NMR studies of flexible peptides in cavities mimicking the synaptic cleft

The interaction of neuropeptides with post-synaptic receptors is characterised by a high entropic barrier originating from the combination of nanomolar concentration with low conformer population. The influence of high viscosity environments on conformer distribution can help overcome this difficulty. In an attempt to simulate the physicochemical conditions of the synaptic cleft, (15)N-labelled enkephalin has been studied in polyacrylamide gels swollen by different aqueous solutions in the temperature range 273-293 K. Nuclear Overhauser enhancement spectra in the gel pores are consistent with a conformational selection or a slowing down of internal motions that can favour the interaction of the peptide with the receptor.     

Solid-state geometry and conformation of linear,diastereoisomeric oligoprolines

We have carried out a systematic analysis of the solid-state conformational preferences of a number of linear homo-oligoprolines (to the tetramer) by ir absorption and x-ray diffraction. The peptides present different chiral sequences (tacticities), various types (urethane and amide) of N-protecting groups, and free and blocked C-termini (which imply different capabilities of forming H-bonds). The following conclusions can be drawn: (i) values for the geometry of the prolyl residue and the peptide bond in the cis and in the trans conformations are proposed; (ii) in general the conformational angles φ and ψ in the linear homo-oligoprolines have values appropriate for the polyproline II structure (conformation F); (iii) the pyrrolidine ring shows various types of puckering with no apparent relation to the backbone conformation; (iv) Pro-Pro peptide bonds generally take the trans conformation, the few cases of cis conformation being formed by Pro residues of different chirality; (v) the single H-bond donor — OH, when present, is always bonded to H-acceptors, which can be either the urethane or the amide or the peptide carbonyl but never the carbonyl group of the — COOH moiety.     

Pulmonary impedance and alveolar instability during injurious ventilation in rats.

The mechanical derangements in the acutely injured lung have long been ascribed, in large part, to altered mechanical function at the alveolar level. This has not been directly demonstrated, however, so we investigated the issue in a rat model of overinflation injury. After thoracotomy, rats were mechanically ventilated with either 1) high tidal volume (Vt) or 2) low Vt with periodic deep inflations (DIs). Forced oscillations were used to measure pulmonary impedance every minute, from which elastance (H) and hysteresivity (eta) were derived. Subpleural alveoli were imaged every 15 min using in vivo video microscopy. Cross-sectional areas of individual alveoli were measured at peak inspiration and end exhalation, and the percent change was used as an index of alveolar instability (%I-EDelta). Low Vt never led to an increase in %I-EDelta but did result in progressive atelectasis that coincided with an increase in H but not eta. DI reversed atelectasis due to low Vt, returning H to baseline. %I-EDelta, H, and eta all began to rise by 30 min of high Vt and were not reduced by DI. We conclude that simultaneous increases in both H and eta are reflective of lung injury in the form of alveolar instability, whereas an isolated and reversible increase in H during low Vt reflects merely derecruitment of alveoli.     

Novel substituted tetrahydrotriazaacenaphthylene derivatives as potent CRF1 receptor antagonists

Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.     

Novel imidazobenzazepine derivatives as dual H1/5-HT2A antagonists for the treatment of sleep disorders

A novel imidazobenzazepine template (5a) with potent dual H₁/5-HT_2A antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R¹-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H₁/5-HT_2A receptor antagonist activities and good developability profiles.     

HETEROZYGOSITY,AGGRESSION, AND POPULATION FLUCTUATIONS IN MEADOW VOLES (MICROTUS PENNSYLVANICUS)

We tested whether variation in heterozygosity could produce cyclic changes in population size in meadow voles (Microtus pennsylvanicus). For this to occur, three conditions must be met: (1) populations are more outbred (heterozygotic) at high than low population density, (2) heterozygotic voles are more aggressive than relatively inbred individuals, and (3) heterozygotic voles have lower reproductive fitness, though being superior at defending resources. We found no evidence that heterozygosity varied with population size or that reproductive success varied with heterozygosity. However, the former test was indirect and relatively weak. We directly measured aggression and heterozygosity of individual voles. Aggression was significantly related to heterozygosity: higher heterozygosity correlated with more aggression in males and less aggression in females. The proportion of variance in aggression that could be explained by heterozygosity was small. These results suggest that changes in population size of meadow voles could not be driven by systematic changes in heterozygosity with population size.     

Noncoded residues as building blocks in the design of specific secondary structures: Symmetrically disubstituted glycines and β-alanine

Structural changes can be induced in a peptide by selective substitution of coded α-amino acid residues by noncoded α-amino acid residues and the consequent production of analogues with modified structure and conformational preferences. In this review article we summarize the solid state structural results and the conformational preferences of two classes of “building blocks”: (a) the linear and cyclic symmetrically α, α-disubstituted glycines in which either two identical n-alkyl groups replace the hydrogen atoms of the glycine residue or a cyclic aliphatic side-chain system is formed by linking the two α-carbon side chains, respectively; and (b) the β-alanine residue. Examples, whenever possible, of the use of these residues for the elucidation of the bioactive conformation in the appropriate biological systems will be given. © 1993 John Wiley & Sons, Inc.     

Jasione sphaerocephala sp.nov. (Campanulaceae) from Italy

Jasione sphaerocephala Brullo, Marcend et Pavone sp.nov. is described from Calabria, S Italy. It grows in rocky places and has some resemblance to J. laevis and J. montana. The chromosome number is 2n = 14.     

And Yet They Act Together: Interpersonal Perception Modulates Visuo-Motor Interference and Mutual Adjustments during a Joint-Grasping Task

Prediction of “when” a partner will act and “what” he is going to do is crucial in joint-action contexts. However, studies on face-to-face interactions in which two people have to mutually adjust their movements in time and space are lacking. Moreover, while studies on passive observation have shown that somato-motor simulative processes are disrupted when the observed actor is perceived as an out-group or unfair individual, the impact of interpersonal perception on joint-actions has never been directly addressed. Here we explored this issue by comparing the ability of pairs of participants who did or did not undergo an interpersonal perception manipulation procedure to synchronise their reach-to-grasp movements during: i) a guided interaction, requiring pure temporal reciprocal coordination, and ii) a free interaction, requiring both time and space adjustments. Behavioural results demonstrate that while in neutral situations free and guided interactions are equally challenging for participants, a negative interpersonal relationship improves performance in guided interactions at the expense of the free interactive ones. This was paralleled at the kinematic level by the absence of movement corrections and by low movement variability in these participants, indicating that partners cooperating within a negative interpersonal bond executed the cooperative task on their own, without reciprocally adapting to the partner''s motor behaviour. Crucially, participants'' performance in the free interaction improved in the manipulated group during the second experimental session while partners became interdependent as suggested by higher movement variability and by the appearance of interference between the self-executed actions and those observed in the partner. Our study expands current knowledge about on-line motor interactions by showing that visuo-motor interference effects, mutual motor adjustments and motor-learning mechanisms are influenced by social perception.