A small-molecule lead compound for the treatment of Alzheimer's disease

At autopsy, Alzheimer's disease is characterised by the presence of amyloid plaques and neurofibrillary tangles, made up of two peptide sequences, amyloid-beta(1-40) (A beta 40) and amyloid-beta(1-42) (A beta 42). In Tyrode's solution (2 mM Ca2+), 10 mu M A beta 42 peptide almost immediately aggregates and eventually forms p-sheets. This aggregation can be inhibited with 4,5-dianilinophthalimide (DAPH). Ca2+-permeant AMPA receptors are involved in the neuronal Ca2+ influx (neurotoxicity) induced by the A beta 42 peptide in cultured neuronal cells. The Ca2+ influx observed with pre-incubated A beta 42 peptide was inhibited by DAPH. DAPH also inhibits epidermal growth factor receptor kinase, and this will prevent its development for use in Alzheimer's disease. The potential of DAPH as a small-molecule lead compound for the treatment of Alzheimer's disease next requires the separation of the structural requirements that reverse fibril formation and inhibit epidermal growth factor receptor kinase.

The effects of affective picture stimuli on blink modulation in adults and children

Two experiments examined blink modulation during viewing of pleasant, neutral and unpleasant picture stimuli in non-selected adults (N = 21) and children (N = 60) and children with anxiety disorders (N = 12). Blink reflexes were elicited by a white noise probe of 105 dB at lead stimulus intervals of 60, 240, 3500, and 5000 ms and during intertrial intervals. Blink modulation during unpleasant pictures was significantly different from blink modulation during neutral pictures at the 60 ms lead interval in children whereas adults showed no significant differences. Picture content had no differential effect on the extent of blink modulation for adults or children at the 240 ms lead interval. At the long lead intervals, blink modulation during unpleasant and pleasant pictures was significantly larger than during neutral pictures in adults. Picture valence did not differentially affect the extent of blink modulation at long lead intervals in children. Comparing the extent of blink modulation in anxious and non-selected children, blinks were significantly modulated during unpleasant pictures at the 60 ms lead interval for both groups. However, the extent of blink modulation was larger overall at this very short lead interval in anxious children. Children did not differ at other lead intervals. (C) 2004 Elsevier B.V. All rights reserved.

Acquisition of negative valence and modified attentional processing by non fear relevant stimuli

The current research examined valence and attentional processing of a priori fear relevant stimuli and investigated the extent to which these characteristics can be acquired by non fear relevant stimuli across an aversive learning episode. The first experiment compared pictures of snakes and spiders with pictures of birds and fish using affective priming, visual search and detection of a dot probe. Snakes and spiders were more negative than birds and fish as indexed by affective priming, and were preferentially attended to in the visual search task. The second experiment exposed the non fear relevant animal pictures, birds and fish, in an aversive learning episode involving an aversive shock US. Skin conductance responding was measured during acquisition. After acquisition, conditioned non fear relevant animal stimuli, CS1, and non conditioned, non fear relevant animal stimuli, CS, were compared across affective priming, visual search and dot probe tasks. During acquisition, skin conductance responses were larger during CS1 than during CS across all three response intervals. After acquisition, CS1 non fear relevant animal pictures were more negative than CS non fear relevant animal pictures as indexed by affective priming, and were preferentially attended to in a dot probe task. These studies provide evidence that negative valence and modified attentional processing can be acquired in a brief aversive learning episode.

Effects of acoustic startle stimuli on interceptive action

In reaction time (RT) tasks, presentation of a startling acoustic stimulus (SAS) together with a visual imperative stimulus can dramatically reduce RT while leaving response execution unchanged. It has been suggested that a prepared motor response program is triggered early by the SAS but is not otherwise affected. Movements aimed at intercepting moving targets are usually considered to be similarly governed by a prepared program. This program is triggered when visual stimulus information about the time to arrival of the moving target reaches a specific criterion. We investigated whether a SAS could also trigger such a movement. Human experimental participants were trained to hit moving targets with movements of a specific duration. This permitted an estimate of when movement would begin (expected onset time). Startling and sub-startle threshold acoustic probe stimuli were delivered unexpectedly among control trials: 65, 85, 115 and 135 ms prior to expected onset (10:1 ratio of control to probe trials). Results showed that startling probe stimuli at 85 and 115 ms produced early response onsets but not those at 65 or 135 ms. Sub-threshold stimuli at 115 and 135 ms also produced early onsets. Startle probes led to an increased vigor in the response, but sub-threshold probes had no detectable effects. These data can be explained by a simple model in which preparatory, response-related activation builds up in the circuits responsible for generating motor commands in anticipation of the GO command. If early triggering by the acoustic probes is the mechanism underlying the findings, then the data support the hypothesis that rapid interceptions are governed by a motor program. © 2006 Published by Elsevier Ltd on behalf of IBRO.

Electrophysiological evidence for linear polarization sensitivity in the compound eyes of the stomatopod crustacean Gonodactylus chiragra

Gonodactyloid stomatopod crustaceans possess polarization vision, which enables them to discriminate light of different e-vector angle. Their unusual apposition compound eyes are divided by an equatorial band of six rows of enlarged, structurally modified ommatidia, the mid-band (MB). The rhabdoms of the two most ventral MB rows 5 and 6 are structurally designed for polarization vision. Here we show, with electrophysiological recordings, that the photoreceptors R1-R7 within these two MB rows in Gonodactylus chiragra are highly sensitive to linear polarized light of two orthogonal directions (PS=6.1). They possess a narrow spectral sensitivity peaking at 565 nm. Unexpectedly, photoreceptors within the distal rhabdomal tier of MB row 2 also possess highly sensitive linear polarization receptors, which are in their spectral and polarization characteristics similar to the receptors of MB rows 5 and 6. Photoreceptors R1-R7 within the remainder of the MB exhibit low polarization sensitivity (PS=2.3). Outside the MB, in the two hemispheres, R1-R7 possess medium linear polarization sensitivity (PS=3.8) and a broad spectral sensitivity peaking at around 500 nm, typical for most crustaceans. Throughout the retina the most distally situated UV-sensitive R8 cells are not sensitive to linear polarized light.

Reaction time facilitation by acoustic task-irrelevant stimuli is not related to startle

Previous research has been interpreted to suggest that the startle reflex mediates the RT facilitation observed if intense, accessory acoustic stimuli are presented coinciding with the onset of a visual imperative stimulus in a forewarned simple RT task. The present research replicated this finding as well as the facilitation of startle observed during the imperative stimulus. It failed, however, to find any relationship between the size of the blink startle reflex elicited by the accessory acoustic stimuli, which differed in intensity and rise time, and RT or RT facilitation observed on trials with accessory acoustic stimuli. This finding suggests that the RT facilitation is not mediated by the startle reflex elicited by the accessory acoustic stimuli. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

Foaming properties of a peptide designed to form stimuli-responsive interfacial films

We have designed an amphipathic peptide, AM1, that can self-assemble at the air-water interface to form an interfacial ensemble capable of switching between a mechanically strong cohesive film state and a mobile detergent state in response to changes in the solution conditions. The mechanical properties of the AM1 ensemble in the cohesive film state are qualitatively equivalent to the protein beta-LG, while in the mobile detergent state they are equivalent to the low molecular weight surfactant, SDS. In this work the foaming properties of AM1 are compared to those of beta-LG and SDS at the same weight concentration and it is found that AM1 adsorbs rapidly to the interface, initially forming a dense foam like that formed by SDS and superior to beta-LG. In addition, under solution conditions where interfacially adsorbed AM1 forms a cohesive film state the foam stability is high, comparable to beta-LG. However when the interfacially adsorbed AM1 forms a foam under detergent-state conditions, the foam stability is poor. We have achieved control of foam stability through the design of a peptide that exhibits stimuli-responsive changes in the extent of intermolecular interactions between peptide molecules adsorbed at the air water interface. These results illustrate the exciting potential of peptide surfactants to form a new class of stimuli-responsive foaming agents.