Propylthiouracil tasting: determination of underlying threshold distributions using maximum likelihood

The ability to taste low concentrations of propylthiouracil (PROP) and related bitter compounds is heritable. The current analysis determines whether the distribution of PROP taste thresholds is consistent with an additive or a dominant mode of Mendelian transmission. To that end, the lowest concentration of PROP detectable was determined for 1015 subjects and models of bi- or tri-modal distributions of PROP taste thresholds were tested. The model with the greatest likelihood had three distributions and followed an additive model of PROP taste sensitivity if the variances associated with the distributions were assumed to be equal. However, if the taste thresholds were transformed to remove skewness, or if the variances were unequal, then three- or two-distribution models were equally likely. Resolution of the mode of inheritance for bitter taste perception awaits additional family studies and the characterization of the molecular basis of taste perception for these bitter compounds.     

Psychophysical Investigations of Cetylpyridinium Chloride in Rats: Its Inherent Taste and Modifying Effects on Salt Taste.

Salts are transduced by at least 2 mechanisms: (a) antagonized by amiloride and (b) antagonized by cetylpyridinium chloride (CPC). The authors report on 4 behavioral experiments in rats that characterize the orosensory properties of CPC itself as well as its effect in suppressing the intensity of NaCl and KCl taste. Experiments 1 and 2 indicated that CPC has a quinine-like taste quality. Experiments 3 and 4 demonstrated that the recognition of KCl, but not NaCl, is modestly reduced by mixture with CPC. However, control experiments call into question the mechanism of the salt suppression of CPC, because both CPC-salt and quinine-salt mixtures had similar effects. The relevance of these studies for understanding salt and bitter taste coding is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of artificial sweeteners on insulin release and cationic fluxes in rat pancreatic islets

Beta-L-glucose pentaacetate, but not alpha-D-galactose pentaacetate, was recently reported to taste bitter and to stimulate insulin release. This finding led, in the present study, to the investigation of the effects of both bitter and non-bitter artificial sweeteners on insulin release and cationic fluxes in isolated rat pancreatic islets. Sodium saccharin (1.0-10.0 mM), sodium cyclamate (5.0-10.0 mM), stevioside (1.0 mM) and acesulfame-K (1.0-15.0 mM), all of which display a bitter taste, augmented insulin release from islets incubated in the presence of 7.0 mM D-glucose. In contrast, aspartame (1.0-10.0 mM), which is devoid of bitter taste, failed to affect insulin secretion. A positive secretory response to acesulfame-K was still observed when the extracellular K+ concentration was adjusted to the same value as that in control media. No major changes in 86Rb and 45Ca outflow from pre-labelled perifused islets could be attributed to the saccharin, cyclamic or acesulfame anions. It is proposed that the insulinotropic action of some artificial sweeteners and, possibly, that of selected hexose pentaacetate esters may require G-protein-coupled receptors similar to those operative in the recognition of bitter compounds by taste buds.     

Synthesis of 11-substituted androstenediones and testosterones as human decidual cell growth inhibitors

11 alpha-Hydroxytestosterone (1a), 11 beta-hydroxytestosterone (1b), 11 alpha-methoxytestosterone (1c), 11 beta-methoxytestosterone (1d), 11-ketotestosterone (1e), and delta 9(11)-testosterone (1f) were synthesized from hydrocortisone (4b) or 11-epi-hydrocortisone (4a). The six target compounds, together with 11 alpha-methoxyandrostenedione (2c), 11 beta-methoxyandrostenedione, (2d) and their lead compound, testosterone (1), were found to effectively inhibit the growth and differentiation of human decidual cells in culture. There is no observable binding of these compounds to estrogen receptor of rabbit uterus. The introduction of a polar group (e.g., hydroxyl and carbonyl) to C-11 of androstenes decreases both the relative binding affinities to progesterone receptor and the inhibitory effects on human decidual cell growth, while the methylation of 11-hydroxyl group minimizes these effects. The similar effects of a polar group at C-11 of testosterone (1) on the inhibitory effects on human decidual cell growth and the relative binding affinities to progesterone receptor of rabbit uterus may suggest that one of the mechanisms of human decidual cell growth inhibition by these compounds is the anti-progestational activity of these androgens.     

Design, synthesis and biological evaluation of nonpeptide integrin antagonists

Recent studies demonstrated that peptide and antibody antagonists of integrin alpha v beta 3 block angiogenesis and tumor growth. In this article, the design, synthesis and biological evaluation of a series of nitroaryl ether-based, nonpeptide mimetics are described. The design of these compounds was based on Merck's arylether/alpha-aminoacid/guanidine framework and incorporates a novel nitroaryl system. The synthesized mimetics were tested against a variety of integrins (alpha v beta 3, alpha IIb beta 3, and alpha v beta 5) in order to determine their binding selectivity and ability to inhibit cell adhesion. Selected compounds were also tested for their ability to inhibit angiogenesis in vivo in the CAM (chick chorioallantoic membrane) assay. From the generated compound library, compounds 16 and 19 proved to be potent and selective inhibitors of alpha IIb beta 3 (IC50 = 14 nM) whereas compound 11 showed excellent in vivo inhibition of angiogenesis (at 30 micrograms/embryo).     

Potentiation of latent inhibition.

Rats were given exposure either to an odor (almond) or a compound of odor plus taste (almond plus saline), prior to training in which the odor served as the conditioned stimulus. It was found, for both appetitive and aversive procedures, that conditioning was retarded by preexposure (a latent inhibition effect), and the extent of the retardation was greater in rats preexposed to the compound (i.e., latent inhibition to the odor was potentiated by the presence of the taste). In contrast, the presence of the taste during conditioning itself overshadowed learning about the odor. We argue that the presence of the salient taste in compound with the odor enhances the rate of associative learning, producing a rapid loss in the associability of the odor. This loss of associability will generate both overshadowing and the potentiation of latent inhibition that is observed after preexposure to the compound. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Attitudes towards suicide among medical students: comparison between Madras (India) and Vienna (Austria)

Twenty-two nitroso compounds with cyano, acyloxy, or carbonyl groups in geminal position were prepared, eight of them for the first time. In the solid state these compounds dimerize to colorless azodioxides. Exceptions are the 4-nitrobenzoyloxynitroso compounds 7b, f, and g which form bright blue crystals. In vitro (Born test, collagen) considerable antiplatelet activity was observed in each class of compounds. Azodioxides with cyano groups in geminal position (3a, b) were most active (IC50 approximately 10 microM) suggesting the importance of strong electron withdrawing groups in geminal position to the azodioxide partial structure. When administered orally to rats (60 mg/kg) all compounds inhibited the thrombus formation in mesenteric arterioles and venules. The acetyloxy derivatives 5d and 5e were most active (18-21% inhibition in arterioles and 11-15% inhibition in venules). In aqueous media at 37 degrees C the cyanonitroso compound 3b and the benzoyloxynitroso compound 7a decomposed to nitric oxide and its reduced form nitrosohydrogen. This suggests that the above pharmacological effects are mediated by a NO dependent mechanism.     

Conditioned satiety in the rat.

In 3 experiments with a total of 72 male albino Wistar or Sprague-Dawley rats, liquid or solid diets differing in carbohydrate or triglyceride content were presented 1 at a time to each S once or twice a day. For a given S, each caloric density consistently had a particular odor and/or taste. Results show the size of the feeding bout on the dilute nutrient became larger than that on the more concentrated nutrient after several pairs of presentations. This differentiation was at least partly controlled by the oral cues which had been paired with nutrient differences. Results were attributable to acquired differences in the development of feeding inhibition during the meal, and not to original or acquired differences in initial rate of feeding or in the preference for 1 diet over the other in 2 stimulus tests. (33 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mechanisms of taste transduction

Taste cells use a wide variety of mechanisms for transduction. Ionic stimuli, such as salts and acids, interact directly with ion channels to depolarize taste cells. More complex stimuli, such as sugars and amino acids, utilize apically located receptors for transduction. Recent molecular biological results suggest that the metabotropic glutamate receptor mGluR4 may function in glutamate taste transduction. New biochemical studies have identified a bitter-responsive receptor that activates gustducin. Unexpected results with knockout mice suggest that gustducin may be directly involved in both bitter and sweet transduction. Electrophysiological experiments indicate that both inositol trisphosphate and cyclic nucleotides function in both bitter and sweet transduction events.     

Neuropsychiatric assessment of patients with hyperkinetic and hypokinetic movement disorders

Exposure of weanling rats to a diet containing 1% elemental tellurium causes segmental demyelination of peripheral nerve, and an inhibition of squalene epoxidase. This inhibition is thought to be the mechanism of action leading to demyelination. Tellurite appears to be the active inhibitory species in a cell-free system but the active species in vivo is unknown. We examined potassium tellurite (K2TeO3) and three organotellurium compounds for their ability to inhibit squalene epoxidase in Schwann cell cultures and to induce demyelination in weanling rats. K2TeO3 had no effect on squalene epoxidase activity in cultured Schwann cells and caused no demyelination in vivo. All three organotellurium compounds caused inhibition of squalene epoxidase in vitro and caused demyelination in vivo. (CH3)2TeCl2 was the most potent of these compounds and its neuropathy most resembled that caused by elemental tellurium. These data are consistent with the hypothesis that tellurium-induced demyelination is a result of squalene epoxidase inhibition and suggest that a dimethyltelluronium compound may be the neurotoxic species presented to Schwann cells in vivo.     

Effects of the neem tree compounds azadirachtin, salannin, nimbin, and 6-desacetylnimbin on ecdysone 20-monooxygenase activity

The effects of azadirachtin, salannin, nimbin, and 6-desacetylnimbin on ecdysone 20-monooxygenase (E-20-M) activity were examined in three insect species. Homogenates of wandering stage third instar larvae of Drosophila melanogaster, or abdomens from adult female Aedes aegypti, or fat body or midgut from fifth instar larvae of Manduca sexta were incubated with radiolabeled ecdysone and increasing concentrations (from 1 x 10(-8) to 1 x 10(-3) M) of the four compounds isolated from seed kernels of the neem tree, Azadirachta indica. All four neem tree compounds were found to inhibit, in a dose-dependent fashion, the E-20-M activity in three insect species. The concentration of these compounds required to elicit a 50% inhibition of this steroid hydroxylase activity in the three insect species examined ranged from approximately 2 x 10(-5) to 1 x 10(-3).     

Clavaric acid and steroidal analogues as Ras- and FPP-directed inhibitors of human farnesyl-protein transferase

We have identified a novel fungal metabolite that is an inhibitor of human farnesyl-protein transferase (FPTase) by randomly screening natural product extracts using a high-throughput biochemical assay. Clavaric acid [24, 25-dihydroxy-2-(3-hydroxy-3-methylglutaryl)lanostan-3-one] was isolated from Clavariadelphus truncatus; it specifically inhibits human FPTase (IC50 = 1.3 microM) and does not inhibit geranylgeranyl-protein transferase-I (GGPTase-I) or squalene synthase activity. It is competitive with respect to Ras and is a reversible inhibitor of FPTase. An alkaline hydrolysis product of clavaric acid, clavarinone [2,24,25-trihydroxylanostan-3-one], lacking the 3-hydroxy-3-methylglutaric acid side chain is less active as a FPTase inhibitor. Similarly, a methyl ester derivative of clavaric acid is also inactive. In Rat1 ras-transformed cells clavaric acid and lovastatin inhibited Ras processing without being overtly cytotoxic. Excess mevalonate reversed the effects of lovastatin but not of clavaric acid suggesting that the block on Ras processing by clavaric acid was due to inhibition of FPTase and not due to inhibition of HMG-CoA reductase. Despite these results, the possibility existed that clavaric acid inhibited Ras processing by directly inhibiting HMG-CoA reductase. To directly examine the effects of clavaric acid and clavarinone on HMG-CoA reductase, cholesterol synthesis was measured in HepG2 cells. No inhibition of HMG-CoA reductase was observed indicating that the inhibition of Ras processing by this class of compounds is due to inhibition of FPTase. To date, clavaric acid is the second reported nitrogen-free compound that competes with Ras to inhibit FPTase activity. A series of related compounds derived from computer-based similarity searches and subsequent rational chemical synthetic design provided compounds that exhibited a range of activity (0.04 --> 100 microM) against FPTase. Modest changes in the structures of these inhibitors dramatically change the inhibitory activity of these inhibitors.     

Taste in chimpanzees II: single chorda tympani fibers

Data are presented from 48 taste fibers in chorda tympani nerves of 10 chimpanzees during taste stimulation with 29 stimuli. The results demonstrated a higher taste fiber specificity than in any other mammalian species reported; breadth of tuning equals 0.3. Hierarchical cluster analysis separated an S-cluster (50% of all fibers), an N-cluster (31%), and a Q-cluster (19%). The S-cluster showed the highest specificity. Its fibers responded, with few exceptions, to every sweetener tested, including the sweet proteins brazzein and monellin. The response grew with increasing sweetener concentration. A large response to one sweetener was generally accompanied by a large response to all other sweeteners, and vice versa. Except for one broadly tuned fiber, the fibers of the S-cluster never responded to the bitter compounds. The fibers of the Q-cluster were more broadly tuned than any other fibers. Quinine hydrochloride was their best stimulus, but most fibers were also stimulated by KCl and NaCl with amiloride. Acids stimulated some of these fibers. The N-cluster could be divided into 3 subclusters: an Na-subcluster (3 fibers), Na-K subcluster (10 fibers), and M-subcluster (3 fibers). The Na-fibers responded strongly to, and were quite specific to, NaCl and LiCl stimulation but not to KCl, and fibers of the Na-K subcluster responded equally well to NaCl and KCl. The response to NaCl was suppressed by amiloride in the fibers of the Na-subcluster, but not in the fibers of the Na-K subcluster. Umami compounds elicited the strongest responses in the M-subcluster.     

Taste agnosia following gustatory neocortex ablation: Dissociation from odor and generality across taste qualities.

In Exp I, 18 male Long-Evans hooded rats trained to avoid drinking in the presence of a compound odor (benzyl acetate) and taste (sucrose) CS lost the taste habit but retained the odor habit following gustatory neocortex (GN) ablation. Conversely, olfactory bulb ablation resulted in loss of the odor habit but retention of the taste habit. In Exp II, with 60 Ss, Ss lacking GN did not retain preoperatively instated learned aversions to a suprathreshold quinine hydrochloride (bitter) taste solution that had been employed as a CS. However, Ss with GN lesions that were virtually identical to those of the bitter-trained group retained a preoperatively learned aversion to a hydrochloric acid (sour) CS. Exp III, with 60 Ss, demonstrated that reliable agnosia for an acid CS could be produced by lesions that extended more deeply into perirhinal areas near the claustrum at the level of the GN. It is concluded that the agnosia following GN ablation is relatively specific to gustation and that agnosia for preoperatively acquired tasted aversion habits occurs for all 4 basic gustatory stimuli following anterolateral cortex ablations centered on the GN. (49 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Functional analysis of the guanylate kinase-like domain in the synapse-associated protein SAP97

The effect of cations on the kinetics of hemolysis caused by organotin compounds was studied. The ions used in the investigation diminish or totally inhibit hemolysis of red cells induced by organotin compounds. The degree of inhibition depends both on the kind of ion and the compounds that induce hemolysis. The ions Zn2+, Co2+, and Cd2+ present in the medium at 50 microM concentration totally protect the erythrocytes against hemolysis induced by the compound (C3H7)3SnCl. The study has also shown the monovalent ions K+ and trimethyldodecylammonium bromide are less potent inhibitors of hemolysis than divalent ions, which is not the case for two non-ionic organotin compounds only. The studies performed indicate that hemolysis induced by organotin compounds is inhibited due to electrostatic interaction between the cations selected and erythrocyte membrane.     

Developmental invariance in distinctiveness effects in memory.

Improvements in 5- and 7-year-olds' acquisition and retention of related concept pairings were examined when additional similarities and differences between pair members were provided. Using a standard paired-associate learning paradigm, children learned 18 related picture pairs; some of the children either were given or produced additional similarities or differences between pair members at the time of learning. Three weeks after learning was complete, children attempted to recall the pairs. Using a model to determine the storage and retrieval loci of these effects, the results showed that (a) all children benefited from self-generated elaborations, regardless of whether these were similarities or differences, and these benefits were storage related, and (b) difference elaborations improved children's retention regardless of whether they were self- or experimenter-generated, and these effects were primarily retrieval based. These results are consistent with theories that (a) view retrieval as the locus of distinctiveness effects and (b) view storage as the locus of self-generated memory improvements. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Relative taste thresholds for ethanol, saccharin, and quinine solutions in three strains of rats nonselected for ethanol: A comparative study.

C. P. Richter and K. H. Campbell (1940b) originally defined taste threshold as "the point at which the rats first indicated that they recognized a difference between the distilled water and the solutions" (p. 34). The present study sought to apply this simple behavioral measure to the investigation of strain differences in taste sensitivities, particularly with respect to predictive relationships in ethanol, saccharin, and quinine preference. Fawn-Hooded, Lewis, and Wistar rats were presented with gradual increments in concentration of ethanol (0.01-15%; C. P. Richter & K. H. Campbell, 1940a), saccharin (0.002-3%) or quinine (0.000 1-0.0055). Results showed that although intake for saccharin was similar in all strains, consumption of ethanol and quinine differed among the groups. Although previous research has proposed that sweet preference is a promising behavioral marker for ethanol preference, these results suggested that bitter preference may be a more reliable predictor of ethanol preference in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Symptom-dependent taste aversion induced by an anticoagulant rodenticide in the brown rat (–Rattus norvegicus–R).

In a series of 3 experiments with different experimental paradigms, feeding patterns of laboratory rats (Rattus norvegicus) were monitored in 2-choice feeding tests after intubation with a sublethal dose of an anticoagulant rodenticide. The authors report for the first time that contrary to accepted wisdom, anticoagulants can induce taste aversions. Furthermore, we report behavioral symptoms within the 1st day after dosing. Our data suggest that the taste aversion is induced through an inhibition of the vitamin K cycle and is transient, attenuating over the same period as the levels of vitamin K-dependent proteins return to normal. Because the taste aversion is expressed most strongly when symptoms are most pronounced and is not expressed after symptoms have disappeared, the authors term this novel form of control symptom-dependent taste aversion. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of intake level of a mixed diet on chewing activity and on particle size of ruminated boli, ruminal digesta fractions and faeces of steers

In the rat cortical taste area (CTA), we recorded 31 pairs of taste neurons and seven pairs of taste and non-taste neurons, with single or double electrodes. By using a cross-correlogram (CCG) in a stationary state, we examined the functional interaction between neurons of the pairs while activating them by taste stimulation. Though only 14.3% of the taste and non-taste neuron pairs were correlated, 54.8% of the taste neuron pairs showed correlated activities, 41.9% of them showing common inputs, including one with an additional excitatory connection. The remainder (12.9%) showed excitatory connections with a time lag of 1-3 ms. When pairs were recorded using single or double electrodes with an intertip distance of < 50 microns in a dorsoventral direction, a larger fraction had correlated activities than when the intertip distance was > 50 microns. Whereas pairs of neurons showed correlated activities in area DI whatever the vertical intertip distance was, most of the pairs having correlated activities in area GI were found within 50 microns of the vertical intertip distance. The taste profiles of common inputs to the pair were estimated on the basis of peak at time 0 in CCGs for various taste stimuli. The efficacy contribution of the source to target neurons tended to be larger when both had the same best stimulus. This tendency held true for pairs showing excitatory connections. Interlayer excitatory connections were also evident. It is concluded that a functional column with a diameter of 50 microns may present in the CTA in rats, and that information flow is larger between pairs of neurons with the same best stimulus.