Statistical and energetic analysis of side-chain conformations in oligopeptides

The distributions of side-chain conformations in 258 crystal structures of oligopeptides have been analyzed. The sample contains 321 residues having side chains that extend beyond the Cβ atom. Statistically observed preferences of side-chain dihedral angles are summarized and correlated with stereochemical and energetic constraints. The distributions are compared with observed distributions in proteins of known X-ray structures and with computed minimum-energy conformations of amino acid derivatives. The distributions are similar in all three sets of data, and they appear to be governed primarily by intraresidue interactions. In side chains with no β-branching, the most important interactions that determine χ1 are those between the CγH₂ group and atoms of the neighboring peptide groups. As a result, the g- conformation (χ1 ? -60°) occurs most frequently for rotation around the Cα-Cβ bond in oligopeptides, followed by the t conformation (χ1 ? 180°), while the g + conformation (χ1 ? 60°) is least favored. In residues with β-branching, steric repulsions between the CγH₂ or CγH₃ groups and backbone atoms govern the distribution of χ1. The extended (t) conformation is highly favored for rotation around the Cβ-Cγ Cγ-Cδ bonds in unbranched side chains, because the t conformer has a lower energy than the g + g - conformers in hydrocarbon chains. This study of the observed side-chain conformations has led to a refinement of one of the energy parameters used in empirical conformational energy computations.     

Effects of Maternal Exposure to Polychlorobiphenyls (PCBs) on F1 Generation Behavior in the Rat

Effects of Maternal Exposure to Polychlorobiphenyls (PCBs) onFl Generation Behavior in the Rat.PANTALEONI, G., FANINI, D.,SPONNTA, A. M., PALUMBO, G., GIORGI, R., AND ADAMS, 5P. M. (1988).Fundam. Appl. Toxicol. 11, 440-449. The effect of Fenclor 42(PCB) exposure of female rats (Fischer 344 strain) was studiedthrough assessment of the behavioral development of their Flprogeny. Female rats were exposed to PCB according to the followingtreatment schedule: (A) (5 days) 2 weeks prior to mating, (B)during gestation (Days 6-15 of pregnancy), (C) during lactation(Days 1-21 after delivery). Behavioral endpoints of motor reflexes,motor coordination, activity (preweaning behaviors), and learning(postweaning behavior) were evaluated for PCB ip dosages of5-10 mg/kg/day for 5 days (preconception exposure), and PCBoral 3 dosages of 2-4 mg/kg/day for 10 days (in mero exposure)and of 1-2 mg/kg/day for 20 days (during lactation exposure).Dosage-dependentdifferences in the evaluated behaviors were found in the offspringof the PCB-exposed females when compared to the offspring ofcorn-oil (vehicle)-exposed females. Significant differencesin the development of cliffavoidance reflexive behavior, swimmingability, and open field activity were particularly evident.Furthermore the PCB exposure of female rats during gestationand lactation resulted in impaired acquisition of the activeavoidance behavior while preconceptional PCB exposure significantlyaffected active avoidance performance as reflected in increasednumber of avoidance responses to reach criterion for extinction.These results show that Fenclor 42 does possess a significantrisk to the offspring of exposed females, and further illustratethe sensitivity of progeny behavioral assessment in detectingsuspected functional teratogenesis.     

DIFFERENT AFFINITY OF CORTICAL GHB BINDING SITES IN SARDINIAN ALCOHOL-PREFERRING (sP) AND-NON PREFERRING (sNP) RATS

Specific gamma-hydroxybutyric acid (GHB) binding sites in corticalmembranes of selectively bred alcohol-preferring sP and alcohol-nonpreferring sNP rats were compared using [2,3³H]GHB ligand. ThesP rat line showed an increased affinity (-40% lower K_d) ofboth the high- and low-affinity sites in comparison with thesNP line. No significant difference in GHB receptor density(B_max) was detected between the two rat lines. The results raisethe possibility that differences in GHB binding sites may playa role in the genetic predisposition to ethanol preference inour rat line.     

REDUCTION OF VOLUNTARY ETHANOL INTAKE IN ETHANOL-PREFERRING sP RATS BY THE CANNABINOID ANTAGONIST SR-141716

The present study assessed the efficacy of the cannabinoid CB₁receptor antagonist, SR-141716, in reducing voluntary ethanolintake in selectively bred Sardinian alcohol-preferring (sP)rats. Ethanol (10%, v/v) and food were available in daily 4hscheduled access periods; water was present 24 h/day. The acuteadministration of a 2.5 and a 5 mg/kg dose of SR-141716 selectivelyreduced ethanol intake, whereas a 10 mg/kg dose of SR-141716reduced to a similar extent both ethanol and food intake. Theseresults suggest that the cannabinoid CB₁ receptor is involvedin the mediation of the ethanol-reinforcing effects in sP rats.     

CIRCADIAN DRINKING PATTERN OF SARDINIAN ALCOHOL-PREFERRING RATS

The present study was designed to assess the temporal patternof ethanol intake over a 24 h period in selectively bred, Sardinianalcohol-preferring (sP) rats Ethanol intake occurred under thetwo-bottle, free choice regimen. sP rats consumed ethanol inthree distinct peaks, rather regularly distributed over the12 h dark phase of the light-dark cycle and positively correlatedwith food intake episodes. The temporal distribution of ethanolintake and estimated blood alcohol levels are consistent withthe hypothesis that sP rats voluntarily drink ethanol for itspharmacological effects     

HIGH SENSITIVITY TO {lambda}-HYDROXYBUTYRIC ACID IN ETHANOL-PREFERRING sP RATS

Sensitivity to the sedative effect of     

S-deoxo-Abu1, Ile3-amaninamide,an inactive amatoxin analogue

The title compound 3, an amatoxin analogue containing l -α-aminobutyric acid instead of l -asparagine in position 1, as in natural toad stool peptides, has been synthesized. It does not inhibit the eukaryotic DNA-dependent RNA polymerase form II (or B) in concentrations up to 10^-4M, whereas 50% inhibition is exerted in M solution by the corresponding Asn-analogue S-deoxo-Ile³-amaninamide 2. The striking difference seems to be due to a relatively small variation of the conformation recognized by sensitive NMR spectroscopic methods.     

SEROTONIN IS REDUCED IN THE FRONTAL CORTEX OF SARDINIAN ETHANOL-PREFERRING RATS

Ethanol-naive Sardinian alcohol-preferring (sP) and Sardinianalcohol-non-preferring (sNP) rats were tested to evaluate thelevels of serotonin (5-HT) and 5-hydroxyindol-3-yl-acetic acid(5-HIAA) in the frontal cortex, hypothalamus, and nucleus accumbens,and the levels of dopamine (DA) and 3,4-dihydroxyphenylaceticacid (DOPAC) in the hypothalamus and nucleus accumbens. Comparedwith the sNP line, the sP rats had lower 5-HT and 5-HIAA concentrationsin the frontal cortex, whereas no differences were found inthe other brain areas tested, neither for neurotransmittersnor their metabolites. As the decreased 5-HT function is a featureshared by different alcohol-preferring strains, it could belinked to the genetic predisposition to voluntary ethanol consumption.     

Respiratory Rate as a Determinant of Optimal Pacing Rate

Des essais ont été faits dans ľutilisation des paramètres bialogiques pour déterminer la fréquence optimale de stimulation cardiaque. Dans cette étude, le rapport entre fréquence respiratoire et fréquence cordiaque a étéétabli chez 67 patients au cours de ľexercice. Ensuite, un système de stimulation cardiaque qui repondrait àľactivation radiotélémétrique a été posé chez onze patients. Dans deux cos un système automatique a été implanté avec succès. A present, les résultats de cette stimulation pilotée par la fréquence respiratoire sont satisfaisants.
Efforts have been made to utilize biologic parameters for determining optimal cardiac pacing rates. In this study of 67 patients, a significant relationship between heart rate and respiratory rate was observed during dynamic exercise. A system using a radiofrequency activator to modify pacing rate is described. Eleven patients have received VVI pacemakers with a similar implanted radioreceiver coil. In two patients the fully automatic system has been successfully implanted. The experience with respiratory rate as a determinant of pacing rate is encouraging.