 months) (i) mitigated cognitive impairments in the Morris water maze; (ii) decreased BACE1, GSK3β activity, p25/CDK5, neuroinflammation, soluble and insoluble Aβ40, Aβ42, plaques and tau pathologies. AF710B differs from conventional σ1 and M1 muscarinic (orthosteric, allosteric or bitopic) agonists. These results highlight AF710B as a potential treatment for Alzheimer's disease (e.g. improving cognitive deficits, synaptic loss, amyloid and tau pathologies, and neuroinflammation) with a superior profile over a plethora of other therapeutic strategies. PMID:26606130

  7. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  8. Alpha2-adrenoreceptors profile modulation. 4. From antagonist to agonist behavior.

    PubMed

    Gentili, Francesco; Cardinaletti, Claudia; Vesprini, Cristian; Carrieri, Antonio; Ghelfi, Francesca; Farande, Aniket; Giannella, Mario; Piergentili, Alessandro; Quaglia, Wilma; Laurila, Jonne M; Huhtinen, Anna; Scheinin, Mika; Pigini, Maria

    2008-07-24

    The goal of the present study was to modulate the receptor interaction properties of known alpha 2-adrenoreceptor (AR) antagonists to obtain novel alpha 2-AR agonists with desirable subtype selectivity. Therefore, a phenyl group or one of its bioisosteres or aliphatic moieties with similar steric hindrance were introduced into the aromatic ring of the antagonist lead basic structure. The functional properties of the novel compounds allowed our previous observations to be confirmed. The high efficacy of 7, 12, and 13 as alpha 2-AR agonists and the significant alpha 2C-AR subtype selective activation displayed by 11 and 15 demonstrated that favorable interactions to induce alpha 2-AR activation were formed between the pendant groups of the ligands and the aromatic cluster present in transmembrane domain 6 of the binding site cavity of the receptors. PMID:18578476

  9. Solar-powered car. Final report

    SciTech Connect

    Plank, D.

    1982-03-30

    The work reported was to modify a commercially available electric vehicle to use power generated by solar cells. Besides the technical and financial aspects of constructing the car, media publicity and public showings of the car are discussed. (LEW)

  10. Inflation Rates, Car Devaluation, and Chemical Kinetics

    NASA Astrophysics Data System (ADS)

    Pogliani, Lionello; Berberan-Santos, Màrio N.

    1996-10-01

    The inflation rate problem of a modern economy shows quite interesting similarities with chemical kinetics and especially with first-order chemical reactions. In fact, capital devaluation during periods of rather low inflation rates or inflation measured over short periods shows a dynamics formally similar to that followed by first-order chemical reactions and they can thus be treated by the aid of the same mathematical formalism. Deviations from this similarity occurs for higher inflation rates. The dynamics of price devaluation for two different types of car, a compact car and a luxury car, has been followed for seven years long and it has been established that car devaluation is a process that is formally similar to a zeroth-order chemical kinetic process disregarding the type of car, if car devaluation is much faster than money devaluation. In fact, expensive cars devaluate with a faster rate than inexpensive cars.

  11. A Demonstration of Car Braking Instabilities.

    ERIC Educational Resources Information Center

    Irwin, Jack; Swinson, Derek

    1990-01-01

    Detailed are the construction of a demonstration car, apparatus and procedures used in the demonstration, and the analysis of the effects of car braking. The cases of rear-wheel and front-wheel braking are considered. (CW)

  12. 49 CFR 174.110 - Car magazine.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 2 2014-10-01 2014-10-01 false Car magazine. 174.110 Section 174.110...) Materials § 174.110 Car magazine. When specially authorized by the carrier, Division 1.1 or 1.2 (explosive) materials in quantity not exceeding 68 kg (150 pounds) may be carried in construction or repair cars if...

  13. 49 CFR 174.110 - Car magazine.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 2 2013-10-01 2013-10-01 false Car magazine. 174.110 Section 174.110...) Materials § 174.110 Car magazine. When specially authorized by the carrier, Division 1.1 or 1.2 (explosive) materials in quantity not exceeding 68 kg (150 pounds) may be carried in construction or repair cars if...

  14. 49 CFR 174.57 - Cleaning cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 2 2012-10-01 2012-10-01 false Cleaning cars. 174.57 Section 174.57... and Loading Requirements § 174.57 Cleaning cars. All hazardous material which has leaked from a package in any rail car or on other railroad property must be carefully removed....

  15. 49 CFR 174.110 - Car magazine.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 2 2012-10-01 2012-10-01 false Car magazine. 174.110 Section 174.110...) Materials § 174.110 Car magazine. When specially authorized by the carrier, Division 1.1 or 1.2 (explosive) materials in quantity not exceeding 68 kg (150 pounds) may be carried in construction or repair cars if...

  16. 49 CFR 174.57 - Cleaning cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 2 2013-10-01 2013-10-01 false Cleaning cars. 174.57 Section 174.57... and Loading Requirements § 174.57 Cleaning cars. All hazardous material which has leaked from a package in any rail car or on other railroad property must be carefully removed....

  17. 49 CFR 174.57 - Cleaning cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 2 2014-10-01 2014-10-01 false Cleaning cars. 174.57 Section 174.57... and Loading Requirements § 174.57 Cleaning cars. All hazardous material which has leaked from a package in any rail car or on other railroad property must be carefully removed....

  18. 49 CFR 215.203 - Restricted cars.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Restricted cars. 215.203 Section 215.203 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Restricted Equipment § 215.203 Restricted cars. (a) This section restricts...

  19. Video monitoring system for car seat

    NASA Technical Reports Server (NTRS)

    Elrod, Susan Vinz (Inventor); Dabney, Richard W. (Inventor)

    2004-01-01

    A video monitoring system for use with a child car seat has video camera(s) mounted in the car seat. The video images are wirelessly transmitted to a remote receiver/display encased in a portable housing that can be removably mounted in the vehicle in which the car seat is installed.

  20. 49 CFR 212.217 - Car inspector.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Car inspector. 212.217 Section 212.217 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION STATE SAFETY PARTICIPATION REGULATIONS State Inspection Personnel § 212.217 Car inspector. (a) The car inspector is...

  1. 49 CFR 1037.2 - Cars.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 8 2010-10-01 2010-10-01 false Cars. 1037.2 Section 1037.2 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION GENERAL RULES AND REGULATIONS BULK GRAIN AND GRAIN PRODUCTS-LOSS AND DAMAGE CLAIMS § 1037.2 Cars. A car is not in suitable condition for...

  2. 49 CFR 231.6 - Flat cars.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Flat cars. 231.6 Section 231.6 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.6 Flat cars. (Cars with sides 12 inches or less above the floor may be equipped the same...

  3. Shuttle-Car System for Continuous Mining

    NASA Technical Reports Server (NTRS)

    Collins, E. R., Jr.

    1984-01-01

    Buffer storage catches coal production between loadings. Telescoping reservoir filled continuously. With tailgate down, shuttle car slides into place along sides and bottom of reservoir. Reservoir retracts along inside of car and out through tailgate, leaving coal behind in car. System not restricted to coal mining and may prove economical for hauling other solid materials.

  4. 49 CFR 174.110 - Car magazine.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 2 2011-10-01 2011-10-01 false Car magazine. 174.110 Section 174.110...) Materials § 174.110 Car magazine. When specially authorized by the carrier, Division 1.1 or 1.2 (explosive) materials in quantity not exceeding 68 kg (150 pounds) may be carried in construction or repair cars if...

  5. 49 CFR 174.57 - Cleaning cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 2 2011-10-01 2011-10-01 false Cleaning cars. 174.57 Section 174.57... and Loading Requirements § 174.57 Cleaning cars. All hazardous material which has leaked from a package in any rail car or on other railroad property must be carefully removed....

  6. Determining the Air Drag on a Car.

    ERIC Educational Resources Information Center

    Farr, John E.

    1983-01-01

    Students' cars and wristwatches are used as "apparatus" to introduce and demonstrate Newton's second law of motion. Forces acting on cars are discussed and typical student data (for different makes of cars) are provided. Data could also be used in discussions of work, horsepower, efficiency, and energy cost. (JN)

  7. The association of thirst, sodium appetite and vasopressin release with c-fos expression in the forebrain of the rat after intracerebroventricular injection of angiotensin II, angiotensin-(1-7) or carbachol.

    PubMed

    Mahon, J M; Allen, M; Herbert, J; Fitzsimons, J T

    1995-11-01

    The effect intracerebroventricular injections of angiotensin II (0.1 nm), angiotensin-(1-7) (1 or 100 nm) and carbachol (500 ng) on c-fos expression was examined in the forebrain of Lister hooded rats. Intense staining of the c-Fos protein was found in the median preoptic nucleus, organum vasculosum of the lamina terminalis, subfornical organ, paraventricular nucleus and supraoptic nucleus after angiotensin II and carbachol Angiotensin II caused significantly more c-fos expression in the ventral median preoptic nucleus and organum vasculosum of the lamina terminalis than carbachol, whereas in the paraventricular and supraoptic nuclei this was reversed, with carbachol having a greater effect on c-fos expression in these areas. Angiotensin-(1-7), however, only induced c-Fos protein in the organum vasculosum of the lamina terminalis and median preoptic nucleus with the number and the intensity of staining of the nuclei significantly less in both areas than after angiotensin II or carbachol. Separate groups of Lister rats were given i.c.v. injections of the same substances at the same doses, but excluding the lower dose of angiotensin-(1-7), and the intakes of water and 1.8% NaCl over 60 min were measured. Angiotensin II stimulated intakes of both water and NaCl. The effect on water intake was almost immediate (<1 min), whereas NaCl intake did not usually start until at least 5 min after injection. Over 60 min, water (12.4 +/- 1.0 ml) and NaCl (4.2 +/- 0.9 ml) intakes were significantly greater than water (1.1 +/- 0.2 ml) and NaCl (0.6 +/- 0.5 ml) intakes of the controls. Carbachol caused less drinking than angiotensin II, the water intake over 60 min being significantly less (4.8 +/- 0.7 ml) and the latency of response greater (>5 min). Carbachol, unlike angiotensin II, had little effect on NaCl intake (0.7 +/- 0.4 ml). Angiotensin-(1-7) had no effect on water (1.1 +/- 0.3 ml) or NaCl (0.3 +/- 0.3 ml) intakes. The plasma levels of vasopressin were measured after i

  8. 49 CFR 1247.1 - Annual Report of Cars Loaded and Cars Terminated.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Annual Report of Cars Loaded and Cars Terminated. 1247.1 Section 1247.1 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION (CONTINUED) ACCOUNTS, RECORDS AND REPORTS REPORT OF CARS LOADED AND CARS TERMINATED §...

  9. A role for protein kinase C subtypes alpha and epsilon in phorbol-ester-enhanced K(+)- and carbachol-evoked noradrenaline release from the human neuroblastoma SH-SY5Y.

    PubMed Central

    Turner, N A; Rumsby, M G; Walker, J H; McMorris, F A; Ball, S G; Vaughan, P F

    1994-01-01

    Protein kinase C (PKC) consists of a family of closely related subtypes which differ in their localization and activation properties. Our previous studies have suggested a role for PKC in the regulation of noradrenaline (NA) release from the human neuroblastoma SH-SY5Y. Here we have used two approaches to characterize the PKC subtypes present in SH-SY5Y cells. Firstly, the PCR was used to show that SH-SY5Y cells contain mRNA encoding PKC subtypes alpha, beta, gamma, delta, epsilon and zeta. Secondly, immunoblotting showed that SH-SY5Y cells express PKC subtypes alpha, epsilon and zeta at the protein level. Prolonged (48 h) exposure of cells to the phorbol ester phorbol 12-myristate 13-acetate (PMA; 100 nM) resulted in a marked decrease in the amounts of PKC-alpha and PKC-epsilon, with no change in levels of PKC-zeta. Prolonged PMA treatment had no significant effect on K(+)-evoked NA release from SH-SY5Y cells, whereas carbachol-evoked release was increased 2.2-fold. However, prolonged exposure to PMA completely inhibited the ability of acute (12 min) PMA treatment to enhance both K(+)- and carbachol-evoked NA release. The specific PKC inhibitor RO 31-7459 (10 microM) was found to inhibit K(+)- and carbachol-evoked release by 27% and 68% respectively. RO 31-7549 also completely inhibited the ability of acute PMA treatment to enhance release. These data suggest that PKC-alpha and/or PKC-epsilon play an essential role in the regulation of PMA-enhanced K(+)- and carbachol-evoked NA release in SH-SY5Y cells. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8297348

  10. Entwurfskonzept einer Car2Car-Multiband-Dachantenne

    NASA Astrophysics Data System (ADS)

    Wang, Y.; Reit, M.; Mathis, W.

    2012-09-01

    Due to the vastly increasing use of wireless services in the car, such as WiFi, Car2Car and LTE, the requirements on bandwidth and radiation pattern of the roof antenna systems become more challenging. In this work, a design concept for multi-band roof antenna systems is presented. We aim to get a higher bandwidth and an almost circular radiation pattern on the horizontal plane. Moreover, the antenna length is considered in order to fulfill the requirements set by construction ECE-regulations (ECE, 2010). The applicability of the design concept is not limited to multi-band roof antennas, it can also be used for a general wideband antenna design. For illustration of this concept, a multi-band roof antenna with a bandwidth of 780 MHz to 5.9 GHz and a near circular radiation pattern with an average gain of G = 3 dBi (at 5.9 GHz) on the horizontal plane is designed. The simulation and measurement results are presented.

  11. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  12. CAR-T cells are serial killers

    PubMed Central

    Davenport, Alexander J; Jenkins, Misty R; Ritchie, David S; Prince, H Miles; Trapani, Joseph A; Kershaw, Michael H; Darcy, Phillip K; Neeson, Paul J

    2015-01-01

    Chimeric antigen receptor (CAR) T cells have enjoyed unprecedented clinical success against haematological malignancies in recent years. However, several aspects of CAR T cell biology remain unknown. We recently compared CAR and T cell receptor (TCR)-based killing in the same effector cell and showed that CAR T cells can not only efficiently kill single tumor targets, they can also kill multiple tumor targets in a sequential manner. Single and serial killing events were not sustained long term due to CAR down-regulation after 20 hours. PMID:26587330

  13. Inhibitory effects of salviae miltiorrhizae radix (danshen) and puerariae lobatae radix (gegen) in carbachol-induced rat detrusor smooth muscle contractility

    PubMed Central

    Liang, Willmann; Teong, Ivy Wen Jia; Koon, Johnny Chi Man; Lau, Clara Bik San; Fung, Kwok Pui; Leung, Ping Chung

    2012-01-01

    Both danshen (D) and gegen (G) have proven relaxant effects on vascular smooth muscle, thus their potential bladder inhibitory effects have impending interests in urology. The aim of this study was to demonstrate the novel effects of D and G on detrusor smooth muscle contractility. Urothelium-intact (+UE) and urothelium-denuded (-UE) detrusor strips were isolated from the rat. Isometric tension was measured using a myograph system. Carbachol (CCh) was used to pre-contract the detrusor strips prior to stepwise relaxation by adding extracts of D, G, and a DG (7:3) formulation. Tonic relaxation level and phasic contractile activity under the herbal treatments were analyzed. There was no difference in the herbal effects between +UE and -UE strips. D alone induced a much smaller relaxation than G alone or DG. G alone also suppressed phasic amplitude but not phasic frequency while DG suppressed both parameters. D and G acted synergistically to yield the observed effects on detrusor smooth muscle. The findings showed that the DG formulation were able to relax the detrusor as well as suppress phasic contractions, both actions important in maintaining normal bladder filling and urine storage processes. Hence DG may have new application in the management of bladder disorders. PMID:22461955

  14. Inhibitory effects of salviae miltiorrhizae radix (danshen) and puerariae lobatae radix (gegen) in carbachol-induced rat detrusor smooth muscle contractility.

    PubMed

    Liang, Willmann; Teong, Ivy Wen Jia; Koon, Johnny Chi Man; Lau, Clara Bik San; Fung, Kwok Pui; Leung, Ping Chung

    2012-01-01

    Both danshen (D) and gegen (G) have proven relaxant effects on vascular smooth muscle, thus their potential bladder inhibitory effects have impending interests in urology. The aim of this study was to demonstrate the novel effects of D and G on detrusor smooth muscle contractility. Urothelium-intact (+UE) and urothelium-denuded (-UE) detrusor strips were isolated from the rat. Isometric tension was measured using a myograph system. Carbachol (CCh) was used to pre-contract the detrusor strips prior to stepwise relaxation by adding extracts of D, G, and a DG (7:3) formulation. Tonic relaxation level and phasic contractile activity under the herbal treatments were analyzed. There was no difference in the herbal effects between +UE and -UE strips. D alone induced a much smaller relaxation than G alone or DG. G alone also suppressed phasic amplitude but not phasic frequency while DG suppressed both parameters. D and G acted synergistically to yield the observed effects on detrusor smooth muscle. The findings showed that the DG formulation were able to relax the detrusor as well as suppress phasic contractions, both actions important in maintaining normal bladder filling and urine storage processes. Hence DG may have new application in the management of bladder disorders. PMID:22461955

  15. PDE4 and PDE5 regulate cyclic nucleotide contents and relaxing effects on carbachol-induced contraction in the bovine abomasum

    PubMed Central

    KANEDA, Takeharu; KIDO, Yuuki; TAJIMA, Tsuyoshi; URAKAWA, Norimoto; SHIMIZU, Kazumasa

    2014-01-01

    The effects of various selective phosphodiesterase (PDE) inhibitors on carbachol (CCh)-induced contraction in the bovine abomasum were investigated. Various selective PDE inhibitors, vinpocetine (type 1), erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, type 2), milrinone (type 3), Ro20-1724 (type 4), vardenafil (type 5), BRL-50481 (type 7) and BAY73-6691 (type 9), inhibited CCh-induced contractions in a concentration-dependent manner. Among the PDE inhibitors, Ro20-1724 and vardenafil induced more relaxation than the other inhibitors based on the data for the IC50 or maximum relaxation. In smooth muscle of the bovine abomasum, we showed the expression of PDE4B, 4C, 4D and 5 by RT-PCR analysis. In the presence of CCh, Ro20-1724 increased the cAMP content, but not the cGMP content. By contrast, vardenafil increased the cGMP content, but not the cAMP content. These results suggest that Ro20-1724-induced relaxation was correlated with cAMP and that vardenafil-induced relaxation was correlated with cGMP in the bovine abomasum. In conclusion, PDE4 and PDE5 are the enzymes involved in regulation of the relaxation associated with cAMP and cGMP, respectively, in the bovine abomasum. PMID:25319411

  16. Agonist activation of cytosolic Ca2+ in subfornical organ cells projecting to the supraoptic nucleus

    NASA Technical Reports Server (NTRS)

    Johnson, R. F.; Beltz, T. G.; Sharma, R. V.; Xu, Z.; Bhatty, R. A.; Johnson, A. K.

    2001-01-01

    The subfornical organ (SFO) is sensitive to both ANG II and ACh, and local application of these agents produces dipsogenic responses and vasopressin release. The present study examined the effects of cholinergic drugs, ANG II, and increased extracellular osmolarity on dissociated, cultured cells of the SFO that were retrogradely labeled from the supraoptic nucleus. The effects were measured as changes in cytosolic calcium in fura 2-loaded cells by using a calcium imaging system. Both ACh and carbachol increased intracellular ionic calcium concentration ([Ca2+]i). However, in contrast to the effects of muscarinic receptor agonists on SFO neurons, manipulation of the extracellular osmolality produced no effects, and application of ANG II produced only moderate effects on [Ca2+]i in a few retrogradely labeled cells. The cholinergic effects on [Ca2+]i could be blocked with the muscarinic receptor antagonist atropine and with the more selective muscarinic receptor antagonists pirenzepine and 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP). In addition, the calcium in the extracellular fluid was required for the cholinergic-induced increase in [Ca2+]i. These findings indicate that ACh acts to induce a functional cellular response in SFO neurons through action on a muscarinic receptor, probably of the M1 subtype and that the increase of [Ca2+]i, at least initially, requires the entry of extracellular Ca2+. Also, consistent with a functional role of M1 receptors in the SFO are the results of immunohistochemical preparations demonstrating M1 muscarinic receptor-like protein present within this forebrain circumventricular organ.

  17. 49 CFR 215.121 - Defective car body.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Defective car body. 215.121 Section 215.121..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Car Bodies § 215.121 Defective car body. A railroad may not place or continue in service a car, if: (a) Any portion...

  18. 49 CFR 215.121 - Defective car body.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Defective car body. 215.121 Section 215.121..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Car Bodies § 215.121 Defective car body. A railroad may not place or continue in service a car, if: (a) Any portion...

  19. 49 CFR 215.121 - Defective car body.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Defective car body. 215.121 Section 215.121..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Car Bodies § 215.121 Defective car body. A railroad may not place or continue in service a car, if: (a) Any portion...

  20. 49 CFR 215.121 - Defective car body.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Defective car body. 215.121 Section 215.121..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Car Bodies § 215.121 Defective car body. A railroad may not place or continue in service a car, if: (a) Any portion...

  1. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  2. RQ-00201894: A motilin receptor agonist causing long-lasting facilitation of human gastric cholinergically-mediated contractions.

    PubMed

    Broad, John; Takahashi, Nobuyuki; Tajimi, Masaomi; Sudo, Masaki; Góralczyk, Adam; Parampalli, Umesh; Mannur, Kesava; Yamamoto, Toshinori; Sanger, Gareth J

    2016-02-01

    The aim was to characterise RQ-00201894, a novel non-macrolide motilin agonist, using human recombinant receptors and then investigate its ability to facilitate cholinergic activity in human stomach. A reporter gene assay assessed motilin receptor function. Selectivity of action was determined using a panel of different receptors, ion channels, transporters and enzymes. Cholinergically-mediated muscle contractions were evoked by electrical field stimulation (EFS) of human gastric antrum. The results showed that RQ-00201894, motilin and erythromycin acted as full motilin receptor agonists (EC50: 0.20, 0.11, 69 nM, respectively). In this function, RQ-00201894 had >90-fold selectivity of action over its ability to activate the human ghrelin receptor (EC50 19 nM) and greater selectivity over all other receptors/mechanisms tested. In human stomach RQ-00201894 0.1-30 μM concentration-dependently increased EFS-evoked contractions (up to 1209%; pEC50 6.0). At 0.1-10 μM this activity was usually prolonged. At higher concentrations (3-30 μM) RQ-00201894 also caused a short-lasting muscle contraction, temporally disconnected from the increase in EFS-evoked contractions. RQ-00201894 10 μM did not consistently affect submaximal contractions evoked by carbachol. In conclusion, RQ-00201894 potently and selectively activates the motilin receptor and causes long-lasting facilitation of cholinergic activity in human stomach, an activity thought to correlate with an ability to increase gastric emptying. PMID:26685754

  3. Piperidine derivatives as nonprostanoid IP receptor agonists.

    PubMed

    Hayashi, Ryoji; Sakagami, Hideki; Koiwa, Masakazu; Ito, Hiroaki; Miyamoto, Mitsuko; Isogaya, Masafumi

    2016-05-01

    The discovery of a new class of nonprostanoid prostaglandin I2 receptor (IP receptor) agonists is reported. Among them, the unique piperidine derivative 31b (2-((1-(2-(N-(4-tolyl)benzamido)ethyl)piperidin-4-yl)oxy)acetic acid) was a good IP receptor agonist and was 50-fold more selective for the human IP receptor than for other human prostanoid receptors. This compound showed good pharmacokinetic properties in dog. PMID:26996371

  4. Research and Development Trends of Car Networking

    NASA Astrophysics Data System (ADS)

    He, Wei; Li, Zhixiong; Xie, Guotao

    With the rapid development of the world economy, road transport has become increasingly busy. An unexpected incident would cause serious traffic disaster due to traffic accidents. To solve this problem, the intelligent transportation system (ITS), which is important for the health developments of the city transportation, has become a hot topic. The car networking provides a new way for intelligent transportation system. It can ensure intelligent control and monitoring of urban road with high performance. This paper described the concept of car networking and related technology both in oversea and domestic. The importance of car networking to achieve vehicle and details of the car networking related technologies were illustrated firstly. Then, attentions focus on the research nodus of the car networking. Lastly, the development trend of car networking research was discussed.

  5. Driving CAR T-cells forward.

    PubMed

    Jackson, Hollie J; Rafiq, Sarwish; Brentjens, Renier J

    2016-06-01

    The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting. PMID:27000958

  6. Identification of three novel natural product compounds that activate PXR and CAR and inhibit inflammation

    PubMed Central

    Kittayaruksakul, Suticha; Zhao, Wenchen; Xu, Meishu; Ren, Songrong; Lu, Jing; Wang, Ju; Downes, Michael; Evans, Ronald M.; Venkataramanan, Raman; Chatsudthipong, Varanuj; Xie, Wen

    2013-01-01

    The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been known to play a role in xenobiotic metabolism by regulating the expression of drug-metabolizing enzymes and transporters. In addition, PXR agonists were found to exert therapeutic effects through multiple mechanisms, such as detoxification of bile acids and inhibition of inflammation. In this study, we first investigated the effects of three natural product compounds, carapin, santonin and isokobusone, on the activity of PXR and CAR. These compounds activated both PXR and CAR in transient transfection and luciferase reporter gene assays. Mutagenesis studies showed that two amino acid residues, Phe305 of the rodent PXR and Leu308 of the human PXR, are critical for the recognition of these compounds by PXR. Importantly, the activation of PXR and CAR by these compounds induced the expression of drug-metabolizing enzymes in primary human and mouse hepatocytes. Furthermore, activation of PXR by these compounds inhibited the expression of inflammatory mediators in response to lipopolysaccharide (LPS). The effects of these natural compounds on drug metabolism and inflammation were abolished in PXR−/− hepatocytes. These natural compounds can be explored for their potential in the treatment of diseases where the PXR activation has been shown to be beneficial, such as inflammatory bowel disease, cholestasis, and hyperbilirubinemia. PMID:23896737

  7. Stock-car racing makes intuitive physicists

    NASA Astrophysics Data System (ADS)

    Gwynne, Peter

    2008-03-01

    Formula One races involve cars festooned with gadgets and complex electronic devices, in which millions of dollars are spent refining a vehicle's aerodynamics and reducing its weight. But in events run by America's National Association of Stock Car Auto Racing (NASCAR), cars hurtle round an oval track at speeds of about 300 km h-1 without the help of the complex sensors that are employed in Formula One cars. To avoid crashing, drivers must make their own adjustments to track conditions, engine problems and the traffic around them.

  8. Heterodyne effect in Hybrid CARS

    NASA Astrophysics Data System (ADS)

    Wang, Xi; Zhang, Aihua; Zhi, Miaochan; Sokolov, Alexei; Welch, George; Scully, Marlan

    2009-10-01

    We study the interaction between the resonant Raman signal and non-Raman field, either the concomitant nonresonant four-wave-mixing (FWM) background or an applied external field, in our recently developed scheme of coherent Anti-Stokes Raman scattering, a hybrid CARS. Our technique combines instantaneous coherent excitation of several characteristic molecular vibrations with subsequent probing of these vibrations by an optimally shaped, time-delayed, narrowband laser pulse. This pulse configuration mitigates the non-resonant FWM background while maximizing the Raman-resonant signal, and allows rapid and highly specific detection even in the presence of multiple scattering. We apply this method to non-invasive monitoring of blood glucose levels. Under certain conditions we find that the measured signal is linearly proportional to the glucose concentration due to optical interference with the residual background light, which allows reliable detection of spectral signatures down to medically-relevant glucose levels. We also study the interference between the CARS field and an external field (the local oscillator) by controlling their relative phase and amplitude. This control allows direct observation of the real and imaginary components of the third-order nonlinear susceptibility (χ^(3)) of the sample. We demonstrate that the heterodyne method can be used to amplify the signal and thus increase detection sensitivity.

  9. Car driver casualty rates in Great Britain by type of car.

    PubMed

    Broughton, Jeremy

    2008-07-01

    Since 1989, the British STATS19 national road accident reporting system has included the Vehicle Registration Mark (VRM). This allows the basic vehicle record to be augmented with details such as the date of first registration and codes that specify the vehicle's make and model. In order to examine the influence of car type upon the driver casualty rate, this paper groups car models into six types, ranging from 'Minis and Superminis' to '4x4s and people carriers (pc)'. Exploratory analyses of data from accidents that occurred between 2001 and 2005 show that the driver casualty rate falls markedly with size of car. In car-car collisions, the rate also rises markedly with the size of the other car. The car's year of first registration also influences the casualty rate, and represents the influence of changes in the characteristics of new cars. Statistical models are fitted to identify the separate influences on a driver's risk of injury in a car-car collision of the type and registration year of the driver's car and the type and registration year of the other car in the collision. The analysis is extended to include collisions with other vehicles such as lorries and buses. PMID:18606288

  10. An improved car-following model with two preceding cars' average speed

    NASA Astrophysics Data System (ADS)

    Yu, Shao-Wei; Shi, Zhong-Ke

    2015-01-01

    To better describe cooperative car-following behaviors under intelligent transportation circumstances and increase roadway traffic mobility, the data of three successive following cars at a signalized intersection of Jinan in China were obtained and employed to explore the linkage between two preceding cars' average speed and car-following behaviors. The results indicate that two preceding cars' average velocity has significant effects on the following car's motion. Then an improved car-following model considering two preceding cars' average velocity was proposed and calibrated based on full velocity difference model and some numerical simulations were carried out to study how two preceding cars' average speed affected the starting process and the traffic flow evolution process with an initial small disturbance, the results indicate that the improved car-following model can qualitatively describe the impacts of two preceding cars' average velocity on traffic flow and that taking two preceding cars' average velocity into account in designing the control strategy for the cooperative adaptive cruise control system can improve the stability of traffic flow, suppress the appearance of traffic jams and increase the capacity of signalized intersections.

  11. An improved car-following model considering velocity fluctuation of the immediately ahead car

    NASA Astrophysics Data System (ADS)

    Yu, Shaowei; Huang, Mengxing; Ren, Jia; Shi, Zhongke

    2016-05-01

    To better describe car-following behaviors in the adaptive cruise control strategy and further increase roadway traffic mobility and reduce fuel consumptions, the linkage between velocity fluctuation of the immediately ahead car and the following car's acceleration or deceleration is explored with respect to the measured car-following data by employing the gray correlation analysis theory and then an improved car-following model considering velocity fluctuation of the immediately ahead car on basis of the full velocity difference model is proposed. Numerical simulations are carried out and the effects of velocity fluctuation of the immediately ahead car on each car's velocity, acceleration, vehicular gap, fuel consumptions and the total fuel consumptions of the whole car-following system with different time window lengths are investigated in detail. The results show that velocity fluctuation of the immediately ahead car has significant effects on car-following behaviors and fuel consumptions, and that considering velocity fluctuation of the immediately ahead car in designing the adaptive cruise control system can improve traffic flow stability and reduce fuel consumptions.

  12. 49 CFR 180.507 - Qualification of tank cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 3 2014-10-01 2014-10-01 false Qualification of tank cars. 180.507 Section 180... MAINTENANCE OF PACKAGINGS Qualification and Maintenance of Tank Cars § 180.507 Qualification of tank cars. (a) Each tank car marked as meeting a “DOT” specification or any other tank car used for the...

  13. 49 CFR 180.507 - Qualification of tank cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Qualification of tank cars. 180.507 Section 180... MAINTENANCE OF PACKAGINGS Qualification and Maintenance of Tank Cars § 180.507 Qualification of tank cars. (a) Each tank car marked as meeting a “DOT” specification or any other tank car used for the...

  14. 49 CFR 180.507 - Qualification of tank cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 3 2012-10-01 2012-10-01 false Qualification of tank cars. 180.507 Section 180... MAINTENANCE OF PACKAGINGS Qualification and Maintenance of Tank Cars § 180.507 Qualification of tank cars. (a) Each tank car marked as meeting a “DOT” specification or any other tank car used for the...

  15. 49 CFR 215.121 - Defective car body.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Defective car body. 215.121 Section 215.121 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Car Bodies § 215.121 Defective car body. A railroad may...

  16. 49 CFR 180.507 - Qualification of tank cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Qualification of tank cars. 180.507 Section 180... MAINTENANCE OF PACKAGINGS Qualification and Maintenance of Tank Cars § 180.507 Qualification of tank cars. (a) Each tank car marked as meeting a “DOT” specification or any other tank car used for the...

  17. beta2-Agonists at the Olympic Games.

    PubMed

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  18. Introduction of a single isomer beta agonist.

    PubMed

    Rau, J L

    2000-08-01

    The release of levalbuterol offers the first approved single-isomer beta agonist for oral inhalation. Data from in vitro studies support the concept that S albuterol is not inactive and may have properties antagonistic to bronchodilation. There is some variability in the results of clinical studies with the separate isomers of albuterol, which suggests the need for further study. The introduction of levalbuterol into general clinical use in managing asthma and chronic obstructive disease should begin to offer additional information on the effects of a single isomer beta agonist in comparison to previous racemic mixtures. PMID:10963321

  19. Tragic Car Accident Involves ESO Employees

    NASA Astrophysics Data System (ADS)

    2000-06-01

    Saturday, May 27, turned into a tragic day for ESO. The team installing TIMMI2 at La Silla, went on an excursion to the Elqui valley, 70 km east of the city of La Serena and suffered a serious car accident, crashing against another car driving from the opposite direction.

  20. Car Stopping Distance on a Tabletop

    ERIC Educational Resources Information Center

    Haugland, Ole Anton

    2013-01-01

    Stopping distances in car braking can be an intriguing topic in physics teaching. It illustrates some basic principles of physics, and sheds valuable light on students' attitude towards aggressive driving. Due to safety considerations, it can be difficult to make experiments with actual car braking. (Contains 2 figures.)

  1. Rear-facing car seat (image)

    MedlinePlus

    A rear-facing car seat position is recommended for a child who is very young. Extreme injury can occur in an accident because ... child. In a frontal crash a rear-facing car seat is best, because it cradles the head, ...

  2. Driving an improved CAR for cancer immunotherapy.

    PubMed

    Huang, Xiaopei; Yang, Yiping

    2016-08-01

    The recent clinical success of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies represents a paradigm shift in cancer immunotherapy. Unfortunately, application of CAR T cell-mediated therapy for solid tumors has so far been disappointing, and the reasons for this poor response in solid tumors remain unknown. In this issue of the JCI, Cherkassky and colleagues report on their use of a murine model of human pleural mesothelioma to explore potential factors that limit CAR T cell efficacy. Their studies have uncovered the importance of the tumor microenvironment in the inhibition of CAR T cell functions, revealed a critical role for the programmed death-1 (PD-1) pathway in CAR T cell exhaustion within the tumor microenvironment, and demonstrated improved antitumor effects with a CAR T cell-intrinsic PD-1 blockade strategy using a dominant negative form of PD-1. Together, the results of this study lay the groundwork for further evaluation of mechanisms underlying CAR T cell immune evasion within the tumor microenvironment for the improvement of CAR T cell-mediated therapy for solid tumors. PMID:27454296

  3. 49 CFR 174.110 - Car magazine.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Car magazine. 174.110 Section 174.110 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS REGULATIONS CARRIAGE BY RAIL Class I (Explosive) Materials § 174.110 Car magazine. When...

  4. 49 CFR 174.57 - Cleaning cars.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Cleaning cars. 174.57 Section 174.57 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS REGULATIONS CARRIAGE BY RAIL General Handling and Loading Requirements § 174.57 Cleaning cars....

  5. Designing CAR T cells for glioblastoma

    PubMed Central

    Maus, Marcela V

    2015-01-01

    Chimeric antigen receptor (CAR)-modified T cells directed against CD19 can mediate long-term durable remissions in B cell malignancies, but bringing a new target antigen to the clinic requires extensive modeling to avoid on-target and off-target toxicity. We recently described a systematic approach to test a new CAR directed against EGFR variant III. PMID:26587317

  6. Automated Coal-Mine Shuttle Car

    NASA Technical Reports Server (NTRS)

    Collins, E. R., Jr.

    1984-01-01

    Cable-guided car increases efficiency in underground coal mines. Unmanned vehicle contains storage batteries in side panels for driving traction motors located in wheels. Batteries recharged during inactive periods or slid out as unit and replaced by fresh battery bank. Onboard generator charges batteries as car operates.

  7. A Radio-Controlled Car Challenge

    ERIC Educational Resources Information Center

    Roman, Harry T.

    2010-01-01

    Watching a radio-controlled car zip along a sidewalk or street has become a common sight. Within this toy are the basic ingredients of a mobile robot, used by industry for a variety of important and potentially dangerous tasks. In this challenge, students consider modifying an of-the-shelf, radio-controlled car, adapting it for a robotic task.

  8. Are natural killer cells superior CAR drivers?

    PubMed Central

    Klingemann, Hans

    2014-01-01

    T lymphocytes engineered to express a chimeric antigen receptor (CAR) are being celebrated as a major breakthrough of anticancer immunotherapy. Natural killer cells have not received similar attention as CAR effectors, although the use of these relatively short-lived cytotoxic cells is associated with several advantages. PMID:25340009

  9. Car Stopping Distance on a Tabletop

    NASA Astrophysics Data System (ADS)

    Haugland, Ole Anton

    2013-05-01

    Stopping distances in car braking can be an intriguing topic in physics teaching. It illustrates some basic principles of physics, and sheds valuable light on students' attitude towards aggressive driving. Due to safety considerations, it can be difficult to make experiments with actual car braking.

  10. Reactions of Met-Cars

    SciTech Connect

    Castleman, A.W. Jr.; Guo, B.C.

    1993-12-31

    A new class of metal-carbon complexes, termed metallo-carbohedrenes (Met-Cars), have been discovered to form in a plasma reactor in which early transition metals are vaporized into a stream carrying small hydrocarbon molecules. The initial discovery involved the species Ti{sub 8}c{sub 12}{sup +}, while subsequent studies revealed the stability of the anon and, most importantly, the neutral species. Subsequent investigations show that similar molecules, predicted to have a pentagonal dodecahedral structure, can also be formed with vanadium, hafnium, and zirconium. In the case of the latter, more recent investigations have displaced an interesting growth pattern. In particular, pentagonal dodecahedrons with dangling carbon atoms can undergo further growth, adding at least a second and third cage. The latest results on the properties and reactivities of these new cage-like molecular clusters will be discussed.

  11. Coal cars - the first three hundred years

    SciTech Connect

    Martin Robert Karig III

    2007-12-15

    This is the comprehensive study of the freight cars that conveyed coal across broad swaths of land that had been impassible before the invention of the steam engine. This volume traces the history and evolution of coal cars from their earliest use in England to the construction of major railways for the purpose of coal hauling and the end of the steam era on American railroads. In addition to contextualizing coal cars in the annals of industrial history, the book features extensive design specifications and drawings as well as a complete history of the various safety and mechanical innovations employed on these freight cars. It concludes with a photographic essay illustrating the development of the coal car over its first 300 years of use. 608 photos.

  12. Dual-tip-enhanced ultrafast CARS nanoscopy

    NASA Astrophysics Data System (ADS)

    Ballmann, Charles W.; Cao, Bin; Sinyukov, Alexander M.; Sokolov, Alexei V.; Voronine, Dmitri V.

    2014-08-01

    Coherent anti-Stokes Raman scattering (CARS) and, in particular, femtosecond adaptive spectroscopic techniques (FAST CARS) have been successfully used for molecular spectroscopy and microscopic imaging. Recent progress in ultrafast nano-optics provides flexibility in generation and control of optical near fields, and holds promise to extend CARS techniques to the nanoscale. In this theoretical study, we demonstrate ultrafast subwavelentgh control of coherent Raman spectra of molecules in the vicinity of a plasmonic nanostructure excited by ultrashort laser pulses. The simulated nanostructure design provides localized excitation sources for CARS by focusing incident laser pulses into subwavelength hot spots via two self-similar nanolens antennas connected by a waveguide. Hot-spot-selective dual-tip-enhanced CARS (2TECARS) nanospectra of DNA nucleobases are obtained by simulating optimized pump, Stokes and probe near fields using tips, laser polarization- and pulse-shaping. This technique may be used to explore ultrafast energy and electron transfer dynamics in real space with nanometre resolution.

  13. Entertainment and Pacification System For Car Seat

    NASA Technical Reports Server (NTRS)

    Elrod, Susan Vinz (Inventor); Dabney, Richard W. (Inventor)

    2006-01-01

    An entertainment and pacification system for use with a child car seat has speakers mounted in the child car seat with a plurality of audio sources and an anti-noise audio system coupled to the child car seat. A controllable switching system provides for, at any given time, the selective activation of i) one of the audio sources such that the audio signal generated thereby is coupled to one or more of the speakers, and ii) the anti-noise audio system such that an ambient-noise-canceling audio signal generated thereby is coupled to one or more of the speakers. The controllable switching system can receive commands generated at one of first controls located at the child car seat and second controls located remotely with respect to the child car seat with commands generated by the second controls overriding commands generated by the first controls.

  14. Acoustic emission testing applied to tank cars

    SciTech Connect

    Stuart, R.L. )

    1989-01-01

    A major portion of the U.S. chemical and related commodities production is transported in railroad tank cars. Performance of this equipment directly impacts the economic health of the chemical industry; therefore, it is important that tank cars be properly maintained. It is important that every effort be made to minimize the chance of product release. Metallurgical defects, such as cracks and corrosion, are examples of problems that cause downtime, add cost and limit good performance. These type defects, if undetected, have potential for threatening proper product containment. In addition, defective tank cars erode good customer relationships. This issue was studied and it was concluded that an improved nondestructive testing method applied to tank cars could lead to a safer and more efficient fleet. This paper reports on a project established to extend acoustic emission (AE) testing to tank car tanks.

  15. Evaluation of damaged tank car structural integrity

    SciTech Connect

    Reuter, W.G.; Mudlin, J.D.; Harris, B.L.; Haggag, F.M.; Epstein, J.S.; Server, W.L.

    1987-06-01

    To assess the safety of moving a damaged tank car, it is necessary to know the sizes and shapes of cracks, the stresses associated with moving the tank car, and the fracture toughness of the material used to fabricate the tank car. This report provides the results and recommendations for the research related to the examination of nondestructive evaluation techniques and measurements of the mechanical properties of deformed steel plate; Evaluation of computer codes to identify those capable of performing a large displacement inelastic analysis; Two 1/5-scale-model tank cars, representing damaged tank cars that were hydroburst to failure; and Preliminary tests conducted using more interferometry for determining residual stresses of rail components. 24 refs., 37 figs., 4 tabs.

  16. The kinematic advantage of electric cars

    NASA Astrophysics Data System (ADS)

    Meyn, Jan-Peter

    2015-11-01

    Acceleration of a common car with with a turbocharged diesel engine is compared to the same type with an electric motor in terms of kinematics. Starting from a state of rest, the electric car reaches a distant spot earlier than the diesel car, even though the latter has a better specification for engine power and average acceleration from 0 to 100 km h-1. A three phase model of acceleration as a function of time fits the data of the electric car accurately. The first phase is a quadratic growth of acceleration in time. It is shown that the tenfold higher coefficient for the first phase accounts for most of the kinematic advantage of the electric car.

  17. Car size or car mass: which has greater influence on fatality risk?

    PubMed Central

    Evans, L; Frick, M C

    1992-01-01

    OBJECTIVES. Proposed increases in corporate average fuel economy standards would probably lead to lighter cars. Well-established relationships between occupant risk and car mass predict consequent additional casualties. However, if size, not mass, is the causative factor in these relationships, then decreasing car mass need not increase risk. This study examines whether mass or size is the causative factor. METHODS. Data from the Fatal Accident Reporting System are used to explore relationships between car mass, car size (as represented by wheelbase), and driver fatality risk in two-car crashes. RESULTS. When cars of identical (or similar) wheelbase but different mass crash into each other, driver fatality risk depends strongly on mass; the relationship is quantitatively similar to that found in studies that ignore wheelbase. On the other hand, when cars of similar mass but different wheelbase crash into each other, the data reveal no dependence of driver fatality risk on wheelbase. CONCLUSIONS. Mass is the dominant causative factor in relationships between driver risk and car size in two-car crashes, with size, as such, playing at most a secondary role. Reducing car mass increases occupant risk. PMID:1636830

  18. 5. VAL CAMERA CAR, DETAIL OF HOIST AT SIDE OF ...

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

    5. VAL CAMERA CAR, DETAIL OF HOIST AT SIDE OF BRIDGE AND ENGINE CAR ON TRACKS, LOOKING NORTHEAST. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  19. 7. VAL CAMERA CAR, DETAIL OF 'FLARE' OR TRAJECTORY CAMERA ...

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

    7. VAL CAMERA CAR, DETAIL OF 'FLARE' OR TRAJECTORY CAMERA INSIDE CAMERA CAR. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  20. 6. VAL CAMERA CAR, DETAIL OF COMMUNICATION EQUIPMENT INSIDE CAMERA ...

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

    6. VAL CAMERA CAR, DETAIL OF COMMUNICATION EQUIPMENT INSIDE CAMERA CAR WITH CAMERA MOUNT IN FOREGROUND. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  1. 1. GENERAL VIEW OF TIPPLE LOOKING NORTHWEST, SHOWING LARRY CARS ...

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

    1. GENERAL VIEW OF TIPPLE LOOKING NORTHWEST, SHOWING LARRY CARS BELOW HOPPER BIN. GRAY FITZSIMONS, HAER HISTORIAN, IS STANDING ON PLATFORM NEXT TO LARRY CARS - Lucernemines Coke Works, Larry Car Tipple, East of Lucerne, Lucerne Mines, Indiana County, PA

  2. Reciprocity of agonistic support in ravens

    PubMed Central

    Fraser, Orlaith N.; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim’s likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  3. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  4. Small molecule TSHR agonists and antagonists.

    PubMed

    Neumann, S; Gershengorn, M C

    2011-04-01

    TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule "drug-like" ligands. Recombinant human TSH (rhTSH, Thyrogen(®)) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential. PMID:21511239

  5. Reciprocity of agonistic support in ravens.

    PubMed

    Fraser, Orlaith N; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  6. Aluminum cars: fast track to coal-haul savings

    SciTech Connect

    McGraw, M.G.

    1983-08-01

    While aluminum railroad cars are not new, South Carolina's Public Service Authority, called Santee Cooper, created a transportation milestone when it ordered 300 lightweight aluminum cars for coal-train service. Sizable cost savings are expected with the two car types: composite aluminum/steel body hopper and all-aluminum gondola. The authors detail the cars' specifications, manufacture, and maintenance; describe other recent aluminum-car productions; and analyze the economics of an aluminum-car unit train. 4 figures, 1 table.

  7. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

    SciTech Connect

    Rogue, Alexandra; Anthérieu, Sébastien; Vluggens, Aurore; Umbdenstock, Thierry; Claude, Nancy; Moureyre-Spire, Catherine de la; Weaver, Richard J.; Guillouzo, André

    2014-04-01

    Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. Conclusion: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients. - Highlights: • There is no pharmacological agent approved for the treatment of NAFLD. • This study demonstrates that PPAR agonists can reduce fatty acid-induced steatosis. • Some nuclear receptors appear to be potent actors in the control

  8. Detection and measurement of the agonistic activities of PCBs and mono-hydroxylated PCBs to the constitutive androstane receptor using a recombinant yeast assay.

    PubMed

    Kamata, Ryo; Shiraishi, Fujio; Kageyama, Shiho; Nakajima, Daisuke

    2015-10-01

    Polychlorinated biphenyls (PCBs) are thought to exert their toxicities mainly by binding to the aryl hydrocarbon receptor and by stimulating transcription of various genes, notably metabolizing enzymes including the cytochrome P450 (CYP) 1 family. However, PCBs and their metabolites could have potential to activate other nuclear receptors and subsequent events. We focused on the constitutive androstane receptor (CAR) inducing CYP2B and measured the agonistic activity of PCBs and mono-hydroxylated PCBs (OH-PCBs) to the CAR using yeast cells transduced with the human CAR and its response pathway. Twenty-nine of 34 tested PCBs and 72 of 91 OH-PCBs exhibited CAR agonistic effects. Of 41 OH-PCBs that had the same chlorination patterns as the tested PCBs, 9 had activities more than twice those of their non-hydroxylated analogs. In particular, 2',4',6'-trichlorobiphenyl-4-ol and 2,2',4',6'-tetrachlorobiphenyl-4-ol were 332- and 22-fold more potent than their analogs and were 15 times and 2.8 times, respectively, as active as a reference substance, 4-tert-octylphenol. The activities of 17 of the OH-PCBs were reduced to less than half those of their non-hydroxylated analogs. Four OH-PCBs derived from 3 active PCBs were inactive. However, a consistent relationship between hydroxyl substituent position and activity could not be discerned. Comprehensive evaluation of the toxic potential of PCBs and their hydroxylated metabolites and their concentrations in the environment are required. PMID:26231822

  9. The human controller in car following

    NASA Technical Reports Server (NTRS)

    Burnham, G. O.; Bekey, G. A.

    1975-01-01

    The man machine interface between the human driver and his automobile during car following tasks was examined. A direct connection between models of the human operator and the theory of optimal control was established for car following situations involving both linear and nonlinear car dynamics. Results obtained from several types of mathematical models are discussed. Conventional parameter identification techniques were used to obtain the parameters of these models by comparing their performance to data obtained by aerial photogrammetry. The results indicate that there are two general classes of model structures: models assumed to have preview information and models without preview.

  10. PC-based car license plate reader

    NASA Astrophysics Data System (ADS)

    Hwang, Chung-Mu; Shu, Shyh-Yeong; Chen, Wen-Yu; Chen, Yie-Wern; Wen, Kuang-Pu

    1992-11-01

    A car license plate reader (CLPR) using fuzzy inference and neural network algorithm has been developed in Industrial Technology Research Institute (ITRI) and installed in highway toll stations to identify stolen cars. It takes an average of 0.7 seconds to recognize a car license plate by using a PC with 80486-50 CPU. The recognition rate of the system is about 97%. The techniques of CLPR include vehicle sensing, image grab control, optic pre- processing, lighting, and optic character recognition (OCR). The CLPR can be used in vehicle flow statistics, the checking of stolen vehicles, automatic charging systems in parking lots or garage management, and so on.

  11. Multimodal CARS microscopy of structured carbohydrate biopolymers

    PubMed Central

    Slepkov, Aaron D.; Ridsdale, Andrew; Pegoraro, Adrian F.; Moffatt, Douglas J.; Stolow, Albert

    2010-01-01

    We demonstrate the utility of multimodal coherent anti-Stokes Raman scattering (CARS) microscopy for the study of structured condensed carbohydrate systems. Simultaneous second-harmonic generation (SHG) and spectrally-scanned CARS microscopy was used to elucidate structure, alignment, and density in cellulose cotton fibers and in starch grains undergoing rapid heat-moisture swelling. Our results suggest that CARS response of the O-H stretch region (3000 cm−1–3400 cm−1), together with the commonly-measured C-H stretch (2750 cm−1–2970 cm−1) and SHG provide potentially important structural information and contrast in these materials. PMID:21258555

  12. CAR models: next-generation CAR modifications for enhanced T-cell function

    PubMed Central

    Abate-Daga, Daniel; Davila, Marco L

    2016-01-01

    T cells genetically targeted with a chimeric antigen receptor (CAR) to B-cell malignancies have demonstrated tremendous clinical outcomes. With the proof in principle for CAR T cells as a therapy for B-cell malignancies being established, current and future research is being focused on adapting CAR technology to other cancers, as well as enhancing its efficacy and/or safety. The modular nature of the CAR, extracellular antigen-binding domain fused to a transmembrane domain and intracellular T-cell signaling domains, allows for optimization by replacement of the various components. These modifications are creating a whole new class of therapeutic CARs. In this review, we discuss the recent major advances in CAR design and how these modifications will impact its clinical application. PMID:27231717

  13. CAR models: next-generation CAR modifications for enhanced T-cell function.

    PubMed

    Abate-Daga, Daniel; Davila, Marco L

    2016-01-01

    T cells genetically targeted with a chimeric antigen receptor (CAR) to B-cell malignancies have demonstrated tremendous clinical outcomes. With the proof in principle for CAR T cells as a therapy for B-cell malignancies being established, current and future research is being focused on adapting CAR technology to other cancers, as well as enhancing its efficacy and/or safety. The modular nature of the CAR, extracellular antigen-binding domain fused to a transmembrane domain and intracellular T-cell signaling domains, allows for optimization by replacement of the various components. These modifications are creating a whole new class of therapeutic CARs. In this review, we discuss the recent major advances in CAR design and how these modifications will impact its clinical application. PMID:27231717

  14. Ultrafast CARS with Improved Spectral Resolution

    NASA Astrophysics Data System (ADS)

    Lütgens, M.; Chatzipapadopoulos, S.; Lochbrunner, S.

    2013-03-01

    Molecular vibrations are investigated by time and frequency resolved CARS applying ultrafast excitation and picosecond probing for high spectral resolution. Enhanced spectral structure and beating phenomena are demonstrated for coalescing Raman bands.

  15. CAR therapy: the CD19 paradigm

    PubMed Central

    Sadelain, Michel

    2015-01-01

    Twenty-five years after its inception, the genetic engineering of T cells is now a therapeutic modality pursued at an increasing number of medical centers. This immunotherapeutic strategy is predicated on gene transfer technology to instruct T lymphocytes to recognize and reject tumor cells. Chimeric antigen receptors (CARs) are synthetic receptors that mediate antigen recognition, T cell activation, and — in the case of second-generation CARs — costimulation to augment T cell functionality and persistence. We demonstrated over a decade ago that human T cells engineered with a CD19-specific CAR eradicated B cell malignancies in mice. Several phase I clinical trials eventually yielded dramatic results in patients with leukemia or lymphoma, especially acute lymphoblastic leukemia (ALL). This review recounts the milestones of CD19 CAR therapy and summarizes lessons learned from the CD19 paradigm. PMID:26325036

  16. Chromosomal aberrations in lymphocytes from car painters.

    PubMed

    Silva, J M; Santos-Mello, R

    1996-05-01

    In the present paper we report the results of biological monitoring of a group of 25 car painters working in different automobile shops in Brasília. There was a significantly higher frequency of aneuplodies and chromosome deletions in the peripheral lymphocytes of car painters than in control subjects. We also detected a significant correlation between the time worked as a car painter and the frequency of aneuploidy. Smoking habits do not represent a significant factor in terms of production of the various types of chromosome aberrations among car painters. These results permitted us to conclude that the individuals studied represent a risk group and should be medically followed up with judicious periodic examinations. PMID:8637507

  17. EcoCAR Challenge Profile: Virginia Tech

    SciTech Connect

    Gantt, Lynn

    2011-01-01

    Since childhood, Lynn Gantt has had a deep seeded passion for cars and the mechanics that drive them. The Virginia native spent his weekends rebuilding antique tractors with his dad to race at tractor pulls across the state, and now the Virginia Tech graduate student is the proud team co-leader of Virginia Tech's EcoCAR Challenge team -- the winners of the three-year long competition, as announced last night at an awards ceremony in Washington, D.C..

  18. EcoCAR Challenge Profile: Virginia Tech

    ScienceCinema

    Gantt, Lynn

    2013-05-29

    Since childhood, Lynn Gantt has had a deep seeded passion for cars and the mechanics that drive them. The Virginia native spent his weekends rebuilding antique tractors with his dad to race at tractor pulls across the state, and now the Virginia Tech graduate student is the proud team co-leader of Virginia Tech's EcoCAR Challenge team -- the winners of the three-year long competition, as announced last night at an awards ceremony in Washington, D.C..

  19. HERG1 Channel Agonists and Cardiac Arrhythmia

    PubMed Central

    Sanguinetti, Michael

    2014-01-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  20. HERG1 channel agonists and cardiac arrhythmia.

    PubMed

    Sanguinetti, Michael C

    2014-04-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  1. Car radiator burns: a prevention issue.

    PubMed

    Rabbitts, Angela; Alden, Nicole E; Conlin, Tara; Yurt, Roger W

    2004-01-01

    Scald burns continue to be the major cause of injury to patients admitted to the burn center. Scald burns occurring from car radiator fluid comprise a significant subgroup. Although manufacturer warning labels have been placed on car radiators, these burns continue to occur. This retrospective review looks at all patients admitted to our burn center who suffered scald burns from car radiator fluid to assess the extent of this problem. During the study period, 86 patients were identified as having suffered scald burns as a result of contact with car radiator fluid. Seventy-one percent of the burn injuries occurred in the summer months. The areas most commonly burned were the head and upper extremities. Burn prevention efforts have improved greatly over the years; however, this study demonstrates that scald burns from car radiator fluid continue to cause physical, emotional, and financial devastation. The current radiator warning labels alone are not effective. The National Highway Traffic Safety Administration has proposed a new federal motor vehicle safety standard to aid in decreasing the number of scald burns from car radiators. The results of this study were submitted to the United States Department of Transportation for inclusion in a docket for federal legislation supporting these safety measures. PMID:15353940

  2. Analysis of car-3-en-5-hydroperoxide.

    PubMed

    Lehnert, Nicole; Krings, Ulrich; Berger, Ralf G

    2011-09-01

    HRGC-MS, using split/splitless injection (230 degrees C), showed that a dioxygenase from Pleurotus sapidus regio-selectively transformed (+)-car-3-ene to car-3-en-5-one as the major volatile product to minor amounts of the corresponding alcohol, and to some other volatiles. Thus, the reaction was assumed to be radical mediated and similar to the lipoxygenase catalyzed peroxidation of polyunsaturated fatty acids, but the expected car-3-ene-hydroperoxides were not detected. TLC of the reaction products, followed by hydroperoxide specific staining, visually indicated the presence of hydroperoxides. TLC spots were eluted and re-analyzed using cool on-column injection, but only tailing peaks showing a mixed mass spectrum of car-3-en-5-ol/one were obtained. An unequivocal identification of car-3-en-5-hydroperoxides was achieved only after using APCI(+)-LC-MS. Upon structural confirmation, the car-3-en-5-hydroperoxide was accumulated by preparative HPLC, re-injected cool on-column, and the continuing degradation of the hydroperoxide to monoterpene ketone and alcohol during chromatography was verified. It was concluded that terpene hydroperoxides may occur in essential oils more frequently than anticipated, but are not recognized due to the principal blindness of capillary gas chromatography techniques and UV/vis LC-detectors. PMID:21941881

  3. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  4. Melanocortin 1 Receptor Agonists Reduce Proteinuria

    PubMed Central

    Ebefors, Kerstin; Johansson, Martin E.; Stefánsson, Bergur; Granqvist, Anna; Arnadottir, Margret; Berg, Anna-Lena; Nyström, Jenny; Haraldsson, Börje

    2010-01-01

    Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. Recent reports suggest that treatment with adrenocorticotropic hormone (ACTH) reduces proteinuria, but the mechanism of action is unknown. Here, we identified gene expression of the melanocortin receptor MC1R in podocytes, glomerular endothelial cells, mesangial cells, and tubular epithelial cells. Podocytes expressed most MC1R protein, which colocalized with synaptopodin but not with an endothelial-specific lectin. We treated rats with passive Heymann nephritis (PHN) with MS05, a specific MC1R agonist, which significantly reduced proteinuria compared with untreated PHN rats (P < 0.01). Furthermore, treatment with MC1R agonists improved podocyte morphology and reduced oxidative stress. In summary, podocytes express MC1R, and MC1R agonism reduces proteinuria, improves glomerular morphology, and reduces oxidative stress in nephrotic rats with PHN. These data may explain the proteinuria-reducing effects of ACTH observed in patients with membranous nephropathy, and MC1R agonists may provide a new therapeutic option for these patients. PMID:20507942

  5. 49 CFR 38.109 - Between-car barriers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false Between-car barriers. 38.109 Section 38.109... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Commuter Rail Cars and Systems § 38.109 Between-car barriers. Where vehicles operate in a high-platform, level-boarding mode, and where between-car bellows are not...

  6. 49 CFR 218.80 - Movement of occupied camp cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Movement of occupied camp cars. 218.80 Section 218... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD OPERATING PRACTICES Protection of Occupied Camp Cars § 218.80 Movement of occupied camp cars. Occupied cars may not be humped or flat switched unless coupled...

  7. 49 CFR 215.119 - Defective freight car truck.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Defective freight car truck. 215.119 Section 215... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Suspension System § 215.119 Defective freight car truck. A railroad may not place or continue in service...

  8. 49 CFR 218.80 - Movement of occupied camp cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Movement of occupied camp cars. 218.80 Section 218... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD OPERATING PRACTICES Protection of Occupied Camp Cars § 218.80 Movement of occupied camp cars. Occupied cars may not be humped or flat switched unless coupled...

  9. 49 CFR 173.10 - Tank car shipments.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 2 2012-10-01 2012-10-01 false Tank car shipments. 173.10 Section 173.10... SHIPMENTS AND PACKAGINGS General § 173.10 Tank car shipments. (a) Tank cars containing any 2.1 material... facilities which have been equipped for piping the liquid from tank cars to permanent storage tanks...

  10. 49 CFR 1033.1 - Car hire rates.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    .... (1) Market rate cars shall not be subject to prescribed rates or to the provisions of 49 CFR 1039.14... 49 Transportation 8 2013-10-01 2013-10-01 false Car hire rates. 1033.1 Section 1033.1... OF TRANSPORTATION GENERAL RULES AND REGULATIONS CAR SERVICE § 1033.1 Car hire rates. (a)...

  11. 36 CFR 1192.109 - Between-car barriers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 3 2014-07-01 2014-07-01 false Between-car barriers. 1192... Commuter Rail Cars and Systems § 1192.109 Between-car barriers. Where vehicles operate in a high-platform, level-boarding mode, and where between-car bellows are not provided, devices or systems shall...

  12. 49 CFR 215.119 - Defective freight car truck.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Defective freight car truck. 215.119 Section 215... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Suspension System § 215.119 Defective freight car truck. A railroad may not place or continue in service...

  13. 49 CFR 173.10 - Tank car shipments.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 2 2013-10-01 2013-10-01 false Tank car shipments. 173.10 Section 173.10... SHIPMENTS AND PACKAGINGS General § 173.10 Tank car shipments. (a) Tank cars containing any 2.1 material... facilities which have been equipped for piping the liquid from tank cars to permanent storage tanks...

  14. 49 CFR 1033.1 - Car hire rates.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    .... (1) Market rate cars shall not be subject to prescribed rates or to the provisions of 49 CFR 1039.14... 49 Transportation 8 2014-10-01 2014-10-01 false Car hire rates. 1033.1 Section 1033.1... OF TRANSPORTATION GENERAL RULES AND REGULATIONS CAR SERVICE § 1033.1 Car hire rates. (a)...

  15. 36 CFR 1192.109 - Between-car barriers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 3 2013-07-01 2012-07-01 true Between-car barriers. 1192.109... Commuter Rail Cars and Systems § 1192.109 Between-car barriers. Where vehicles operate in a high-platform, level-boarding mode, and where between-car bellows are not provided, devices or systems shall...

  16. 49 CFR 215.303 - Stenciling of restricted cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Stenciling of restricted cars. 215.303 Section 215... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Stenciling § 215.303 Stenciling of restricted cars. (a) Each restricted railroad freight car that is described in § 215.205(a)...

  17. 49 CFR 38.109 - Between-car barriers.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 1 2013-10-01 2013-10-01 false Between-car barriers. 38.109 Section 38.109... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Commuter Rail Cars and Systems § 38.109 Between-car barriers. Where vehicles operate in a high-platform, level-boarding mode, and where between-car bellows are not...

  18. 49 CFR 38.109 - Between-car barriers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false Between-car barriers. 38.109 Section 38.109... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Commuter Rail Cars and Systems § 38.109 Between-car barriers. Where vehicles operate in a high-platform, level-boarding mode, and where between-car bellows are not...

  19. 49 CFR 218.80 - Movement of occupied camp cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Movement of occupied camp cars. 218.80 Section 218... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD OPERATING PRACTICES Protection of Occupied Camp Cars § 218.80 Movement of occupied camp cars. Occupied cars may not be humped or flat switched unless coupled...

  20. 49 CFR 215.303 - Stenciling of restricted cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Stenciling of restricted cars. 215.303 Section 215... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Stenciling § 215.303 Stenciling of restricted cars. (a) Each restricted railroad freight car that is described in § 215.205(a)...

  1. 36 CFR 1192.109 - Between-car barriers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 3 2012-07-01 2012-07-01 false Between-car barriers. 1192... Commuter Rail Cars and Systems § 1192.109 Between-car barriers. Where vehicles operate in a high-platform, level-boarding mode, and where between-car bellows are not provided, devices or systems shall...

  2. 49 CFR 1033.1 - Car hire rates.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    .... (1) Market rate cars shall not be subject to prescribed rates or to the provisions of 49 CFR 1039.14... 49 Transportation 8 2012-10-01 2012-10-01 false Car hire rates. 1033.1 Section 1033.1... OF TRANSPORTATION GENERAL RULES AND REGULATIONS CAR SERVICE § 1033.1 Car hire rates. (a)...

  3. 49 CFR 215.303 - Stenciling of restricted cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Stenciling of restricted cars. 215.303 Section 215... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Stenciling § 215.303 Stenciling of restricted cars. (a) Each restricted railroad freight car that is described in § 215.205(a)...

  4. 49 CFR 173.10 - Tank car shipments.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 2 2014-10-01 2014-10-01 false Tank car shipments. 173.10 Section 173.10... SHIPMENTS AND PACKAGINGS General § 173.10 Tank car shipments. (a) Tank cars containing any 2.1 material... facilities which have been equipped for piping the liquid from tank cars to permanent storage tanks...

  5. 49 CFR 1033.1 - Car hire rates.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    .... (1) Market rate cars shall not be subject to prescribed rates or to the provisions of 49 CFR 1039.14... 49 Transportation 8 2011-10-01 2011-10-01 false Car hire rates. 1033.1 Section 1033.1... OF TRANSPORTATION GENERAL RULES AND REGULATIONS CAR SERVICE § 1033.1 Car hire rates. (a)...

  6. 49 CFR 173.10 - Tank car shipments.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 2 2011-10-01 2011-10-01 false Tank car shipments. 173.10 Section 173.10... SHIPMENTS AND PACKAGINGS General § 173.10 Tank car shipments. (a) Tank cars containing any 2.1 material... facilities which have been equipped for piping the liquid from tank cars to permanent storage tanks...

  7. 49 CFR 38.109 - Between-car barriers.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 1 2011-10-01 2011-10-01 false Between-car barriers. 38.109 Section 38.109... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Commuter Rail Cars and Systems § 38.109 Between-car barriers. Where vehicles operate in a high-platform, level-boarding mode, and where between-car bellows are not...

  8. 49 CFR 218.80 - Movement of occupied camp cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Movement of occupied camp cars. 218.80 Section 218... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD OPERATING PRACTICES Protection of Occupied Camp Cars § 218.80 Movement of occupied camp cars. Occupied cars may not be humped or flat switched unless coupled...

  9. 36 CFR 1192.109 - Between-car barriers.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 3 2011-07-01 2011-07-01 false Between-car barriers. 1192... Commuter Rail Cars and Systems § 1192.109 Between-car barriers. Where vehicles operate in a high-platform, level-boarding mode, and where between-car bellows are not provided, devices or systems shall...

  10. 49 CFR 215.303 - Stenciling of restricted cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Stenciling of restricted cars. 215.303 Section 215... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Stenciling § 215.303 Stenciling of restricted cars. (a) Each restricted railroad freight car that is described in § 215.205(a)...

  11. 49 CFR 215.119 - Defective freight car truck.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Defective freight car truck. 215.119 Section 215... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Suspension System § 215.119 Defective freight car truck. A railroad may not place or continue in service...

  12. 49 CFR 1033.1 - Car hire rates.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    .... (1) Market rate cars shall not be subject to prescribed rates or to the provisions of 49 CFR 1039.14... 49 Transportation 8 2010-10-01 2010-10-01 false Car hire rates. 1033.1 Section 1033.1... OF TRANSPORTATION GENERAL RULES AND REGULATIONS CAR SERVICE § 1033.1 Car hire rates. (a)...

  13. 49 CFR 38.109 - Between-car barriers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Between-car barriers. 38.109 Section 38.109... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Commuter Rail Cars and Systems § 38.109 Between-car barriers. Where vehicles operate in a high-platform, level-boarding mode, and where between-car bellows are not...

  14. Effect of droplet-induced breakdown on CARS temperature measurements

    SciTech Connect

    Dunn-Rankin, D. ); Switzer, G.L. ); Obringer, C.A.; Jackson, T. )

    1990-07-20

    This research examines the potential for coherent anti-Stokes Raman scattering (CARS) to rovide reliable gas temperature measurements in the presence of liquid droplets. The droplets cause dielectric breakdown by focusing the CARS laser beams. This breakdown produces a plasma that can disrupt or obscure the CARS signal. Specifically, we examine the influence of laser induced breakdown on the CARS signal, and we determine the importance of droplet position relative to the CARS focal volume and droplet concentration on the reliability of CARS temperature measurements in droplet-laden flows. In addition, we propose a reliable data reduction procedure to minimize the disruptive influence of laser induced breakdown on CARS temperature.

  15. Are Weeds Hitchhiking a Ride on Your Car? A Systematic Review of Seed Dispersal on Cars

    PubMed Central

    Ansong, Michael; Pickering, Catherine

    2013-01-01

    When traveling in cars, we can unintentionally carry and disperse weed seed; but which species, and where are they a problem? To answer these questions, we systematically searched the scientific literature to identify all original research studies that assess seed transported by cars and listed the species with seed on/in cars. From the 13 studies that fit these criteria, we found 626 species from 75 families that have seed that can be dispersed by cars. Of these, 599 are listed as weeds in some part of the world, with 439 listed as invasive or naturalized alien species in one or more European countries, 248 are invasive/noxious weeds in North America, 370 are naturalized alien species in Australia, 167 are alien species in India, 77 are invasive species in China and 23 are declared weeds/invaders in South Africa. One hundred and one are classified as internationally important environmental weeds. Although most (487) were only recorded once, some species such as Chenopodium album, Poa pratensis and Trifolium repens were common among studies. Perennial graminoids seem to be favoured over annual graminoids while annual forbs are favoured over perennial forbs. Species characteristics including seed size and morphology and where the plants grew affected the probability that their seed was transported by cars. Seeds can be found in many different places on cars including under the chassis, front and rear bumpers, wheel wells and rims, front and back mudguards, wheel arches, tyres and on interior floor mats. With increasing numbers of cars and expanding road networks in many regions, these results highlight the importance of cars as a dispersal mechanism, and how it may favour invasions by some species over others. Strategies to reduce the risk of seed dispersal by cars include reducing seed on cars by mowing road verges and cleaning cars. PMID:24265803

  16. Are weeds hitchhiking a ride on your car? A systematic review of seed dispersal on cars.

    PubMed

    Ansong, Michael; Pickering, Catherine

    2013-01-01

    When traveling in cars, we can unintentionally carry and disperse weed seed; but which species, and where are they a problem? To answer these questions, we systematically searched the scientific literature to identify all original research studies that assess seed transported by cars and listed the species with seed on/in cars. From the 13 studies that fit these criteria, we found 626 species from 75 families that have seed that can be dispersed by cars. Of these, 599 are listed as weeds in some part of the world, with 439 listed as invasive or naturalized alien species in one or more European countries, 248 are invasive/noxious weeds in North America, 370 are naturalized alien species in Australia, 167 are alien species in India, 77 are invasive species in China and 23 are declared weeds/invaders in South Africa. One hundred and one are classified as internationally important environmental weeds. Although most (487) were only recorded once, some species such as Chenopodium album, Poa pratensis and Trifolium repens were common among studies. Perennial graminoids seem to be favoured over annual graminoids while annual forbs are favoured over perennial forbs. Species characteristics including seed size and morphology and where the plants grew affected the probability that their seed was transported by cars. Seeds can be found in many different places on cars including under the chassis, front and rear bumpers, wheel wells and rims, front and back mudguards, wheel arches, tyres and on interior floor mats. With increasing numbers of cars and expanding road networks in many regions, these results highlight the importance of cars as a dispersal mechanism, and how it may favour invasions by some species over others. Strategies to reduce the risk of seed dispersal by cars include reducing seed on cars by mowing road verges and cleaning cars. PMID:24265803

  17. 49 CFR 231.8 - Tank cars without side sills and tank cars with short side sills and end platforms.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Tank cars without side sills and tank cars with... APPLIANCE STANDARDS § 231.8 Tank cars without side sills and tank cars with short side sills and end platforms. (a) Hand brakes—(1) Number. Same as specified for “Box and other house cars” (see §...

  18. 49 CFR 231.8 - Tank cars without side sills and tank cars with short side sills and end platforms.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Tank cars without side sills and tank cars with... APPLIANCE STANDARDS § 231.8 Tank cars without side sills and tank cars with short side sills and end platforms. (a) Hand brakes—(1) Number. Same as specified for “Box and other house cars” (see §...

  19. Gasoline-powered serial hybrid cars cause lower life cycle carbon emissions than battery cars

    NASA Astrophysics Data System (ADS)

    Meinrenken, Christoph J.; Lackner, Klaus S.

    2011-04-01

    Battery cars powered by grid electricity promise reduced life cycle green house gas (GHG) emissions from the automotive sector. Such scenarios usually point to the much higher emissions from conventional, internal combustion engine cars. However, today's commercially available serial hybrid technology achieves the well known efficiency gains from regenerative breaking, lack of gearbox, and light weighting - even if the electricity is generated onboard, from conventional fuels. Here, we analyze emissions for commercially available, state-of the-art battery cars (e.g. Nissan Leaf) and those of commercially available serial hybrid cars (e.g., GM Volt, at same size and performance). Crucially, we find that serial hybrid cars driven on (fossil) gasoline cause fewer life cycle GHG emissions (126g CO2e per km) than battery cars driven on current US grid electricity (142g CO2e per km). We attribute this novel finding to the significant incremental life cycle emissions from battery cars from losses during grid transmission, battery dis-/charging, and larger batteries. We discuss crucial implications for strategic policy decisions towards a low carbon automotive sector as well as relative land intensity when powering cars by biofuel vs. bioelectricity.

  20. Gasoline-powered series hybrid cars cause lower life cycle carbon emissions than battery cars

    NASA Astrophysics Data System (ADS)

    Meinrenken, Christoph; Lackner, Klaus S.

    2012-02-01

    Battery cars powered by grid electricity promise reduced life cycle green house gas (GHG) emissions from the automotive sector. Such scenarios usually point to the much higher emissions from conventional, internal combustion engine cars. However, today's commercially available series hybrid technology achieves the well known efficiency gains in electric drivetrains (regenerative breaking, lack of gearbox) even if the electricity is generated onboard, from conventional fuels. Here, we analyze life cycle GHG emissions for commercially available, state-of the-art plug-in battery cars (e.g. Nissan Leaf) and those of commercially available series hybrid cars (e.g., GM Volt, at same size and performance). Crucially, we find that series hybrid cars driven on (fossil) gasoline cause fewer emissions (126g CO2eq per km) than battery cars driven on current US grid electricity (142g CO2eq per km). We attribute this novel finding to the significant incremental emissions from plug-in battery cars due to losses during grid transmission and battery dis-/charging, and manufacturing larger batteries. We discuss crucial implications for strategic policy decisions towards a low carbon automotive sector as well as relative land intensity when powering cars by biofuel vs. bioelectricity.

  1. 49 CFR 172.330 - Tank cars and multi-unit tank car tanks.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Tank cars and multi-unit tank car tanks. 172.330 Section 172.330 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS REGULATIONS HAZARDOUS MATERIALS TABLE, SPECIAL PROVISIONS,...

  2. 49 CFR 173.314 - Compressed gases in tank cars and multi-unit tank cars.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Compressed gases in tank cars and multi-unit tank cars. 173.314 Section 173.314 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS REGULATIONS SHIPPERS-GENERAL REQUIREMENTS FOR...

  3. 49 CFR 173.314 - Compressed gases in tank cars and multi-unit tank cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 2 2012-10-01 2012-10-01 false Compressed gases in tank cars and multi-unit tank cars. 173.314 Section 173.314 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS REGULATIONS SHIPPERS-GENERAL REQUIREMENTS FOR...

  4. Dopamine agonist: pathological gambling and hypersexuality.

    PubMed

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication. PMID:19536937

  5. Separation of CARS image contributions with a Gaussian mixture model.

    PubMed

    Vogler, Nadine; Bocklitz, Thomas; Mariani, Melissa; Deckert, Volker; Markova, Aneta; Schelkens, Peter; Rösch, Petra; Akimov, Denis; Dietzek, Benjamin; Popp, Jürgen

    2010-06-01

    Coherent anti-Stokes Raman scattering (CARS) gained a lot of importance in chemical imaging. This is due to the fast image acquisition time, the high spatial resolution, the non-invasiveness, and the molecular sensitivity of this method. By using the single-line CARS in contrast to the multiplex CARS, different signal contributions stemming from resonant and non-resonant light-matter interactions are indistinguishable. Here a numerical method is presented in order to extract more information from univariate CARS images: vibrational composition, morphological information, and contributions from index-of-refraction steps can be separated from single-line CARS images. The image processing algorithm is based on the physical properties of CARS process as reflected in the shape of the intensity histogram of univariate CARS images. Because of this the comparability of individual CARS images recorded with different experimental parameters is achieved. The latter is important for a quantitative evaluation of CARS images. PMID:20508705

  6. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  7. Mechanisms of agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Lin, Hong; Strange, Philip G

    2004-12-01

    In this study, we investigated the biochemical mechanisms of agonist action at the G protein-coupled D2 dopamine receptor expressed in Chinese hamster ovary cells. Stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding by full and partial agonists was determined at different concentrations of [35S]GTPgammaS (0.1 and 10 nM) and in the presence of different concentrations of GDP. At both concentrations of [35S]GTPgammaS, increasing GDP decreased the [35S]GTPgammaS binding observed with maximally stimulating concentrations of agonist, with partial agonists exhibiting greater sensitivity to the effects of GDP than full agonists. The relative efficacy of partial agonists was greater at the lower GDP concentrations. Concentration-response experiments were performed for a range of agonists at the two [35S]GTPgammaS concentrations and with different concentrations of GDP. At 0.1 nM [35S]GTPgammaS, the potency of both full and partial agonists was dependent on the GDP concentration in the assays. At 10 nM [35S]GTPgammaS, the potency of full agonists exhibited a greater dependence on the GDP concentration, whereas the potency of partial agonists was virtually independent of GDP. We concluded that at the lower [35S]GTPgammaS concentration, the rate-determining step in G protein activation is the binding of [35S]GTPgammaS to the G protein. At the higher [35S]GTPgammaS concentration, for full agonists, [35S]GTPgammaS binding remains the slowest step, whereas for partial agonists, another (GDP-independent) step, probably ternary complex breakdown, becomes rate-determining. PMID:15340043

  8. ChemMatCARS Data Archive

    DOE Data Explorer

    ChemMatCARS is a high-brilliance national synchrotron x-ray facility dedicated primarily to static and dynamic condensed matter chemistry and materials science. The scientific focus of the facility includes the study of surface and interfacial properties of liquids and solids as well as their bulk structure at atomic, molecular and mesoscopic length scales with high spatial and energy resolution. Experimental techniques supported by the facility include: 1) Liquid Surface X-ray Scattering; 2) Solid Surface X-ray Scattering; 3) Time-Resolved Crystallography; 4) Micro-Crystal Diffraction; 5) Small and Wide-angle X-ray Scattering. The data archive referenced here contains data for various components along the beamline within the First Optics Enclosure and is intended to be input or parameter data. See the Science Nuggets at http://cars9.uchicago.edu/chemmat/pages/nuggets.html for leads to some of the research conducted at the ChemMatCARS beamline.

  9. Aerodynamic characteristics of the Fiat UNO car

    SciTech Connect

    Costelli, A.F.

    1984-01-01

    The purpose of this article is to describe the work conducted in the aerodynamic field throughout the 4-year development and engineering time span required by the project of the UNO car. A description is given of all the parametric studies carried out. Through these studies two types of cars at present in production were defined and the characteristics of a possible future sports version laid down. A movable device, to be fitted in the back window, was also set up and patented. When actuated it reduces soiling of back window. A description is also provided of the measurements made in the car flow field and some considerations are outlined about the method applied. This method is still in development phase but it already permits some considerations and in-depth investigations to be made on the vehicle wake.

  10. 49 CFR 179.300 - General specifications applicable to multi-unit tank car tanks designed to be removed from car...

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... tank car tanks designed to be removed from car structure for filling and emptying (Classes DOT-106A and...) SPECIFICATIONS FOR TANK CARS Specifications for Multi-Unit Tank Car Tanks (Classes DOT-106A and 110AW) § 179.300 General specifications applicable to multi-unit tank car tanks designed to be removed from car...

  11. 49 CFR 179.300 - General specifications applicable to multi-unit tank car tanks designed to be removed from car...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... tank car tanks designed to be removed from car structure for filling and emptying (Classes DOT-106A and...) SPECIFICATIONS FOR TANK CARS Specifications for Multi-Unit Tank Car Tanks (Classes DOT-106A and 110AW) § 179.300 General specifications applicable to multi-unit tank car tanks designed to be removed from car...

  12. 49 CFR 179.300 - General specifications applicable to multi-unit tank car tanks designed to be removed from car...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... tank car tanks designed to be removed from car structure for filling and emptying (Classes DOT-106A and...) SPECIFICATIONS FOR TANK CARS Specifications for Multi-Unit Tank Car Tanks (Classes DOT-106A and 110AW) § 179.300 General specifications applicable to multi-unit tank car tanks designed to be removed from car...

  13. 49 CFR 179.300 - General specifications applicable to multi-unit tank car tanks designed to be removed from car...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... tank car tanks designed to be removed from car structure for filling and emptying (Classes DOT-106A and...) SPECIFICATIONS FOR TANK CARS Specifications for Multi-Unit Tank Car Tanks (Classes DOT-106A and 110AW) § 179.300 General specifications applicable to multi-unit tank car tanks designed to be removed from car...

  14. Computational modeling toward understanding agonist binding on dopamine 3.

    PubMed

    Zhao, Yaxue; Lu, Xuefeng; Yang, Chao-Yie; Huang, Zhimin; Fu, Wei; Hou, Tingjun; Zhang, Jian

    2010-09-27

    The dopamine 3 (D3) receptor is a promising therapeutic target for the treatment of nervous system disorders, such as Parkinson's disease, and current research interests primarily focus on the discovery/design of potent D3 agonists. Herein, a well-designed computational protocol, which combines pharmacophore identification, homology modeling, molecular docking, and molecular dynamics (MD) simulations, was employed to understand the agonist binding on D3 aiming to provide insights into the development of novel potent D3 agonists. We (1) identified the chemical features required in effective D3 agonists by pharmacophore modeling based upon 18 known diverse D3 agonists; (2) constructed the three-dimensional (3D) structure of D3 based on homology modeling and the pharmacophore hypothesis; (3) identified the binding modes of the agonists to D3 by the correlation between the predicted binding free energies and the experimental values; and (4) investigated the induced fit of D3 upon agonist binding through MD simulations. The pharmacophore models of the D3 agonists and the 3D structure of D3 can be used for either ligand- or receptor-based drug design. Furthermore, the MD simulations further give the insight that the long and flexible EL2 acts as a "door" for agonist binding, and the "ionic lock" at the bottom of TM3 and TM6 is essential to transduce the activation signal. PMID:20695484

  15. CARS system for turbulent flame measurements

    NASA Technical Reports Server (NTRS)

    Antcliff, R. R.; Jarrett, O., Jr.; Rogers, R. C.

    1984-01-01

    Simultaneous nitrogen number density and rotational-vibrational temperatures were measured in a turbulent diffusion flame with a Coherent Anti-Stokes Raman Scattering (CARS) instrument. The fuel jet was diluted with nitrogen (20 percent by volume) to allow temperature measurements across the entire jet mixing region. These measurements were compared with fluid dynamics computations. The CARS system incorporated a neodymium YAG laser, an intensified silicon photodiode array detector, and unique dynamic range enhancement methods. Theoretical calculations were based on a parabolic Navier-Stokes computer code. The comparison of these techniques will aid their development in the study of complex flowfields.

  16. Passenger car hydrocarbon emissions speciation. Final report

    SciTech Connect

    Black, F.; High, L.

    1980-05-01

    Emission factors for over 60 individual hydrocarbon compounds were determined for four passenger cars. The cars included a 1963 Chevrolet, a 1977 Mustang, and 1978 Monarch, and 1979 LTD II. The speciation data is reported for both tailpipe and evaporative emissions. The tailpipe emissions were for the urban driving conditions of the Federal Test Procedure used in motor vehicle certification. The evaporative emissions were for both diurnal and hot soak conditions, also prescribed in the Federal Test Procedure for certification. The vehicle tests involved four gasoline fuels of varying composition.

  17. Strategies for designing synthetic immune agonists.

    PubMed

    Wu, Tom Y-H

    2016-08-01

    Enhancing the immune system is a validated strategy to combat infectious disease, cancer and allergy. Nevertheless, the development of immune adjuvants has been hampered by safety concerns. Agents that can stimulate the immune system often bear structural similarities with pathogen-associated molecular patterns found in bacteria or viruses and are recognized by pattern recognition receptors (PRRs). Activation of these PRRs results in the immediate release of inflammatory cytokines, up-regulation of co-stimulatory molecules, and recruitment of innate immune cells. The distribution and duration of these early inflammatory events are crucial in the development of antigen-specific adaptive immunity in the forms of antibody and/or T cells capable of searching for and destroying the infectious pathogens or cancer cells. However, systemic activation of these PRRs is often poorly tolerated. Hence, different strategies have been employed to modify or deliver immune agonists in an attempt to control the early innate receptor activation through temporal or spatial restriction. These approaches include physicochemical manipulation, covalent conjugation, formulation and conditional activation/deactivation. This review will describe recent examples of discovery and optimization of synthetic immune agonists towards clinical application. PMID:27213842

  18. Proglumide exhibits delta opioid agonist properties.

    PubMed

    Rezvani, A; Stokes, K B; Rhoads, D L; Way, E L

    1987-01-01

    Recently, it was reported that proglumide, a cholecystokinin (CCK) antagonist, potentiates the analgetic effects of morphine and endogenous opioid peptides and reverses morphine tolerance by antagonizing the CCK system in the central nervous system of the rat. In order to provide additional insight into the mode of action of this agent, we assessed the effect of proglumide in the isolated guinea pig ileum and the mouse, rat and rabbit vas deferens. Furthermore, we studied the in vitro binding affinity of this substance to mouse brain synaptosomes. Our results show that proglumide inhibits, dose dependently, the electrically stimulated twitches in the mouse vas deferens and guinea pig ileum, but not in the rat or rabbit vas deferens. The inhibitory action of proglumide on the mouse vas deferens, but not on the guinea pig ileum, is antagonized by naloxone and by the selective delta-antagonist, ICI 174,864, in a competitive fashion. Other CCK antagonists were found to be devoid of such activity on the mouse vas deferens. In vitro binding studies showed that proglumide displaces D-ala-D-[leucine]5-enkephalin (DADLE), a delta agonist, but not ethylketocyclazocine (EKC), a preferentially selective kappa agonist. The effect of proglumide appeared to be elicited presynaptically since it did not alter the norepinephrine-induced contractions of the mouse vas deferens. Our results suggest that proglumide might exert its opiate-like effects by activation of delta-opioid receptors. PMID:3030338

  19. Chimpanzees Extract Social Information from Agonistic Screams

    PubMed Central

    Slocombe, Katie E.; Kaller, Tanja; Call, Josep; Zuberbühler, Klaus

    2010-01-01

    Chimpanzee (Pan troglodytes) agonistic screams are graded vocal signals that are produced in a context-specific manner. Screams given by aggressors and victims can be discriminated based on their acoustic structure but the mechanisms of listener comprehension of these calls are currently unknown. In this study, we show that chimpanzees extract social information from these vocal signals that, combined with their more general social knowledge, enables them to understand the nature of out-of-sight social interactions. In playback experiments, we broadcast congruent and incongruent sequences of agonistic calls and monitored the response of bystanders. Congruent sequences were in accordance with existing social dominance relations; incongruent ones violated them. Subjects looked significantly longer at incongruent sequences, despite them being acoustically less salient (fewer call types from fewer individuals) than congruent ones. We concluded that chimpanzees categorised an apparently simple acoustic signal into victim and aggressor screams and used pragmatics to form inferences about third-party interactions they could not see. PMID:20644722

  20. Pyrene is a Novel Constitutive Androstane Receptor (CAR) Activator and Causes Hepatotoxicity by CAR.

    PubMed

    Zhang, Xiao-Jie; Shi, Zhe; Lyv, Jing-Xi; He, Xuyan; Englert, Neal A; Zhang, Shu-Yun

    2015-10-01

    Polycyclic aromatic hydrocarbons (PAHs) are a class of ubiquitous persistent environmental pollutants which are primarily formed from the incomplete combustion of organic materials. Many potential sources of human exposure to PAHs exist, including daily exposures from the ambient environment or occupational settings. PAHs have been found to cause harmful effects on human health. Here, we evaluated the adverse effects of pyrene, a common PAH, on the liver. The present study demonstrates that pyrene is able to activate mouse constitutive androstane receptor (CAR). CAR protein, as measured by Western blot analysis, was observed to translocate into the nucleus from the cytoplasm in mouse liver after exposure to pyrene. Utilizing CAR null mice, we identified that CAR mediates pyrene-induced hepatotoxicity. Increased relative liver weight, hepatocellular hypertrophy, and elevated serum alanine aminotransferase levels were found in wild-type but not CAR null mice after orally administered pyrene. We further show that pyrene induced the expression of mouse liver metabolism enzymes including CYP2B10, CYP3A11, GSTm1, GSTm3, and SULT1A1, and caused hepatic glutathione depletion in wild-type but not CAR null mice. Moreover, by luciferase reporter assay and quantitative real-time PCR analysis, pyrene was found to be a potential inducer of CYP2B6 expression via activation of human CAR in HepG2 cells and human primary hepatocytes. Our observations suggest that pyrene is a novel CAR activator and that CAR is essential for mediating pyrene-induced liver injury. PMID:26160115

  1. Effects of age on muscarinic agonist-induced contraction an IP accumulation in airway smooth muscle

    SciTech Connect

    Wills-Karp, M. )

    1991-01-01

    The effects of age on carbachol-stimulated force development and ({sup 3}H)inositol phosphate production was studied in tracheal rings from guinea pigs aged 1 month and 25 months of age. The pD{sub 2} for the contractile response to carbachol was significantly reduced in tracheal tissues from old animals as compared to that of the young tissues, respectively. In contrast, inositol phosphate formation was not altered with increasing age when stimulated by carbachol or NaF, a direct activator of G proteins. Carbachol-induced inositol phosphate accumulation was inhibited by treatment with 1{mu}g/ml pertussis toxin, suggesting that IP1 accumulation is coupled to a pertussis-toxin-sensitive protein. The pD{sub 2} values for contraction were significantly different from the pD{sub 2} values for IP1 accumulation, in both young and old tissues, respectively. These data suggest that IP1 accumulation is not responsible for the decreased contractile ability in tracheal smooth muscle during aging.

  2. What Happens at a Car Wash?

    ERIC Educational Resources Information Center

    Gallick, Barbara; Lee, Lisa

    2010-01-01

    A class of 3- to 5-year-old children in a child care center in the midwestern United States chose to study a car wash as a group project. This article discusses how the project evolved, describes the three phases of the project, and provides the teachers' reflections on the project. Photos taken during the project and children's sketches are…

  3. 49 CFR 212.217 - Car inspector.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... (ii) The Freight Car Safety Standards (49 CFR part 215), Safety Glazing Standards (49 CFR part 223... Safety Standards (49 CFR part 215), Safety Glazing Standards (49 CFR part 223), Safety Appliance Standards (49 CFR part 231) and Power Brake Standards (49 CFR part 232), to make reports of...

  4. 49 CFR 212.217 - Car inspector.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... (ii) The Freight Car Safety Standards (49 CFR part 215), Safety Glazing Standards (49 CFR part 223... Safety Standards (49 CFR part 215), Safety Glazing Standards (49 CFR part 223), Safety Appliance Standards (49 CFR part 231) and Power Brake Standards (49 CFR part 232), to make reports of...

  5. 49 CFR 212.217 - Car inspector.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... (ii) The Freight Car Safety Standards (49 CFR part 215), Safety Glazing Standards (49 CFR part 223... Safety Standards (49 CFR part 215), Safety Glazing Standards (49 CFR part 223), Safety Appliance Standards (49 CFR part 231) and Power Brake Standards (49 CFR part 232), to make reports of...

  6. Electric hybrid module based specialty car design

    SciTech Connect

    Bohan, K.R.

    1995-12-31

    The vast majority of automobiles made in the United states today are manufactured by one of three major auto manufacturers. It is intrinsic in their nature to act conservatively. The big three`s large production runs represents a huge amount of capitalization. The amount of capital being invested is the real driving factor behind the conservative nature of these companies. In the computer industries we have seen a significant number of small start up companies as the driving force behind technological change. If a large company does not do it, a small venture capital company will certainly fill the vacuum. Unfortunately, the existing auto industry does not have a strong startup company presence. Even into the 1920`s, the specialty car or custom coach work manufactures represented a lively part of the auto economy. It was not until the coming of the great depression that the small specialty car manufacture was virtually eliminated. Today we see the beginnings of a comeback of the specialty car manufacturer in the kit car industry of today.

  7. 75 FR 10567 - Commerce Acquisition Regulation (CAR)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-08

    ... proposed rule published on October 13, 2009 in the Federal Register (74 FR 52541). The document is also... Commerce 48 CFR Chapter 13 Commerce Acquisition Regulation (CAR); Final Rule #0;#0;Federal Register / Vol. 75, No. 44 / Monday, March 8, 2010 / Rules and Regulations#0;#0; ] DEPARTMENT OF COMMERCE 48...

  8. Technology, Linear Equations, and Buying a Car.

    ERIC Educational Resources Information Center

    Sandefur, James T.

    1992-01-01

    Discusses the use of technology in solving compound interest-rate problems that can be modeled by linear relationships. Uses a graphing calculator to solve the specific problem of determining the amount of money that can be borrowed to buy a car for a given monthly payment and interest rate. (MDH)

  9. Inflation Rates, Car Devaluation, and Chemical Kinetics.

    ERIC Educational Resources Information Center

    Pogliani, Lionello; Berberan-Santos, Mario N.

    1996-01-01

    Describes the inflation rate problem and offers an interesting analogy with chemical kinetics. Presents and solves the car devaluation problem as a normal chemical kinetic problem where the order of the rate law and the value of the rate constant are derived. (JRH)

  10. Colleges Drive Research on Electric Cars

    ERIC Educational Resources Information Center

    Basken, Paul

    2009-01-01

    As the General Motors Corporation shuts assembly plants and veers toward bankruptcy, the lonely remnants of one of its top technological achievements--the first modern mass-produced electric car--lie scattered across a few dozen American college campuses. GM produced and leased to customers more than 1,000 "EV1" automobiles beginning in 1996. In…

  11. 49 CFR 174.615 - Cleaning cars.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Cleaning cars. 174.615 Section 174.615 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS REGULATIONS CARRIAGE BY RAIL Detailed Requirements for Division 6.1 (Poisonous) Materials...

  12. Costimulation Engages the Gear in Driving CARs.

    PubMed

    Abken, Hinrich

    2016-02-16

    In this issue of Immunity,Kawalekar et al. (2016) find that costimulation by a chimeric antigen receptor (CAR) can control T cell metabolism and balance the response toward long-lived memory or short-lived effector cells. The results provide a rationale of how to tune cancer immunotherapy more effectively in a hostile tumor environment. PMID:26885852

  13. 49 CFR 212.217 - Car inspector.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... (ii) The Freight Car Safety Standards (49 CFR part 215), Safety Glazing Standards (49 CFR part 223... Safety Standards (49 CFR part 215), Safety Glazing Standards (49 CFR part 223), Safety Appliance Standards (49 CFR part 231) and Power Brake Standards (49 CFR part 232), to make reports of...

  14. Aerodynamic Noise Generated by Shinkansen Cars

    NASA Astrophysics Data System (ADS)

    KITAGAWA, T.; NAGAKURA, K.

    2000-03-01

    The noise value (A -weighted sound pressure level, SLOW) generated by Shinkansen trains, now running at 220-300 km/h, should be less than 75 dB(A) at the trackside. Shinkansen noise, such as rolling noise, concrete support structure noise, and aerodynamic noise are generated by various parts of Shinkansen trains. Among these aerodynamic noise is important because it is the major contribution to the noise generated by the coaches running at high speed. In order to reduce the aerodynamic noise, a number of improvements to coaches have been made. As a result, the aerodynamic noise has been reduced, but it still remains significant. In addition, some aerodynamic noise generated from the lower parts of cars remains. In order to investigate the contributions of these noises, a method of analyzing Shinkansen noise has been developed and applied to the measured data of Shinkansen noise at speeds between 120 and 315 km/h. As a result, the following conclusions have been drawn: (1) Aerodynamic noise generated from the upper parts of cars was reduced considerably by smoothing car surfaces. (2) Aerodynamic noise generated from the lower parts of cars has a major influence upon the wayside noise.

  15. Picasso, Car Classics, and the Engineers.

    ERIC Educational Resources Information Center

    Wosk, Julie H.

    1982-01-01

    Describes a college course which introduces engineering and business students to abstract art. Students study the relationships between abstract styles in painting and abstract styles in twentieth-century architecture and industrial design. The relevance of abstract design principles is shown by referring students to "Car and Driver" magazine. (AM)

  16. Rear-facing car seat (image)

    MedlinePlus

    ... spinal cord of the child. In a frontal crash a rear-facing car seat is best, because it cradles the head, neck, and back of the child causing less injury. Therefore, the rear-facing position is recommended for as long as possible for ...

  17. 20. TURNTABLE WITH CABLE CAR BAY & TAYLOR: View ...

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

    20. TURNTABLE WITH CABLE CAR - BAY & TAYLOR: View to northwest of the Bay and Taylor turntable. The gripman and conductor are turning the car around. - San Francisco Cable Railway, Washington & Mason Streets, San Francisco, San Francisco County, CA

  18. Interior view; Street Car Waiting House North Philadelphia Station, ...

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

    Interior view; Street Car Waiting House - North Philadelphia Station, Street Car Waiting House, 2900 North Broad Street, on northwest corner of Broad Street & Glenwood Avenue, Philadelphia, Philadelphia County, PA

  19. 11. VIEW OF CIRCULAR CAR SHOP OVER TOPS OF BOX ...

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

    11. VIEW OF CIRCULAR CAR SHOP OVER TOPS OF BOX CARS LOOKING NORTHEAST. - Baltimore & Ohio Railroad, Mount Clare Shops, South side of Pratt Street between Carey & Poppleton Streets, Baltimore, Independent City, MD

  20. CAR MACHINE SHOP, FIRST FLOOR, DETAIL OF WOOD COLUMN AND ...

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

    CAR MACHINE SHOP, FIRST FLOOR, DETAIL OF WOOD COLUMN AND INVERTED KING-POST TRUSS TO PROVIDE INCREASED SPAN BETWEEN COLUMNS, LOOKING SOUTH. - Southern Pacific, Sacramento Shops, Car Machine Shop, 111 I Street, Sacramento, Sacramento County, CA

  1. 35. EAST FRONT OF POWERHOUSE AND CAR BARN: East front ...

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

    35. EAST FRONT OF POWERHOUSE AND CAR BARN: East front of powerhouse and car barn. 'Annex' is right end of building. - San Francisco Cable Railway, Washington & Mason Streets, San Francisco, San Francisco County, CA

  2. 8. VAL CAMERA CAR, CLOSEUP VIEW OF 'FLARE' OR TRAJECTORY ...

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

    8. VAL CAMERA CAR, CLOSE-UP VIEW OF 'FLARE' OR TRAJECTORY CAMERA ON SLIDING MOUNT. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  3. 33. VAL, DETAIL OF PERSONNEL CAR AT THE TOP OF ...

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

    33. VAL, DETAIL OF PERSONNEL CAR AT THE TOP OF THE COUNTERWEIGHT SLAB WITH THE COUNTERWEIGHT CAR IN DISTANCE LOOKING NORTH. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  4. 3. GENERAL VIEW OF PASSENGER CAR SHOP; RAILROAD TRACKS IN ...

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

    3. GENERAL VIEW OF PASSENGER CAR SHOP; RAILROAD TRACKS IN FOREGROUND - Baltimore & Ohio Railroad, Mount Clare Passenger Car Shop, Southwest corner of Pratt & Poppleton Streets, Baltimore, Independent City, MD

  5. 23. POWELLTYPE CAR THROUGH GRIP REMOVAL DOOR: View looking through ...

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

    23. POWELL-TYPE CAR THROUGH GRIP REMOVAL DOOR: View looking through grip removal door into interior of a Powell-type cable car. - San Francisco Cable Railway, Washington & Mason Streets, San Francisco, San Francisco County, CA

  6. CAR MACHINE SHOP, SECOND FLOOR, LYE TANKS FOR CLEANING METAL ...

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

    CAR MACHINE SHOP, SECOND FLOOR, LYE TANKS FOR CLEANING METAL PRIOR TO PLATING, LOOKING SOUTHWEST FROM ATTIC. - Southern Pacific, Sacramento Shops, Car Machine Shop, 111 I Street, Sacramento, Sacramento County, CA

  7. East yard, north elevation of car department tool house (converted ...

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

    East yard, north elevation of car department tool house (converted from express car). - Chesapeake & Ohio Railroad, Thurmond Yards, East side New River, mouths of Arbuckle & Dunlop Circles, Thurmond, Fayette County, WV

  8. North view; Street Car Waiting House, south (front) elevation ...

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

    North view; Street Car Waiting House, south (front) elevation - North Philadelphia Station, Street Car Waiting House, 2900 North Broad Street, on northwest corner of Broad Street & Glenwood Avenue, Philadelphia, Philadelphia County, PA

  9. 10. VIEW OF BOILER SHOP FROM TOP OF BOX CAR ...

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

    10. VIEW OF BOILER SHOP FROM TOP OF BOX CAR WITH CIRCULAR CAR SHOP IN BACKGROUND LOOKING NORTHEAST. - Baltimore & Ohio Railroad, Mount Clare Shops, South side of Pratt Street between Carey & Poppleton Streets, Baltimore, Independent City, MD

  10. CAR MACHINE SHOP, SECOND FLOOR, PAINT SPRAY ROOM EXTERIOR AND ...

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

    CAR MACHINE SHOP, SECOND FLOOR, PAINT SPRAY ROOM EXTERIOR AND ATTIC FLOOR SUPPORT COLUMNS AND BEAMS, LOOKING WEST. - Southern Pacific, Sacramento Shops, Car Machine Shop, 111 I Street, Sacramento, Sacramento County, CA

  11. Detail; Street Car Waiting House window, north wall North ...

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

    Detail; Street Car Waiting House window, north wall - North Philadelphia Station, Street Car Waiting House, 2900 North Broad Street, on northwest corner of Broad Street & Glenwood Avenue, Philadelphia, Philadelphia County, PA

  12. Inside the covered hopper car loading dock at railroad level, ...

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

    Inside the covered hopper car loading dock at railroad level, looking east from the 1945 elevator into the 1913 elevator, control for the railroad car puller in background - Stewart Company Grain Elevator, 16 West Carson Street, Pittsburgh, Allegheny County, PA

  13. CAR MACHINE SHOP, SECOND FLOOR, LYE TANKS FOR CLEANING METAL ...

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

    CAR MACHINE SHOP, SECOND FLOOR, LYE TANKS FOR CLEANING METAL PRIOR TO PLATING, LOOKING SOUTH FROM ATTIC. - Southern Pacific, Sacramento Shops, Car Machine Shop, 111 I Street, Sacramento, Sacramento County, CA

  14. West view; Street Car Waiting House, east elevation North ...

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

    West view; Street Car Waiting House, east elevation - North Philadelphia Station, Street Car Waiting House, 2900 North Broad Street, on northwest corner of Broad Street & Glenwood Avenue, Philadelphia, Philadelphia County, PA

  15. Detail; Street Car Waiting House, support for exterior light fixture ...

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

    Detail; Street Car Waiting House, support for exterior light fixture - North Philadelphia Station, Street Car Waiting House, 2900 North Broad Street, on northwest corner of Broad Street & Glenwood Avenue, Philadelphia, Philadelphia County, PA

  16. 31. REAR OF CAR BARN DURING RECONSTRUCTION: Photocopy of July ...

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

    31. REAR OF CAR BARN DURING RECONSTRUCTION: Photocopy of July 1908 photograph showing west rear of powerhouse and car barn. View from the north. - San Francisco Cable Railway, Washington & Mason Streets, San Francisco, San Francisco County, CA

  17. 14. AERIAL VIEW OF ENGINE DISPLAY INSIDE PASSENGER CAR SHOP ...

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

    14. AERIAL VIEW OF ENGINE DISPLAY INSIDE PASSENGER CAR SHOP (NOW A TRANSPORTATION MUSEUM) - Baltimore & Ohio Railroad, Mount Clare Passenger Car Shop, Southwest corner of Pratt & Poppleton Streets, Baltimore, Independent City, MD

  18. 35. BOILER HOUSE, TRACK FOR COAL CARS LEADING TO COAL ...

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

    35. BOILER HOUSE, TRACK FOR COAL CARS LEADING TO COAL TOWER No. 2 (NOTE: SKYLIGHT ABOVE; COAL CARS IN FAR BACKGROUND) - Delaware County Electric Company, Chester Station, Delaware River at South end of Ward Street, Chester, Delaware County, PA

  19. 34. BARGE LOADING PIER, DETAIL SHOWING CABLE CAR TRACKS, CABLE ...

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

    34. BARGE LOADING PIER, DETAIL SHOWING CABLE CAR TRACKS, CABLE CARS AND WALKWAYS. LOOKING TOWARD THE EAST END FROM THE WEST END - Pennsylvania Railroad, Canton Coal Pier, Clinton Street at Keith Avenue (Canton area), Baltimore, Independent City, MD

  20. Child Dies in Hot Car Almost Once a Week

    MedlinePlus

    ... gov/news/fullstory_160479.html Child Dies in Hot Car Almost Once a Week Safe Kids Worldwide ... being left in a car that got too hot, according to Safe Kids Worldwide. Sometimes parents forget ...

  1. 130. Photocopied July 1978. 'CAR NO. 8 PARKED AT QUINCY ...

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

    130. Photocopied July 1978. 'CAR NO. 8 PARKED AT QUINCY NO. 2 SHAFT.' CAR NO. 8 CARRIED BUREAU OF MINES EMERGENCY TEAM TO QUINCY TO HELP FIGHT AN UNDERGROUND FIRE. JULY 1927. - Quincy Mining Company, Hancock, Houghton County, MI

  2. Cellular automaton model considering the velocity effect of a car on the successive car.

    PubMed

    Li, X; Wu, Q; Jiang, R

    2001-12-01

    In this paper we present a cellular automata model for one-lane traffic flow. The update rules of velocity of a car depend not only on the positions of this car and the car ahead of it, but also on the velocities of the two cars. Using computer simulations we obtain some basic qualitative results and the fundamental diagram of the proposed model. In comparison with those of the existing models in the literature, we find that the fundamental diagram of the proposed model is more consistent with the results measured in the real traffic, and the model is able to reproduce some relevant macroscopic states that are found in the real traffic flow but cannot be predicted by the existing models. PMID:11736257

  3. Effect of interferences on indoor visible light car-to-car communication systems

    NASA Astrophysics Data System (ADS)

    Kim, Jong-Young; Park, Bong-Seok; Choi, Hyun-Sik; Kim, So Eun; Moon, Inkyu; Lee, Chung Ghiu

    2016-04-01

    We report the effect of interferences on visible light car-to-car communication system. The interferences from floor reflections and fluorescent lamps are taken into account for indoor car-to-car visible light communication (VLC) systems. The system is composed of a white LED lamp as a VLC transmitter and a photo-receiver with an appropriate optical filter as a VLC receiver. The signal power distribution patterns are measured and analyzed at a transmission distance, considering the positions of the transmitter and receiver. Generally, the light from fluorescent lamps in indoor environment affects the DC level of the received signal power, which is more significant at higher receiver positions. The measurements show that the indoor VLC communication performance can be varied depending on floor reflections. Also, the fluorescent ceiling illuminations affect the DC level change of the received VLC signal waveforms.

  4. Can a road-driven car outrace a free-falling car?

    NASA Astrophysics Data System (ADS)

    Castaño, Diego J.

    2011-11-01

    Motivated by an advertising scenario in which a luxury sports sedan races against a similar car falling under the influence of gravity, a calculation using undergraduate physics and calculus is performed to theoretically predict the outcome.

  5. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  6. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  7. Development of an in vitro high content imaging assay for quantitative assessment of CAR-dependent mouse, rat, and human primary hepatocyte proliferation.

    PubMed

    Soldatow, Valerie; Peffer, Richard C; Trask, O Joseph; Cowie, David E; Andersen, Melvin E; LeCluyse, Edward; Deisenroth, Chad

    2016-10-01

    Rodent liver tumors promoted by constitutive androstane receptor (CAR) activation are known to be mediated by key events that include CAR-dependent gene expression and hepatocellular proliferation. Here, an in vitro high content imaging based assay was developed for quantitative assessment of nascent DNA synthesis in primary hepatocyte cultures from mouse, rat, and human species. Detection of DNA synthesis was performed using direct DNA labeling with the nucleoside analog 5-ethynyl-2'-deoxyuridine (EdU). The assay was multiplexed to enable direct quantitation of DNA synthesis, cytotoxicity, and cell count endpoints. An optimized defined medium cocktail was developed to sensitize hepatocytes to cell cycle progression. The baseline EdU response to defined medium was greatest for mouse, followed by rat, and then human. Hepatocytes from all three species demonstrated CAR activation in response to the CAR agonists TCPOBOP, CITCO, and phenobarbital based on increased gene expression for Cyp2b isoforms. When evaluated for a proliferation phenotype, TCPOBOP and CITCO exhibited significant dose-dependent increases in frequency of EdU labeling in mouse and rat hepatocytes that was not observed in hepatocytes from three human donors. The observed species differences are consistent with CAR activators inducing a proliferative response in rodents, a key event in the liver tumor mode of action that is not observed in humans. PMID:27530964

  8. Is This Car Looking at You? How Anthropomorphism Predicts Fusiform Face Area Activation when Seeing Cars

    PubMed Central

    Kühn, Simone; Brick, Timothy R.; Müller, Barbara C. N.; Gallinat, Jürgen

    2014-01-01

    Anthropomorphism encompasses the attribution of human characteristics to non-living objects. In particular the human tendency to see faces in cars has long been noticed, yet its neural correlates are unknown. We set out to investigate whether the fusiform face area (FFA) is associated with seeing human features in car fronts, or whether, the higher-level theory of mind network (ToM), namely temporoparietal junction (TPJ) and medial prefrontal cortex (MPFC) show a link to anthropomorphism. Twenty participants underwent fMRI scanning during a passive car-front viewing task. We extracted brain activity from FFA, TPJ and MPFC. After the fMRI session participants were asked to spontaneously list adjectives that characterize each car front. Five raters judged the degree to which each adjective can be applied as a characteristic of human beings. By means of linear mixed models we found that the implicit tendency to anthropomorphize individual car fronts predicts FFA, but not TPJ or MPFC activity. The results point to an important role of FFA in the phenomenon of ascribing human attributes to non-living objects. Interestingly, brain regions that have been associated with thinking about beliefs and mental states of others (TPJ, MPFC) do not seem to be related to anthropomorphism of car fronts. PMID:25517511

  9. Estrogen receptor beta agonists in neurobehavioral investigations.

    PubMed

    Choleris, Elena; Clipperton, Amy E; Phan, Anna; Kavaliers, Martin

    2008-07-01

    Neurobehavioral investigations into the functions of estrogen receptor (ER)alpha and ERbeta have utilized 'knockout' mice, phytoestrogens and, more recently, ER-specific agonists. Feeding, sexual, aggressive and social behavior, anxiety, depression, drug abuse, pain perception, and learning (and associated synaptic plasticity) are affected by ERalpha and ERbeta in a manner that is dependent upon the specific behavior studied, gender and developmental stage. Overall, ERalpha and ERbeta appear to function together to foster sociosexual behavior while inhibiting behaviors that, if occurring at the time of behavioral estrous, may compete with reproduction (eg, feeding). Recently developed pharmacological tools have limited selectivity and availability to the research community at large, as they are not commercially available. The development of highly selective, commercially available ERbeta-specific antagonists would greatly benefit preclinical and applied research. PMID:18600582

  10. Non-Benzodiazepine Receptor Agonists for Insomnia.

    PubMed

    Becker, Philip M; Somiah, Manya

    2015-03-01

    Because of proven efficacy, reduced side effects, and less concern about addiction, non-benzodiazepine receptor agonists (non-BzRA) have become the most commonly prescribed hypnotic agents to treat onset and maintenance insomnia. First-line treatment is cognitive-behavioral therapy. When pharmacologic treatment is indicated, non-BzRA are first-line agents for the short-term and long-term management of transient and chronic insomnia related to adjustment, psychophysiologic, primary, and secondary causation. In this article, the benefits and risks of non-BzRA are reviewed, and the selection of a hypnotic agent is defined, based on efficacy, pharmacologic profile, and adverse events. PMID:26055674

  11. 7 CFR 160.28 - Tank cars of turpentine.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 3 2013-01-01 2013-01-01 false Tank cars of turpentine. 160.28 Section 160.28... STANDARDS FOR NAVAL STORES Analysis, Inspection, and Grading on Request § 160.28 Tank cars of turpentine. A tank car loaded for shipment with spirits of turpentine shall, after the same has been sampled...

  12. 49 CFR 1033.2 - Car service orders.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 8 2012-10-01 2012-10-01 false Car service orders. 1033.2 Section 1033.2 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION GENERAL RULES AND REGULATIONS CAR SERVICE § 1033.2 Car service orders....

  13. 49 CFR 232.305 - Single car air brake tests.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy of the incorporated document from the... 49 Transportation 4 2014-10-01 2014-10-01 false Single car air brake tests. 232.305 Section 232... car air brake tests. (a) Single car air brake tests shall be performed by a qualified person...

  14. 30 CFR 56.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Coupling or uncoupling cars. 56.14215 Section... Equipment Safety Practices and Operational Procedures § 56.14215 Coupling or uncoupling cars. Prior to coupling or uncoupling cars manually, trains shall be brought to a complete stop, and then moved at...

  15. 30 CFR 56.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Coupling or uncoupling cars. 56.14215 Section... Equipment Safety Practices and Operational Procedures § 56.14215 Coupling or uncoupling cars. Prior to coupling or uncoupling cars manually, trains shall be brought to a complete stop, and then moved at...

  16. 40 CFR 201.15 - Standard for car coupling operations.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Standard for car coupling operations... Interstate Rail Carrier Operations Standards § 201.15 Standard for car coupling operations. Effective January 15, 1984, no carrier subject to this regulation shall conduct car coupling operations that exceed...

  17. 49 CFR 238.413 - End structures of trailer cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false End structures of trailer cars. 238.413 Section... II Passenger Equipment § 238.413 End structures of trailer cars. (a) Except as provided in paragraph (b) of this section, the end structure of a trailer car shall be designed to include the...

  18. 36 CFR 1192.63 - Between-car barriers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 3 2014-07-01 2014-07-01 false Between-car barriers. 1192.63... Rail Vehicles and Systems § 1192.63 Between-car barriers. (a) Requirement. Suitable devices or systems... between cars. Acceptable solutions include, but are not limited to, pantograph gates, chains,...

  19. 49 CFR 38.63 - Between-car barriers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false Between-car barriers. 38.63 Section 38.63... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Rapid Rail Vehicles and Systems § 38.63 Between-car barriers. (a... inadvertently stepping off the platform between cars. Acceptable solutions include, but are not limited...

  20. 19 CFR 123.61 - Baggage arriving in baggage car.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 1 2014-04-01 2014-04-01 false Baggage arriving in baggage car. 123.61 Section... OF THE TREASURY CBP RELATIONS WITH CANADA AND MEXICO Baggage § 123.61 Baggage arriving in baggage car... cars....

  1. 40 CFR 201.15 - Standard for car coupling operations.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 26 2012-07-01 2011-07-01 true Standard for car coupling operations... Interstate Rail Carrier Operations Standards § 201.15 Standard for car coupling operations. Effective January 15, 1984, no carrier subject to this regulation shall conduct car coupling operations that exceed...

  2. 49 CFR 38.63 - Between-car barriers.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 1 2013-10-01 2013-10-01 false Between-car barriers. 38.63 Section 38.63... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Rapid Rail Vehicles and Systems § 38.63 Between-car barriers. (a... inadvertently stepping off the platform between cars. Acceptable solutions include, but are not limited...

  3. Looking north toward Locomotive Shop (2 tracks on left), Car ...

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

    Looking north toward Locomotive Shop (2 tracks on left), Car Shop on right, and flat car in foreground. Note locomotive and car tires leaning on stock shed at left - East Broad Top Railroad & Coal Company, State Route 994, West of U.S. Route 522, Rockhill Furnace, Huntingdon County, PA

  4. 19 CFR 123.61 - Baggage arriving in baggage car.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 1 2013-04-01 2013-04-01 false Baggage arriving in baggage car. 123.61 Section... OF THE TREASURY CBP RELATIONS WITH CANADA AND MEXICO Baggage § 123.61 Baggage arriving in baggage car... cars....

  5. 40 CFR 201.13 - Standard for rail car operations.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 25 2014-07-01 2014-07-01 false Standard for rail car operations. 201... Interstate Rail Carrier Operations Standards § 201.13 Standard for rail car operations. Effective December 31, 1976, no carrier subject to this regulation shall operate any rail car or combination of rail...

  6. 36 CFR 1192.85 - Between-car barriers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 3 2013-07-01 2012-07-01 true Between-car barriers. 1192.85... Rail Vehicles and Systems § 1192.85 Between-car barriers. Where vehicles operate in a high-platform... inadvertently stepping off the platform between cars. Appropriate devices include, but are not limited...

  7. 49 CFR 37.93 - One car per train rule.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false One car per train rule. 37.93 Section 37.93... DISABILITIES (ADA) Acquisition of Accessible Vehicles By Public Entities § 37.93 One car per train rule. (a) The definition of accessible for purposes of meeting the one car per train rule is spelled out in...

  8. 30 CFR 56.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Coupling or uncoupling cars. 56.14215 Section... Equipment Safety Practices and Operational Procedures § 56.14215 Coupling or uncoupling cars. Prior to coupling or uncoupling cars manually, trains shall be brought to a complete stop, and then moved at...

  9. 40 CFR 201.13 - Standard for rail car operations.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 26 2012-07-01 2011-07-01 true Standard for rail car operations. 201... Interstate Rail Carrier Operations Standards § 201.13 Standard for rail car operations. Effective December 31, 1976, no carrier subject to this regulation shall operate any rail car or combination of rail...

  10. 40 CFR 201.15 - Standard for car coupling operations.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 25 2014-07-01 2014-07-01 false Standard for car coupling operations... Interstate Rail Carrier Operations Standards § 201.15 Standard for car coupling operations. Effective January 15, 1984, no carrier subject to this regulation shall conduct car coupling operations that exceed...

  11. 49 CFR 38.85 - Between-car barriers.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 1 2013-10-01 2013-10-01 false Between-car barriers. 38.85 Section 38.85... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Light Rail Vehicles and Systems § 38.85 Between-car barriers. Where..., deter or warn individuals from inadvertently stepping off the platform between cars. Appropriate...

  12. 49 CFR 38.63 - Between-car barriers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false Between-car barriers. 38.63 Section 38.63... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Rapid Rail Vehicles and Systems § 38.63 Between-car barriers. (a... inadvertently stepping off the platform between cars. Acceptable solutions include, but are not limited...

  13. Elevation (typical EBT Coal Hopper Car) with scale. 3 Bay ...

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

    Elevation (typical EBT Coal Hopper Car) with scale. 3 Bay Steel Hopper Car with side extensions raising coal carrying capacity to 80,000 pounds. Note cars on either side lack extensions limiting their coal capacity to 70,000 pounds - East Broad Top Railroad & Coal Company, State Route 994, West of U.S. Route 522, Rockhill Furnace, Huntingdon County, PA

  14. 49 CFR 231.22 - Operation of track motor cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Operation of track motor cars. 231.22 Section 231... motor cars. On and after August 1, 1963, it shall be unlawful for any railroad subject to the requirements of the Safety Appliance Acts to operate or permit to be operated on its line track motor cars...

  15. 49 CFR 38.85 - Between-car barriers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false Between-car barriers. 38.85 Section 38.85... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Light Rail Vehicles and Systems § 38.85 Between-car barriers. Where..., deter or warn individuals from inadvertently stepping off the platform between cars. Appropriate...

  16. 49 CFR 232.305 - Single car air brake tests.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy of the incorporated document from the... 49 Transportation 4 2012-10-01 2012-10-01 false Single car air brake tests. 232.305 Section 232... car air brake tests. (a) Single car air brake tests shall be performed by a qualified person...

  17. 49 CFR 1033.2 - Car service orders.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 8 2014-10-01 2014-10-01 false Car service orders. 1033.2 Section 1033.2 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION GENERAL RULES AND REGULATIONS CAR SERVICE § 1033.2 Car service orders....

  18. 40 CFR 201.13 - Standard for rail car operations.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Standard for rail car operations. 201... Interstate Rail Carrier Operations Standards § 201.13 Standard for rail car operations. Effective December 31, 1976, no carrier subject to this regulation shall operate any rail car or combination of rail...

  19. 7 CFR 160.28 - Tank cars of turpentine.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 3 2012-01-01 2012-01-01 false Tank cars of turpentine. 160.28 Section 160.28... STANDARDS FOR NAVAL STORES Analysis, Inspection, and Grading on Request § 160.28 Tank cars of turpentine. A tank car loaded for shipment with spirits of turpentine shall, after the same has been sampled...

  20. 49 CFR 1033.2 - Car service orders.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 8 2013-10-01 2013-10-01 false Car service orders. 1033.2 Section 1033.2 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION GENERAL RULES AND REGULATIONS CAR SERVICE § 1033.2 Car service orders....

  1. 36 CFR 1192.85 - Between-car barriers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 3 2014-07-01 2014-07-01 false Between-car barriers. 1192.85... Rail Vehicles and Systems § 1192.85 Between-car barriers. Where vehicles operate in a high-platform... inadvertently stepping off the platform between cars. Appropriate devices include, but are not limited...

  2. 49 CFR 231.18 - Cars of special construction.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Cars of special construction. 231.18 Section 231... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.18 Cars of special construction. Cars of construction not covered specifically in the foregoing sections in this part, relative...

  3. 49 CFR 231.18 - Cars of special construction.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Cars of special construction. 231.18 Section 231... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.18 Cars of special construction. Cars of construction not covered specifically in the foregoing sections in this part, relative...

  4. 49 CFR 231.18 - Cars of special construction.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Cars of special construction. 231.18 Section 231... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.18 Cars of special construction. Cars of construction not covered specifically in the foregoing sections in this part, relative...

  5. 37. WEST REAR OF POWERHOUSE AND CAR BARN: West rear ...

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

    37. WEST REAR OF POWERHOUSE AND CAR BARN: West rear of powerhouse and car barn, showing the turntable and tracks used to move cars in and out of the building's repair and storage area. - San Francisco Cable Railway, Washington & Mason Streets, San Francisco, San Francisco County, CA

  6. 19 CFR 123.61 - Baggage arriving in baggage car.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Baggage arriving in baggage car. 123.61 Section... OF THE TREASURY CBP RELATIONS WITH CANADA AND MEXICO Baggage § 123.61 Baggage arriving in baggage car... cars....

  7. 36 CFR 1192.63 - Between-car barriers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 3 2012-07-01 2012-07-01 false Between-car barriers. 1192.63... Rail Vehicles and Systems § 1192.63 Between-car barriers. (a) Requirement. Suitable devices or systems... between cars. Acceptable solutions include, but are not limited to, pantograph gates, chains,...

  8. 36 CFR 1192.63 - Between-car barriers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 3 2013-07-01 2012-07-01 true Between-car barriers. 1192.63... Rail Vehicles and Systems § 1192.63 Between-car barriers. (a) Requirement. Suitable devices or systems... between cars. Acceptable solutions include, but are not limited to, pantograph gates, chains,...

  9. 49 CFR 232.305 - Single car air brake tests.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy of the incorporated document from the... 49 Transportation 4 2013-10-01 2013-10-01 false Single car air brake tests. 232.305 Section 232... car air brake tests. (a) Single car air brake tests shall be performed by a qualified person...

  10. 49 CFR 37.93 - One car per train rule.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 1 2013-10-01 2013-10-01 false One car per train rule. 37.93 Section 37.93... DISABILITIES (ADA) Acquisition of Accessible Vehicles By Public Entities § 37.93 One car per train rule. (a) The definition of accessible for purposes of meeting the one car per train rule is spelled out in...

  11. 49 CFR 231.22 - Operation of track motor cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Operation of track motor cars. 231.22 Section 231... motor cars. On and after August 1, 1963, it shall be unlawful for any railroad subject to the requirements of the Safety Appliance Acts to operate or permit to be operated on its line track motor cars...

  12. 49 CFR 238.413 - End structures of trailer cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false End structures of trailer cars. 238.413 Section... II Passenger Equipment § 238.413 End structures of trailer cars. (a) Except as provided in paragraph (b) of this section, the end structure of a trailer car shall be designed to include the...

  13. 49 CFR 231.22 - Operation of track motor cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Operation of track motor cars. 231.22 Section 231... motor cars. On and after August 1, 1963, it shall be unlawful for any railroad subject to the requirements of the Safety Appliance Acts to operate or permit to be operated on its line track motor cars...

  14. 49 CFR 37.93 - One car per train rule.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false One car per train rule. 37.93 Section 37.93... DISABILITIES (ADA) Acquisition of Accessible Vehicles By Public Entities § 37.93 One car per train rule. (a) The definition of accessible for purposes of meeting the one car per train rule is spelled out in...

  15. 36 CFR 1192.85 - Between-car barriers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 3 2012-07-01 2012-07-01 false Between-car barriers. 1192.85... Rail Vehicles and Systems § 1192.85 Between-car barriers. Where vehicles operate in a high-platform... inadvertently stepping off the platform between cars. Appropriate devices include, but are not limited...

  16. 49 CFR 38.85 - Between-car barriers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false Between-car barriers. 38.85 Section 38.85... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Light Rail Vehicles and Systems § 38.85 Between-car barriers. Where..., deter or warn individuals from inadvertently stepping off the platform between cars. Appropriate...

  17. 49 CFR 238.413 - End structures of trailer cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false End structures of trailer cars. 238.413 Section... II Passenger Equipment § 238.413 End structures of trailer cars. (a) Except as provided in paragraph (b) of this section, the end structure of a trailer car shall be designed to include the...

  18. 7 CFR 160.28 - Tank cars of turpentine.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 3 2014-01-01 2014-01-01 false Tank cars of turpentine. 160.28 Section 160.28... STANDARDS FOR NAVAL STORES Analysis, Inspection, and Grading on Request § 160.28 Tank cars of turpentine. A tank car loaded for shipment with spirits of turpentine shall, after the same has been sampled...

  19. Buying a Car: Using On-Line Tools. Technology Update.

    ERIC Educational Resources Information Center

    McCoy, Kimberly

    This lesson plan was created to assist learners in adult basic and literacy education programs with the car-buying process. The goal for the lesson is to "effectively use the Internet to research necessary items before purchasing a car." These nine learning objectives are set: (1) determine what kind of car is needed; (2) determine how much one…

  20. Shifting the Evolving CAR T Cell Platform into Higher Gear.

    PubMed

    Holohan, Daniel R; Lee, James C; Bluestone, Jeffrey A

    2015-10-12

    In this issue of Cancer Cell, Zhao and colleagues test various chimeric antigen receptor (CAR) T cells to show that CD28-CD3ζ CAR T cells that constitutively express 4-1BBL promote T cell expansion and tumor eradication while reducing exhaustion. The results have important implications for the development of effective CAR T cell therapies in cancer patients. PMID:26461084

  1. 49 CFR 215.119 - Defective freight car truck.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Defective freight car truck. 215.119 Section 215.119 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Suspension System § 215.119 Defective freight...

  2. 49 CFR 215.303 - Stenciling of restricted cars.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Stenciling of restricted cars. 215.303 Section 215.303 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Stenciling § 215.303 Stenciling of restricted cars. (a) Each...

  3. Engineering Analysis in the Chem-E-Car Competition

    ERIC Educational Resources Information Center

    Lewis, Randy S.; Moshfeghian, Aliakbar; Madihally, Sundararajan V.

    2006-01-01

    The AIChE Chem-E-Car competition provides students an opportunity to demonstrate their design and teamwork skills. Engineering analysis is not required at the national competition and is often not applied. This work describes an engineering analysis of a Chem-E-Car to predict the distance traveled by the car. Engineering analysis is advantageous…

  4. 49 CFR 1033.2 - Car service orders.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 8 2010-10-01 2010-10-01 false Car service orders. 1033.2 Section 1033.2 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION GENERAL RULES AND REGULATIONS CAR SERVICE § 1033.2 Car service orders. Emergency and temporary service orders are issued...

  5. 49 CFR 218.80 - Movement of occupied camp cars.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Movement of occupied camp cars. 218.80 Section 218.80 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD OPERATING PRACTICES Protection of Occupied Camp Cars § 218.80 Movement of occupied camp cars....

  6. 49 CFR 231.18 - Cars of special construction.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Cars of special construction. 231.18 Section 231.18 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.18 Cars of special construction. Cars of construction not...

  7. 49 CFR 37.93 - One car per train rule.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false One car per train rule. 37.93 Section 37.93... DISABILITIES (ADA) Acquisition of Accessible Vehicles By Public Entities § 37.93 One car per train rule. (a) The definition of accessible for purposes of meeting the one car per train rule is spelled out in...

  8. 40 CFR 201.13 - Standard for rail car operations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Standard for rail car operations. 201... Interstate Rail Carrier Operations Standards § 201.13 Standard for rail car operations. Effective December 31, 1976, no carrier subject to this regulation shall operate any rail car or combination of rail...

  9. 49 CFR 238.413 - End structures of trailer cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false End structures of trailer cars. 238.413 Section... II Passenger Equipment § 238.413 End structures of trailer cars. (a) Except as provided in paragraph (b) of this section, the end structure of a trailer car shall be designed to include the...

  10. 49 CFR 231.22 - Operation of track motor cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Operation of track motor cars. 231.22 Section 231... motor cars. On and after August 1, 1963, it shall be unlawful for any railroad subject to the requirements of the Safety Appliance Acts to operate or permit to be operated on its line track motor cars...

  11. 49 CFR 1033.2 - Car service orders.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 8 2011-10-01 2011-10-01 false Car service orders. 1033.2 Section 1033.2 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION GENERAL RULES AND REGULATIONS CAR SERVICE § 1033.2 Car service orders....

  12. 49 CFR 37.93 - One car per train rule.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 1 2011-10-01 2011-10-01 false One car per train rule. 37.93 Section 37.93... DISABILITIES (ADA) Acquisition of Accessible Vehicles By Public Entities § 37.93 One car per train rule. (a) The definition of accessible for purposes of meeting the one car per train rule is spelled out in...

  13. 49 CFR 38.63 - Between-car barriers.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 1 2011-10-01 2011-10-01 false Between-car barriers. 38.63 Section 38.63... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Rapid Rail Vehicles and Systems § 38.63 Between-car barriers. (a... inadvertently stepping off the platform between cars. Acceptable solutions include, but are not limited...

  14. 36 CFR 1192.63 - Between-car barriers.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 3 2011-07-01 2011-07-01 false Between-car barriers. 1192.63... Rail Vehicles and Systems § 1192.63 Between-car barriers. (a) Requirement. Suitable devices or systems... between cars. Acceptable solutions include, but are not limited to, pantograph gates, chains,...

  15. 49 CFR 38.85 - Between-car barriers.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 1 2011-10-01 2011-10-01 false Between-car barriers. 38.85 Section 38.85... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Light Rail Vehicles and Systems § 38.85 Between-car barriers. Where..., deter or warn individuals from inadvertently stepping off the platform between cars. Appropriate...

  16. 49 CFR 232.305 - Single car air brake tests.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy of the incorporated document from the... 49 Transportation 4 2011-10-01 2011-10-01 false Single car air brake tests. 232.305 Section 232... car air brake tests. (a) Single car air brake tests shall be performed by a qualified person...

  17. 49 CFR 231.18 - Cars of special construction.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Cars of special construction. 231.18 Section 231... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.18 Cars of special construction. Cars of construction not covered specifically in the foregoing sections in this part, relative...

  18. 36 CFR 1192.85 - Between-car barriers.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 3 2011-07-01 2011-07-01 false Between-car barriers. 1192.85... Rail Vehicles and Systems § 1192.85 Between-car barriers. Where vehicles operate in a high-platform... inadvertently stepping off the platform between cars. Appropriate devices include, but are not limited...

  19. 19 CFR 123.61 - Baggage arriving in baggage car.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Baggage arriving in baggage car. 123.61 Section... OF THE TREASURY CBP RELATIONS WITH CANADA AND MEXICO Baggage § 123.61 Baggage arriving in baggage car... cars....

  20. 40 CFR 201.15 - Standard for car coupling operations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Standard for car coupling operations... Interstate Rail Carrier Operations Standards § 201.15 Standard for car coupling operations. Effective January 15, 1984, no carrier subject to this regulation shall conduct car coupling operations that exceed...

  1. 30 CFR 56.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Coupling or uncoupling cars. 56.14215 Section... Equipment Safety Practices and Operational Procedures § 56.14215 Coupling or uncoupling cars. Prior to coupling or uncoupling cars manually, trains shall be brought to a complete stop, and then moved at...

  2. 7 CFR 160.28 - Tank cars of turpentine.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 3 2011-01-01 2011-01-01 false Tank cars of turpentine. 160.28 Section 160.28... STANDARDS FOR NAVAL STORES Analysis, Inspection, and Grading on Request § 160.28 Tank cars of turpentine. A tank car loaded for shipment with spirits of turpentine shall, after the same has been sampled...

  3. CARS detection of ClO[sub 2

    SciTech Connect

    Zhang, J.X.; Aker, P.M. )

    1994-01-20

    Coherent anti-Stokes Raman scattering (CARS) spectroscopy has been used to detect the v[sub 1] fundamental of gas-phase ClO[sub 2]. CARS detection limits are reported. The results show that the CARS technique is ideally suited for gas-phase ClO[sub 2] photodissociation dynamics studies. 25 refs., 1 fig.

  4. 49 CFR 38.85 - Between-car barriers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Between-car barriers. 38.85 Section 38.85... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Light Rail Vehicles and Systems § 38.85 Between-car barriers. Where..., deter or warn individuals from inadvertently stepping off the platform between cars. Appropriate...

  5. 49 CFR 38.63 - Between-car barriers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Between-car barriers. 38.63 Section 38.63... SPECIFICATIONS FOR TRANSPORTATION VEHICLES Rapid Rail Vehicles and Systems § 38.63 Between-car barriers. (a... inadvertently stepping off the platform between cars. Acceptable solutions include, but are not limited...

  6. 76 FR 53717 - Notice of National Grain Car Council Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-29

    ... Surface Transportation Board Notice of National Grain Car Council Meeting AGENCY: Surface Transportation Board. ACTION: Notice of National Grain Car Council meeting. SUMMARY: Notice is hereby given of a meeting of the National Grain Car Council (NGCC), pursuant to section 10(a)(2) of the Federal...

  7. 49 CFR 238.413 - End structures of trailer cars.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false End structures of trailer cars. 238.413 Section... II Passenger Equipment § 238.413 End structures of trailer cars. (a) Except as provided in paragraph (b) of this section, the end structure of a trailer car shall be designed to include the...

  8. 40 CFR 201.13 - Standard for rail car operations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Standard for rail car operations. 201... Interstate Rail Carrier Operations Standards § 201.13 Standard for rail car operations. Effective December 31, 1976, no carrier subject to this regulation shall operate any rail car or combination of rail...

  9. 49 CFR 232.305 - Single car air brake tests.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy of the incorporated document from the... 49 Transportation 4 2010-10-01 2010-10-01 false Single car air brake tests. 232.305 Section 232... car air brake tests. (a) Single car air brake tests shall be performed by a qualified person...

  10. 77 FR 50763 - Notice of National Grain Car Council Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-22

    ... Surface Transportation Board Notice of National Grain Car Council Meeting AGENCY: Surface Transportation Board, DOT. ACTION: Notice of National Grain Car Council meeting. SUMMARY: Notice is hereby given of a meeting of the National Grain Car Council (NGCC), pursuant to section 10(a)(2) of the Federal...

  11. 40 CFR 201.15 - Standard for car coupling operations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Standard for car coupling operations... Interstate Rail Carrier Operations Standards § 201.15 Standard for car coupling operations. Effective January 15, 1984, no carrier subject to this regulation shall conduct car coupling operations that exceed...

  12. 75 FR 53736 - Notice of National Grain Car Council Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-01

    ... Surface Transportation Board Notice of National Grain Car Council Meeting AGENCY: Surface Transportation Board, DOT. ACTION: Notice of National Grain Car Council meeting. SUMMARY: Notice is hereby given of a meeting of the National Grain Car Council (NGCC), pursuant to section 10(a)(2) of the Federal...

  13. 78 FR 52606 - Notice of National Grain Car Council Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-23

    ... Surface Transportation Board Notice of National Grain Car Council Meeting AGENCY: Surface Transportation Board, DOT. ACTION: Notice of National Grain Car Council meeting. SUMMARY: Notice is hereby given of a meeting of the National Grain Car Council (NGCC), pursuant to the Federal Advisory Committee Act, 5...

  14. 30 CFR 56.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Coupling or uncoupling cars. 56.14215 Section... Equipment Safety Practices and Operational Procedures § 56.14215 Coupling or uncoupling cars. Prior to coupling or uncoupling cars manually, trains shall be brought to a complete stop, and then moved at...

  15. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  16. 49 CFR 174.304 - Class 3 (flammable liquid) materials in tank cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... (flammable liquid) materials in tank cars. A tank car containing a Class 3 (flammable liquid) material, other... the liquid from the tank car to permanent storage tanks of sufficient capacity to receive the entire contents of the car....

  17. 49 CFR 231.8 - Tank cars without side sills and tank cars with short side sills and end platforms.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Tank cars without side sills and tank cars with short side sills and end platforms. 231.8 Section 231.8 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.8 Tank cars...

  18. Car Builder: Design, Construct and Test Your Own Cars. School Version with Lesson Plans. [CD-ROM].

    ERIC Educational Resources Information Center

    Highsmith, Joni Bitman

    Car Builder is a scientific CD-ROM-based simulation program that lets students design, construct, modify, test, and compare their own cars. Students can design sedans, four-wheel-drive vehicles, vans, sport cars, and hot rods. They may select for aerodynamics, power, and racing ability, or economic and fuel efficiency. It is a program that teaches…

  19. 49 CFR 180.519 - Periodic retest and inspection of tank cars other than single-unit tank car tanks.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Periodic retest and inspection of tank cars other... § 180.519 Periodic retest and inspection of tank cars other than single-unit tank car tanks. (a) General... periodically as specified in Retest Table 1 of paragraph (b)(5) of this section. Retests may be made at...

  20. 49 CFR 180.519 - Periodic retest and inspection of tank cars other than single-unit tank car tanks.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 3 2014-10-01 2014-10-01 false Periodic retest and inspection of tank cars other... § 180.519 Periodic retest and inspection of tank cars other than single-unit tank car tanks. (a) General... periodically as specified in Retest Table 1 of paragraph (b)(5) of this section. Retests may be made at...

  1. The basic principles of chimeric antigen receptor (CAR) design

    PubMed Central

    Sadelain, Michel; Brentjens, Renier; Riviere, Isabelle

    2013-01-01

    CARs are recombinant receptors that provide both antigen-binding and T cell activating functions. A multitude of CARs has been reported over the past decade, targeting an array of cell surface tumor antigens. Their biological functions have dramatically changed following the introduction of tri-partite receptors comprising a costimulatory domain, termed second generation CARs. These have recently demonstrated clinical benefit in patients treated with CD19-targeted autologous T cells. CARs may be combined with costimulatory ligands, chimeric costimulatory receptors or cytokines to further enhance T cell potency, specificity and safety. CARs represent a new class of drugs with exciting potential for cancer immunotherapy. PMID:23550147

  2. Simultaneous CARS and Interferometric Rayleigh Scattering

    NASA Technical Reports Server (NTRS)

    Bivolaru, Daniel; Danehy, Paul M.; Grinstead, Keith D., Jr.; Tedder, Sarah; Cutler, Andrew D.

    2006-01-01

    This paper reports for the first time the combination of a dual-pump coherent anti-Stokes Raman scattering system with an interferometric Rayleigh scattering system (CARS - IRS) to provide time-resolved simultaneous measurement of multiple properties in combustion flows. The system uses spectrally narrow green (seeded Nd:YAG at 532 nm) and yellow (552.9 nm) pump beams and a spectrally-broad red (607 nm) beam as the Stokes beam. A spectrometer and a planar Fabry-Perot interferometer used in the imaging mode are used to record the spectrally broad CARS spectra and the spontaneous Rayleigh scattering spectra, respectively. Time-resolved simultaneous measurement of temperature, absolute mole fractions of N2, O2, and H2, and two components of velocity in a Hencken burner flame were performed to demonstrate the technique.

  3. Car Accident Reconstruction and Head Injury Correlation

    NASA Astrophysics Data System (ADS)

    Chawla, A.; Grover, V.; Mukherjee, S.; Hassan, A. M.

    2013-04-01

    Estimation of brain damage remains an elusive issue and controlled tests leading to brain damage cannot be carried out on volunteers. This study reconstructs real-world car accidents to estimate the kinematics of the head impact. This data is to be used to estimate the head injury measures through computer simulations and then correlate reported skull as well as brain damage to impact measures; whence validating the head FE model (Willinger, IJCrash 8:605-617, 2003). In this study, two crash cases were reconstructed. Injury correlation was successful in one of these cases in that the injuries to the brain of one of the car drivers could be correlated in terms of type, location and severity when compared with the tolerance limits of relevant injury parameters (Willinger, IJCrash 8:605-617, 2003).

  4. Engineering CAR-T Cells: Design Concepts

    PubMed Central

    Srivastava, Shivani; Riddell, Stanley R.

    2016-01-01

    Despite being empirically designed based on a simple understanding of TCR signaling, T cells engineered with chimeric antigen receptors (CARs) have been remarkably successful in treating patients with advanced refractory B cell malignancies. However, many challenges remain in improving the safety and efficacy of this therapy and extending it toward the treatment of epithelial cancers. Other aspects TCR signaling beyond those directly provided by CD3ζ and CD28 phosphorylation strongly influence a T cell’s ability to differentiate and acquire full effector functions. Here, we discuss how the principles of TCR recognition, including spatial constraints, Kon/Koff rates, and synapse formation, along with in-depth analysis of CAR signaling might be applied to develop safer and more effective synthetic tumor targeting receptors. PMID:26169254

  5. A broken heart in a broken car.

    PubMed

    Schlossbauer, Susanne Anna; Ghadri, Jelena-Rima; Cammann, Victoria Lucia; Maier, Willibald; Lüscher, Thomas F; Templin, Christian

    2016-01-01

    Takotsubo syndrome (TTS) is still a relatively understudied and often undetected disease. It is usually preceded by emotional or physical triggers. We here report a case of TTS following a car accident. Typical apical ballooning with moderate reduction of left ventricular ejection fraction (LVEF) and increased level of pro-B-type natriuretic peptide (BNP) as well as slightly increased creatine kinase and troponin T values were found in this 76-year-old female patient, 6 h after a car accident. At 10 weeks follow-up, we observed a normalization of regional wall motion, LVEF, electrocardiogram and pro-BNP. TTS is an acute heart failure syndrome and an important differential diagnosis of acute coronary syndrome. PMID:27377800

  6. Multiply enhanced site selective CARS spectroscopy

    NASA Astrophysics Data System (ADS)

    Steehler, J. K.; Wright, J. C.

    1985-10-01

    Three tunable lasers are used to perform site selective coherent anti-Stokes Raman (CARS) spectroscopy in pentacene:p-terphenyl crystals at 2 K. The vibrational and vibronic levels of pentacene in the individual substitutional sites of p-terphenyl can be selectively examined by matching the resonances of a particular site. The signals from a site and the selectivity between sites are much higher than CARS performed with two tunable lasers. The spectra are dominated by lines from processes where the vibrational and vibronic states involved in the four-wave mixing are associated with the same molecular mode. There are also important lines from processes where different vibrational and vibronic modes are involved in the nonlinear mixing. The intensities of lines from the resonant site are strongly dependent on the laser energy because of saturation of the electronic transition.

  7. [The compensatory light for car plate recognition].

    PubMed

    Yu, Chun-yu; Chang, Ben-kang; Wang, Qing-bao

    2005-07-01

    In the intelligent traffic system, the automatic recognition system of the car plate is an important development field. This system must satisfy the requirement of all-day long inspection. In the course of inspection, the lack of natural light(such as at night, in rainy day...) could be a problem, that is to say there could be backlighting problem, and this problem can be solved by using compensatory light. By now, the high-power floodlight has been adopted. Because of its own characteristics of the floodlight, the satisfied result cannot be obtained. In the present thesis, how to select the right light is analyzed, including car lights' spectra and visual response, and so on. The results of the practices are very satisfied. PMID:16241082

  8. A multivariate CAR model for mismatched lattices.

    PubMed

    Porter, Aaron T; Oleson, Jacob J

    2014-10-01

    In this paper, we develop a multivariate Gaussian conditional autoregressive model for use on mismatched lattices. Most current multivariate CAR models are designed for each multivariate outcome to utilize the same lattice structure. In many applications, a change of basis will allow different lattices to be utilized, but this is not always the case, because a change of basis is not always desirable or even possible. Our multivariate CAR model allows each outcome to have a different neighborhood structure which can utilize different lattices for each structure. The model is applied in two real data analysis. The first is a Bayesian learning example in mapping the 2006 Iowa Mumps epidemic, which demonstrates the importance of utilizing multiple channels of infection flow in mapping infectious diseases. The second is a multivariate analysis of poverty levels and educational attainment in the American Community Survey. PMID:25457598

  9. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. PMID:22269613

  10. [PPAR receptors and insulin sensitivity: new agonists in development].

    PubMed

    Pégorier, J-P

    2005-04-01

    Thiazolidinediones (or glitazones) are synthetic PPARgamma (Peroxisome Proliferator-Activated Receptors gamma) ligands with well recognized effects on glucose and lipid metabolism. The clinical use of these PPARgamma agonists in type 2 diabetic patients leads to an improved glycemic control and an inhanced insulin sensitivity, and at least in animal models, to a protective effect on pancreatic beta-cell function. However, they can produce adverse effects, generally mild or moderate, but some of them (mainly peripheral edema and weight gain) may conduct to treatment cessation. Several pharmacological classes are currently in pre-clinical or clinical development, with the objective to retain the beneficial metabolic properties of PPARgamma agonists, either alone or in association with the PPARalpha agonists (fibrates) benefit on lipid profile, but devoid of the side-effects on weight gain and fluid retention. These new pharmacological classes: partial PPARgamma agonists, PPARgamma antagonists, dual PPARalpha/PPARgamma agonists, pan PPARalpha/beta(delta)/gamma agonists, RXR receptor agonists (rexinoids), are presented in this review. Main results from in vitro cell experiments and animal model studies are discussed, as well as the few published short-term studies in type 2 diabetic patients. PMID:15959400

  11. Risk versus benefit considerations for the beta(2)-agonists.

    PubMed

    Kelly, H William

    2006-09-01

    Short-acting beta(2)-agonists are the mainstay of therapy for acute bronchospasm associated with asthma and chronic obstructive pulmonary disease, whereas long-acting beta(2)-agonists are used in maintaining disease control in these respiratory disorders. This review describes and compares the pharmacology of the beta(2)-agonists and explains how these differences translate into differences in efficacy and beta(2)-adrenergic-mediated adverse effects. Questions commonly asked by clinicians regarding the efficacy and safety of short- and long-acting beta(2)-agonists include issues about cardiovascular effects, tolerance to their bronchodilator and bronchoprotective effects, blunting of albuterol response by long-acting beta(2)-agonists, potential masking of worsening asthma control, and the role of long-acting beta(2)-agonists as adjunctive therapy with inhaled corticosteroids in maintaining asthma control. Pharmacogenetics may play a role in determining which patients may be at risk for a reduced response to a beta(2)-agonist. The continued use of racemic albuterol, which contains a mixture of R-albuterol and S-albuterol, has been questioned because of data from preclinical and clinical studies suggesting that S-albuterol causes proinflammatory effects and may increase bronchial hyperreactivity. The preclinical and clinical effects of these two stereoisomers are reviewed. Data describing the efficacy and safety of levalbuterol (R-albuterol) and racemic albuterol are presented. PMID:16945063

  12. Effects of motivation on car-following

    NASA Technical Reports Server (NTRS)

    Boesser, T.

    1982-01-01

    Speed- and distance control by automobile-drivers is described best by linear models when the leading vehicles speed varies randomly and when the driver is motivated to keep a large distance. A car-following experiment required subjects to follow at 'safe' or at 'close' distance. Transfer-characteristics of the driver were extended by 1 octave when following 'closely'. Nonlinear properties of drivers control-movements are assumed to reflect different motivation-dependent control strategies.

  13. Health Monitoring System for Car Seat

    NASA Technical Reports Server (NTRS)

    Elrod, Susan Vinz (Inventor); Dabney, Richard W. (Inventor)

    2004-01-01

    A health monitoring system for use with a child car seat has sensors mounted in the seat to monitor one or more health conditions of the seat's occupant. A processor monitors the sensor's signals and generates status signals related to the monitored conditions. A transmitter wireless transmits the status signals to a remotely located receiver. A signaling device coupled to the receiver produces at least one sensory (e.g., visual, audible, tactile) output based on the status signals.

  14. How energy efficient is your car?

    NASA Astrophysics Data System (ADS)

    Roura, Pere; Oliu, Daniel

    2012-07-01

    A detailed energy balance indicating how fuel energy is transferred from the engine to the wheels of a commercial car is obtained using non-specialized experiments that can be readily understood using elementary mechanics. These experiments allow us to determine the engine's thermal efficiency, its mechanical losses, and the rolling (friction) and aerodynamic (drag) coefficients. We find that approximately 28% of the fuel energy is transferred to the wheels.

  15. Visual system for automatic car registration

    NASA Astrophysics Data System (ADS)

    Altamirano-Robles, Leopoldo; Arias-Estrada, Miguel; Lopez-Lopez, Aurelio; Lemuz-Lopez, Rafael

    2001-04-01

    In this paper we propose a system for capturing and processing car identification labels. The system captures the required images for the registration process using a CCD camera with an appropriate mount. Images are analyzed and stored by the system, generating a report, where all the captured visual information is included. The information is further stored in a way, that allows the retrieval of each report. Results and discussion about the system are presented.

  16. Establishing guidelines for CAR-T cells: challenges and considerations.

    PubMed

    Wang, Wei; Qin, Di-Yuan; Zhang, Bing-Lan; Wei, Wei; Wang, Yong-Sheng; Wei, Yu-Quan

    2016-04-01

    T cells, genetically modified by chimeric antigen receptors (CAR-T), are endowed with specificity to a desired antigen and are cytotoxic to cells expressing the targeted antigen. CAR-T-based cancer immunotherapy is a promising therapy for curing hematological malignancy, such as acute lymphoid leukemia, and is promising for extending their efficacy to defeat solid tumors. To date, dozens of different CAR-T cells have been evaluated in clinical trials to treat tumors; this necessitates the establishment of guidelines for the production and application of CAR-T cells. However, it is challenging to standardize CAR-T cancer therapy because it involves a combination of gene therapy and cell therapy. In this review, we compare the existing guidelines for CAR-T cells and discuss the challenges and considerations for establishing guidance for CAR-T-based cancer immunotherapy. PMID:26965523

  17. Bessel beam CARS of axially structured samples

    PubMed Central

    Heuke, Sandro; Zheng, Juanjuan; Akimov, Denis; Heintzmann, Rainer; Schmitt, Michael; Popp, Jürgen

    2015-01-01

    We report about a Bessel beam CARS approach for axial profiling of multi-layer structures. This study presents an experimental implementation for the generation of CARS by Bessel beam excitation using only passive optical elements. Furthermore, an analytical expression is provided describing the generated anti-Stokes field by a homogeneous sample. Based on the concept of coherent transfer functions, the underling resolving power of axially structured geometries is investigated. It is found that through the non-linearity of the CARS process in combination with the folded illumination geometry continuous phase-matching is achieved starting from homogeneous samples up to spatial sample frequencies at twice of the pumping electric field wave. The experimental and analytical findings are modeled by the implementation of the Debye Integral and scalar Green function approach. Finally, the goal of reconstructing an axially layered sample is demonstrated on the basis of the numerically simulated modulus and phase of the anti-Stokes far-field radiation pattern. PMID:26046671

  18. The Fuel Cell Powered Club Car Carryall

    NASA Technical Reports Server (NTRS)

    Eichenberg, Dennis J.

    2005-01-01

    The NASA Glenn Research Center initiated development of the Fuel Cell Powered Club Car Carryall as a way to reduce pollution in industrial settings, reduce fossil fuel consumption and reduce operating costs for transportation systems. The Club Car Carryall provides an inexpensive approach to advance the state of the art in electric vehicle technology in a practical application. The project transfers space technology to terrestrial use via non-traditional partners, and provides power system data valuable for future aeronautics and space applications. The work was done under the Hybrid Power Management (HPM) Program. The Carryall is a state of the art, dedicated, electric utility vehicle. Hydrogen powered proton exchange membrane (PEM) fuel cells are the primary power source. Ultracapacitors were used for energy storage as long life, maintenance free operation, and excellent low temperature performance is essential. Metal hydride hydrogen storage was used to store hydrogen in a safe and efficient low-pressure solid form. The report concludes that the Fuel Cell Powered Club Car Carryall can provide excellent performance, and that the implementation of fuel cells in conjunction with ultracapacitors in the power system can provide significant reliability and performance improvements.

  19. Bessel beam CARS of axially structured samples

    NASA Astrophysics Data System (ADS)

    Heuke, Sandro; Zheng, Juanjuan; Akimov, Denis; Heintzmann, Rainer; Schmitt, Michael; Popp, Jürgen

    2015-06-01

    We report about a Bessel beam CARS approach for axial profiling of multi-layer structures. This study presents an experimental implementation for the generation of CARS by Bessel beam excitation using only passive optical elements. Furthermore, an analytical expression is provided describing the generated anti-Stokes field by a homogeneous sample. Based on the concept of coherent transfer functions, the underling resolving power of axially structured geometries is investigated. It is found that through the non-linearity of the CARS process in combination with the folded illumination geometry continuous phase-matching is achieved starting from homogeneous samples up to spatial sample frequencies at twice of the pumping electric field wave. The experimental and analytical findings are modeled by the implementation of the Debye Integral and scalar Green function approach. Finally, the goal of reconstructing an axially layered sample is demonstrated on the basis of the numerically simulated modulus and phase of the anti-Stokes far-field radiation pattern.

  20. New Life For The Cable Cars

    NASA Technical Reports Server (NTRS)

    1979-01-01

    NASA-Arnes' major recommendations involved ways of extending cable life in the interests of safety and economy. Other recommendations included redesign of the cablegripping device, substitution of modern braking mechanisms, improvements in cable pulleys and other components, and new inspection and repair procedures. Ames followed up by designing and installing new equipment to lengthen cable life, which averages only about two months. These cables-four of them for four different car routes--are endless belts, like ski lift cables, running from the downtown car barn to the end of each line. When a cable is installed, the loop is closed by splicing the ends together in a 72-footlong splice. The splice is the weakest part of the cable and a source of problems. When the car operator applies his grip while over a splice, the resulting friction sometimes causes the splice to "unbraid" and fail; this means shutting down the line until the splice can be repaired. Even when unbraiding does not occur, gripping a splice shortens cable life by friction wear. Worn cables are a safety hazard and must be replaced, which is expensive at $1.60 a foot for 10,000 to 20,000 feet of cable.

  1. EcoCAR Challenge: Finish Line

    SciTech Connect

    2011-01-01

    The EcoCAR Challenege is a competition that challenges participating students from across North America to re-engineer a vehicle donated by General Motors. With the goal of minimizing the vehicle's fuel consumption and emissions, while maintaining its utility, safety and performance, teams had to find the best combination of cutting-edge technologies to meet these objectives. In the final year, the vehicles ran through a series of safety and technical tests at GM's Proving Ground in Milford, Michigan very similar to those GM's own production vehicles undergo. As EcoCAR wraps up, it is only the beginning for the next chapter in the DOE's 23-year history of advanced vehicle technology competitions. In April, Assistant Secretary for Policy and International Affairs David Sandalow announced the launch of EcoCAR 2: Plugging into the Future http://www.ecocar2.org/index.html . We look forward to seeing the new and innovative designs that students bring to this challenge and know they will find a way to exceed even our highest expectations.

  2. CARS microscopy of Alzheimer's diseased brain tissue

    NASA Astrophysics Data System (ADS)

    Enejder, Annika; Kiskis, Juris; Fink, Helen; Nyberg, Lena; Thyr, Jakob; Li, Jia-Yi

    2014-02-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder currently without cure, characterized by the presence of extracellular plaques surrounded by dystrophic neurites. In an effort to understand the underlying mechanisms, biochemical analysis (protein immunoblot) of plaque extracts reveals that they consist of amyloid-beta (Aβ) peptides assembled as oligomers, protofibrils and aggregates. Their spatial distribution has been confirmed by Thioflavin-S or immuno-staining with fluorescence microscopy. However, it is increasingly understood that the protein aggregation is only one of several mechanism that causes neuronal dysfunction and death. This raises the need for a more complete biochemical analysis. In this study, we have complemented 2-photon fluorescence microscopy of Thioflavin-S and Aβ immuno-stained human AD plaques with CARS microscopy. We show that the chemical build-up of AD plaques is more complex and that Aβ staining does not provide the complete picture of the spatial distribution or the molecular composition of AD plaques. CARS images provide important complementary information to that obtained by fluorescence microscopy, motivating a broader introduction of CARS microscopy in the AD research field.

  3. Burning Cars in a Parking Lot

    NASA Astrophysics Data System (ADS)

    Bertoin, Jean

    2011-08-01

    Knuth's parking scheme is a model in computer science for hashing with linear probing. One may imagine a circular parking lot with n sites; cars arrive at each site with unit rate. When a car arrives at a vacant site, it parks there; otherwise it turns clockwise and parks at the first vacant site which is found. We incorporate fires into this model by throwing Molotov cocktails on each site at a smaller rate n - α , where 0 < α < 1 is a fixed parameter. When a car is hit by a Molotov cocktail, it burns and the fire propagates to the entire occupied interval which turns vacant. We show that with high probability when n → ∞, the parking lot becomes saturated at a time close to 1 (i.e. as in the absence of fire) for α > 2/3, whereas for α < 2/3, the average occupation approaches 1 at time 1 but then quickly drops to 0 before the parking lot is ever saturated. Our study relies on asymptotics for the occupation of the parking lot without fires in certain regimes which may be of independent interest.

  4. EcoCAR Challenge: Finish Line

    ScienceCinema

    None

    2013-05-29

    The EcoCAR Challenege is a competition that challenges participating students from across North America to re-engineer a vehicle donated by General Motors. With the goal of minimizing the vehicle's fuel consumption and emissions, while maintaining its utility, safety and performance, teams had to find the best combination of cutting-edge technologies to meet these objectives. In the final year, the vehicles ran through a series of safety and technical tests at GM's Proving Ground in Milford, Michigan very similar to those GM's own production vehicles undergo. As EcoCAR wraps up, it is only the beginning for the next chapter in the DOE's 23-year history of advanced vehicle technology competitions. In April, Assistant Secretary for Policy and International Affairs David Sandalow announced the launch of EcoCAR 2: Plugging into the Future http://www.ecocar2.org/index.html . We look forward to seeing the new and innovative designs that students bring to this challenge and know they will find a way to exceed even our highest expectations.

  5. The shape of cars to come

    SciTech Connect

    Ashley, S.

    1991-05-01

    Ford's new concept car achieves weight, size, and cost savings with an innovative lightweight aluminum space frame composed of simple extrusions that are fitted together like Lego blocks and adhesively bonded. On the outside, the design is a blend of art and technology that is a modern restatement of a large luxury car. The other major focus of the design is the Contour's compact T-drive powertrain configuration (also shared by the Mystique). This consists of a transversely mounted engine stuffed into the front of the chassis with a longitudinally positioned transmission right behind it. The T-drive arrangement shrinks the car's engine bay and overall length while expanding the passenger compartment. In addition, powerplants with from four to eight cylinders as well as front-wheel-, rear-wheel-, and four-wheel-drive transmission systems can all be incorporated into the T-drive. Other technical innovations on the Contour include an unusual ducted cooling system, a compact brake assembly, a lightweight high-efficiency air conditioner, centralized single-source lighting, and simple but effective suspension technology.

  6. Dopamine agonist withdrawal syndrome: implications for patient care.

    PubMed

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper. PMID:23686524

  7. 49 CFR 210.9 - Movement of a noise defective locomotive, rail car, or consist of a locomotive and rail cars.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Movement of a noise defective locomotive, rail car, or consist of a locomotive and rail cars. 210.9 Section 210.9 Transportation Other Regulations... locomotive, rail car, or consist of a locomotive and rail cars. A locomotive, rail car, or consist of...

  8. 49 CFR 210.9 - Movement of a noise defective locomotive, rail car, or consist of a locomotive and rail cars.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Movement of a noise defective locomotive, rail car, or consist of a locomotive and rail cars. 210.9 Section 210.9 Transportation Other Regulations... locomotive, rail car, or consist of a locomotive and rail cars. A locomotive, rail car, or consist of...

  9. 49 CFR 210.9 - Movement of a noise defective locomotive, rail car, or consist of a locomotive and rail cars.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Movement of a noise defective locomotive, rail car, or consist of a locomotive and rail cars. 210.9 Section 210.9 Transportation Other Regulations... locomotive, rail car, or consist of a locomotive and rail cars. A locomotive, rail car, or consist of...

  10. 49 CFR 210.9 - Movement of a noise defective locomotive, rail car, or consist of a locomotive and rail cars.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Movement of a noise defective locomotive, rail car, or consist of a locomotive and rail cars. 210.9 Section 210.9 Transportation Other Regulations... locomotive, rail car, or consist of a locomotive and rail cars. A locomotive, rail car, or consist of...

  11. Supra-physiological efficacy at GPCRs: superstition or super agonists?

    PubMed

    Langmead, Christopher J; Christopoulos, Arthur

    2013-05-01

    The concept of 'super agonism' has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. PMID:23441648

  12. Effect of car speed on amount of air supplied by ventilation system to the space of car cabin

    NASA Astrophysics Data System (ADS)

    Fišer, Jan; Pokorný, Jan

    2014-03-01

    The amount of air supplied by ventilation system (HVAC system) of a car into a cabin is one of the main parameters for the correct simulation and prediction of a car cabin heat load. This amount is not based only on the current setting of the HVAC system, but also on the actual operating conditions and speed of the car. The authors therefore carried out experiments in the cabin of a passenger car in real traffic, while observing the amount of air on the speed of the car and setting of flap in mixing chamber. In a subsequent analysis the authors defined dependence of the airflow rate supplied by HVAC system on the speed of the car. Obtained empirical formulas were then used as a part of the code which calculates the data for the HVAC boundary conditions in the simulation of the car cabin environment.

  13. Relamorelin: A Novel Gastrocolokinetic Synthetic Ghrelin Agonist

    PubMed Central

    Camilleri, Michael; Acosta, Andres

    2015-01-01

    Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately 6-fold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin. In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a pre-specified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders. PMID:25545036

  14. Effects of ritobegron (KUC-7483), a novel β3-adrenoceptor agonist, on both rat bladder function following partial bladder outlet obstruction and on rat salivary secretion: a comparison with the effects of tolterodine.

    PubMed

    Maruyama, Itaru; Yonekubo, Saori; Tatemichi, Satoshi; Maruyama, Kazuyasu; Hoyano, Yuji; Yamazaki, Yoshinobu; Kusama, Hiroshi

    2012-01-01

    The objective of this study was to investigate the effects of the β3-adrenoceptor (AR) agonist ritobegron on rat bladder function following partial bladder outlet obstruction and on rat salivary secretion. In addition, the effects of ritobegron were compared with those of the anti-muscarinic agent tolterodine. After a 6-week partial bladder outlet obstruction (BOO), drug effects on bladder functions were evaluated using cystometrography. Effects on carbachol (CCh)-induced salivary secretion were evaluated in urethane-anesthetized rats. Ritobegron significantly decreased the frequency of non-voiding contractions (NVC), while both ritobegron and tolterodine each significantly decreased the amplitude of NVC. Ritobegron had no effect on either the micturition pressure (MP) or the residual volume (RV). In contrast, tolterodine dose-dependently decreased MP and increased RV. Ritobegron had no effect on CCh-induced salivary secretion, whereas tolterodine dose-dependently decreased it. Ritobegron decreased both the frequency and amplitude of NVC, which is similar to its effect on the contractions associated with detrusor overactivity (DO) in patients with an overactive bladder (OAB), without affecting MP, RV, or CCh-induced salivary secretion. Although tolterodine reduced the amplitude of NVC, it also markedly increased RV and significantly inhibited CCh-induced salivary secretion. These results suggest that use of ritobegron, a β3-AR agonist, is unlikely to lead to the residual urine and dry mouth symptoms that are associated with anti-muscarinic drugs, and that ritobegron may hold promise as a safe and effective agent for OAB treatment. PMID:23538508

  15. Selecting agonists from single cells infected with combinatorial antibody libraries.

    PubMed

    Zhang, Hongkai; Yea, Kyungmoo; Xie, Jia; Ruiz, Diana; Wilson, Ian A; Lerner, Richard A

    2013-05-23

    We describe a system for direct selection of antibodies that are receptor agonists. Combinatorial antibody libraries in lentiviruses are used to infect eukaryotic cells that contain a fluorescent reporter system coupled to the receptor for which receptor agonist antibodies are sought. In this embodiment of the method, very large numbers of candidate antibodies expressing lentivirus and eukaryotic reporter cells are packaged together in a format where each is capable of replication, thereby forging a direct link between genotype and phenotype. Following infection, cells that fluoresce are sorted and the integrated genes encoding the agonist antibodies recovered. We validated the system by illustrating its ability to generate rapidly potent antibody agonists that are complete thrombopoietin phenocopies. The system should be generalizable to any pathway where its activation can be linked to production of a selectable phenotype. PMID:23706638

  16. 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

  17. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    PubMed

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. PMID:20579229

  18. 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

  19. 10 Years of Car-2-X Communication - a Success Story?

    NASA Astrophysics Data System (ADS)

    Wischhof, Lars; Ebner, André

    2012-05-01

    For more than ten years, car-2-x communication has been a major topic of research in the scientific community and an important development focus for the automotive industry. First, this article takes a retrospective look at the evolution of car-2-x and the two different communication paradigms: decentralized car-2-car communication and centralized cellular solutions. Afterwards, a comparison of their technical advantages and limitations is presented, respectively. The result shows that in order to implement safety-relevant applications, car-2-car communication has strong advantages compared to cellular technologies but requires high market penetration. However, its introduction solely for safety applications is difficult since the required penetration will not be achieved until several years after initial deployment. Therefore, car-2-car communication must provide a benefit to the customer, even in the phase of market introduction. For this purpose, the article outlines an approach called SODAD (Segment-Oriented Data Abstraction and Dissemination). It offers a possibility to introduce decentralized vehicular applications with early customer benefit, in order to enable safety applications based on car-2-car communication on a long term.

  20. Use of seatbelts in cars with automatic belts.

    PubMed Central

    Williams, A F; Wells, J K; Lund, A K; Teed, N J

    1992-01-01

    Use of seatbelts in late model cars with automatic or manual belt systems was observed in suburban Washington, DC, Chicago, Los Angeles, and Philadelphia. In cars with automatic two-point belt systems, the use of shoulder belts by drivers was substantially higher than in the same model cars with manual three-point belts. This finding was true in varying degrees whatever the type of automatic belt, including cars with detachable nonmotorized belts, cars with detachable motorized belts, and especially cars with nondetachable motorized belts. Most of these automatic shoulder belts systems include manual lap belts. Use of lap belts was lower in cars with automatic two-point belt systems than in the same model cars with manual three-point belts; precisely how much lower could not be reliably estimated in this survey. Use of shoulder and lap belts was slightly higher in General Motors cars with detachable automatic three-point belts compared with the same model cars with manual three-point belts; in Hondas there was no difference in the rates of use of manual three-point belts and the rates of use of automatic three-point belts. PMID:1561301