Effects of Antimitotic Agents on Secretion and Detergent Extractibility of Adrenal Nicotinic Acetylcholine Receptors

1. Evidence exists that associations of adrenal nicotinic acetylcholine receptors (nAChRs) with the cytoskeleton play an important role in signal transduction pathways by maintaining these receptors in a functional state. These studies were designed to explore this possibility and elucidate the mechanism by which antimitotic agents inhibit activation of adrenal nAChRs.2. Functional studies demonstrated that vincristine, tubulozole, podophyllotoxin, and demecolcine inhibited nAChR-stimulated catecholamine release noncompetitively and in a concentration-dependent manner, with IC₅₀ values of 3 (1–10), 5 (2–10), 8 (4–15), and 19 (9–39) M, respectively.3. Detergent extraction experiments indicated that approximately 36% of adrenal nAChRs were associated with the detergent-insoluble cytoskeletal fraction. When chromaffin cells were first treated with antimitotic agents and then detergent solubilized, a significant reduction occurred in the population of adrenal nAChRs associated with the detergent-insoluble cytoskeleton.4. These studies support an association of adrenal nAChRs with microtubules and suggest that the mechanism by which the antimitotic drugs interfere with the signal transduction pathway is by inducing dissociation of nAChRs from the microtubular network.     

Memory for Expectation-Violating Concepts: The Effects of Agents and Cultural Familiarity

Previous research has shown that ideas which violate our expectations, such as schema-inconsistent concepts, enjoy privileged status in terms of memorability. In our study, memory for concepts that violate cultural (cultural schema-level) expectations (e.g., “illiterate teacher”, “wooden bottle”, or “thorny grass”) versus domain-level (ontological) expectations (e.g., “speaking cat”, “jumping maple”, or “melting teacher”) was examined. Concepts that violate cultural expectations, or counter-schematic, were remembered to a greater extent compared with concepts that violate ontological expectations and with intuitive concepts (e.g., “galloping pony”, “drying orchid”, or “convertible car”), in both immediate recall, and delayed recognition tests. Importantly, concepts related to agents showed a memory advantage over concepts not pertaining to agents, but this was true only for expectation-violating concepts. Our results imply that intuitive, everyday concepts are equally attractive and memorable regardless of the presence or absence of agents. However, concepts that violate our expectations (cultural-schema or domain-level) are more memorable when pertaining to agents (humans and animals) than to non-agents (plants or objects/artifacts). We conclude that due to their evolutionary salience, cultural ideas which combine expectancy violations and the involvement of an agent are especially memorable and thus have an enhanced probability of being successfully propagated.     

Modulation of KvAP Unitary Conductance and Gating by 1-Alkanols and Other Surface Active Agents

The actions of alcohols and anesthetics on ion channels are poorly understood. Controversy continues about whether bilayer restructuring is relevant to the modulatory effects of these surface active agents (SAAs). Some voltage-gated K channels (Kv), but not KvAP, have putative low affinity alcohol-binding sites, and because KvAP structures have been determined in bilayers, KvAP could offer insights into the contribution of bilayer mechanics to SAA actions. We monitored KvAP unitary conductance and macroscopic activation and inactivation kinetics in PE:PG/decane bilayers with and without exposure to classic SAAs (short-chain 1-alkanols, cholesterol, and selected anesthetics: halothane, isoflurane, chloroform). At levels that did not measurably alter membrane specific capacitance, alkanols caused functional changes in KvAP behavior including lowered unitary conductance, modified kinetics, and shifted voltage dependence for activation. A simple explanation is that the site of SAA action on KvAP is its entire lateral interface with the PE:PG/decane bilayer, with SAA-induced changes in surface tension and bilayer packing order combining to modulate the shape and stability of various conformations. The KvAP structural adjustment to diverse bilayer pressure profiles has implications for understanding desirable and undesirable actions of SAA-like drugs and, broadly, predicts that channel gating, conductance and pharmacology may differ when membrane packing order differs, as in raft versus nonraft domains.     

Increased Viability of a Strain of Neurospora crassa After Treatment with Ultraviolet Radiation or Other Agents

A strain of Neurospora crassa with low viability but near normal germination shows a two- to sixfold increase in the number of colonies formed after treatment with ultraviolet radiation, X radiation, nitrous acid, or heat (50 C). Effective dosages of these agents produce moderate killing of the wild type.     

In Vitro Effects of Some Chemotherapeutic Agents on Mycobacteria

Examination of the bactericidal and bacteriostatic effects of nine antibiotics on atypical mycobacteria revealed that streptovaricin complex and streptovaricin C exerted bactericidal effects on several strains in concentrations lower than 1.0 mug/ml. An exposure to the drug for 48 hr at 37 C was necessary to effect a complete inactivation of more than 99.9% of the exposed microorganisms. The appearance of strepto-varicin-resistant mutants was observed. However, these mutants were unstable, and reversion to streptovaricin susceptibility occurred. Celesticetin salicylate, added in a concentration of 100.0 mug/ml to the medium of Olitzki and Gershon inoculated with Mycobacterium leprae, effected a complete change of the uniformly stained mycobacteria to bipolarity, which indicates the devitalization of this microorganism.     

THE DIRICHLET-MULTINOMIAL MODEL: ACCOUNTING FOR INTER-TRIAL VARIATION IN REPLICATED RATINGS

Differences in sensory acuity and hedonic reactions to products lead to latent groups in pooled ratings data. Manufacturing locations and time differences also are sources of rating heterogeneity. Intensity and hedonic ratings are ordered categorical data. Categorical responses follow a multinomial distribution and this distribution can be applied to pooled data over trials if the multinomial probabilities are constant from trial to trial. The common test statistic used for comparing vectors of proportions or frequencies is the Pearson chi-square statistic. When ratings data are obtained from repeated ratings experiments or from a cluster sampling procedure, the covariance matrix for the vector of category proportions can differ dramatically from the one assumed for the multinomial model because of inter-trial. This effect is referred to as overdispersion. The standard multinomial model does not fit overdispersed multinomial data. The practical implication of this is that an inflated Type I error can result in a seriously erroneous conclusion. Another implication is that overdispersion is a measurable quantity that may be of interest because it can be used to signal the presence of latent segments. The Dirichlet-Multinomial (DM) model is introduced in this paper to fit overdispersed intensity and hedonic ratings data. Methods for estimating the parameters of the DM model and the test statistics based on them to test against a specified vector or compare vectors of proportions are given. A novel theoretical contribution of this paper is a method for calculating the power of the tests. This method is useful both in evaluating the tests and determining sample size and the number of trials. A test for goodness of fit of the multinomial model against the DM model is also given. The DM model can be extended further to the Generalized Dirichlet-Multinomial (GDM) model, in which multiple sources of variation are considered. The GDM model and its applications are discussed in this paper. Applications of the DM and GDM models in sensory and consumer research are illustrated using numerical examples.     

Absence of 6-Hydroxydopamine in the Rat Brain After Treatment with Stimulants and Other Dopaminergic Agents: A Mass Fragmentographic Study

Abstract: Formation of 6-hydroxydopamine (6-OHDA) from dopamine has been hypothesized to mediate neuro-degeneration induced by some psychostimulants. Although the emergence of a 6-OHDA-like substance was reported in the striatum of methamphetamine-treated rats, this substance has not been identified by a direct approach. We used mass fragmentography to search for 6-OHDA in the rat frontal cortex and striatum after the administration of a number of drugs including 3,4-dihy-droxyphenyl-L-alanine, methamphetamine, amphetamine, and cocaine, all of which increase synaptic dopamine. No 6-OHDA was detected after the acute systemic administration of these agents. Intraventricular administration of 6-OHDA (10 μg/rat.) produced measurable concentrations of 6-OHDA that were higher in the striatum than in the frontal cortex. Intraventricular administration of 2,4,5-trihydroxy-phenyl-D,L-alanine (6-OHDOPA; 10 μg/rat) produced similar concentrations of 6-OHDA in both regions. Pargyline, but not carbidopa (α-methyldopahydrazine), enhanced the effect of intraperitoneal 6-OHDOPA administration (80 mg/kg). We conclude that (1) 6-OHDOPA can cross the blood-brain barrier and is converted to 6-OHDA in the brain, (2) 6-OHDA is a substrate for monoamine oxidase(s) and therefore a search for its purported deaminated metabolite is warranted, and (3) acute treatment with the above stimulants either does not lead to the formation of 6-OHDA or produces concentrations below the detection limit of the assay (<34 pg/mg of protein).     

Adenosine Triphosphate and Other Requirements for the Utilization of Glucose by Agents of the Psittacosis-Trachoma Group.

Weiss, Emilio (Naval Medical Research Institute, Bethesda, Md.). Adenosine triphosphate and other requirements for the utilization of glucose by agents of the psittacosis-trachoma group. J. Bacteriol. 90:243-253. 1965.-The agent of meningopneumonitis cultivated in the allantoic cavity of chick embryos and purified by differential centrifugations was employed for most of the studies of the requirements for glucose utilization. The evolution of C(14)O(2) from glucose-1-C(14) was used as the criterion of metabolic activity in most experiments. The rate of glucose utilization increased somewhat during the first hour of incubation at 34.4 C and became approximately constant during the second hour. Changes in glucose concentration from 1 to 5 mm did not appreciably affect metabolic activity. More vigorous CO(2) production was obtained when the ratio of K(+)-Na(+) was >1 and, under certain conditions, when the concentration of inorganic phosphate was relatively high (0.05 m). Glucose utilization was entirely dependent on added adenosine triphosphate (ATP) and Mg(++). The effect of ATP was greatly reduced when the microorganisms were partially disrupted with sonic energy. Adenosine diphosphate (ADP) could be substituted for ATP, but the activity was reduced to less than 20%. ATP was not required when glucose-6-phosphate was substituted for glucose. With ADP and glucose, glucose-6-phosphate was an effective competitor of glucose utilization. Nicotinamide adenine dinucleotide phosphate (NADP) enhanced CO(2) production from carbon 1, but not from other carbons, with glucose and, especially, glucose-6-phosphate as substrates. ATP and NADP produced the above-described effects only when their concentrations were comparable to those of the substrates. These concentrations always exceeded the amount of CO(2) produced (0.05 to 0.5 mumole/mg of agent protein). The concentration of NADP could be reduced when oxidized glutathione was added. Diphosphothiamine had no effect on CO(2) production. Qualitatively similar results were obtained with the agent of trachoma purified from yolk sac. These experiments furnish evidence that agents of the psittacosistrachoma group, despite their enzymatic capabilities, require an exogenous source of energy.     

Modelling the Brain for Rotational Loading: Shear Effects and Other Complications

Abstract

This study considers modelling the brain due to rotation of the skull where, at lower frequencies, the shear property of the material is important. Investigations reported here cover the effect of elastic and viscoelastic (lossy) cerebral material, the effect of the Falx protruding into the brain, the gap around the Falx and the brain filled with non viscous fluid in addition to different models of the Falx with bending or membrane stiffness. Analytical benchmark formulations are also described for the simple 2D plane strain in a cylinder produced by a half-sine rotation on the outer periphery which allows numerical (Finite Element) models to be validated. The results show the importance of the material properties, duration of loading and amplitude of loading as well as the influence of the partition. The results are shown for predicted maximum Principal strains in the models, as this may well be indicative of whether damage of the brain tissue occurs.