A mixed helix--beta-sheet model of the transmembrane region of the nicotinic acetylcholine receptor

We have modelled the transmembrane region of the 7 nicotinicacetylcholine receptor as a mixed -helical/ß-sheetstructure. The model was mainly based on the crystal structureof a pore-forming toxin, heat-labile enterotoxin. This is apentameric protein having a central pore or channel composedof five -helices, one from each of the 5 B subunits that formthis pentamer. The remainder of this structure is ß-sheet,loops and a short -helix, not included in the model. The modeluses this channel as a template to build the transmembrane region,from M1 to the middle of M3. The remainder of M3 and M4 werebuilt de novo as -helices. Great consideration was given tolabelling data available for the transmembrane region. In generalterms, the shape of the model agrees very well with that obtainedindependently by electron microscopic analysis and the secondarystructure predicted by the model is in accord with that estimatedindependently by Fourier transform infrared spectroscopy. TheM2 helical region of the model is only slightly kinked, contraryto what is inferred from electron microscopic analysis, buthas the same overall shape and form. On the membrane face ofthe model, the presence of deep pockets may provide the structuralbasis for the distinction between annular and non-annular lipidbinding sites. Also, the transmembrane region is clearly asymmetricin the direction perpendicular to the membrane, and this mayhave strong influence on the surrounding lipid composition ofeach leaflet of the cytoplasmic membrane.     

Attentional orienting within visual field in a lexical decision task.

The influence of spatial attention on lexical decisions to lateralized target letter-strings appearing either along with a distractor (Experiment 1) or in an otherwise empty field (Experiments 2–6) was examined. Attentional orienting was controlled by peripheral (Experiments 1, 2, 3, and 6) and central (Experiments 4–5) cuing methods. Manipulations of spatial attention, including cue validity and cue–target stimulus onset asynchrony, were combined with manipulations of word frequency in Experiments 3-6. All the attentional manipulations were effective, but they did not modify the right visual field advantage in word performance, In addition, the attentional effects did not interact with either the presence or absence of distractors or with stimulus familiarity. Implications of these results regarding the influence of spatial attention (the posterior attention system) on word processing are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of prime–probe stimulus onset asynchrony and prime precuing manipulations on semantic priming effects with words in a lexical-decision task.

The present research examines semantic priming from attended and unattended parafoveal words. Participants made a lexical decision in response to a single central target. The target was preceded by two parafoveal prime words, with one of them (the attended prime) being precued by a peripheral cue. The main variables manipulated across experiments were cue informativeness (valid vs. neutral cues) and stimulus onset asynchrony (SOA) between prime and probe (200, 300, 600, or 1,000 ms). The results showed (a) reliable semantic priming from both attended and ignored prime words and (b) that the ignored priming effects were either negative or positive, depending on both the prime-probe SOA and cue informativeness. The present findings are discussed in relation to inhibitory versus episodic retrieval models of negative priming. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of Al<Subscript>2</Subscript>O<Subscript>3</Subscript> Particle Size on Microstructure,Mechanical Properties and Abrasive Wear Behavior of Flame-Sprayed and Remelted NiCrBSi Coatings

The influence of micrometric alumina (low surface area-to-volume ratio) and nanometric alumina (high surface area-to-volume ratio) on microstructure, hardness and abrasive wear of a NiCrBSi hardfacing alloy coating applied to an AISI 304 substrate using flame spraying (FS) combined with surface flame melting (SFM) is studied. Remelting after spraying improved the mechanical and tribological properties of the coatings. Microstructural characterization using XRD, SEM and EDS indicated that alumina additions produced similar phases (NiSi, Ni₃B, CrC and Ni₃₁Si₁₂) regardless of the alumina size, but the phases differed in morphology, size distribution and relative proportions from one coating to another. The addition of 12 wt.% nanometric Al₂O₃ increased the phases concentration more than five- to sixfold and reduced the hard phases size about four-to threefold compared with NiCrBSi + 12 wt.% micrometric Al₂O₃. Nanoalumina led to reduced mass loss during abrasive wear compared to micrometric alumina and greater improvement in hardness.     

Distortion product otoacoustic emissions in healthy newborns: normative data

Distortion product otoacoustic emissions (DPOAE) offer an alternative to transiently evoked otoacoustic emissions (TEOAE) as an audiological test. The former can be used as a screening technique, and may also provide frequency-specific information about the functional state of the cochlea. We recorded DPOAE in a group of healthy newborns to establish the characteristics of a DPOAE "audiogram" (DP-gram) in this population. The DP-gram can be obtained with characteristics quite similar to those observed in adults, with two sharp peaks of maximum amplitude at F2 frequencies of 2 kHz and 5-6 kHz, and a decline in DPOAE amplitude in midfrequencies. The results confirm the limitations of DPOAE recording for testing parts of the basilar membrane where lower frequencies are coded.     

Understanding channel blocking in the nicotinic acetylcholine receptor.

Ion-channel blockers are molecules that obstruct the path used by ions to cross the membrane through a protein channel. Many of these are local anesthetics, toxins or drugs of abuse, and the knowledge of their mechanism of action at the atomic level is an important step towards the development of new compounds on a structural basis. A molecular model of the transmembrane region of the nicotinic acetylcholine receptor, an important brain and muscle fast signaling protein, was used as a target for docking several channel blockers by means of an automatic docking method. The combination of the independent docking method and molecular models (of the receptor and blockers) reproduced or explained quite accurately experimental data (photoaffinity labeling, site-directed mutagenesis, binding assays). This represents a strong support for the validity of the predictions made for those molecules for which no experimental data is available and also for the models and methods on which are based.     

Molecular modelling of the nicotinic acetylcholine receptor transmembrane region in the open state

A model of the nicotinic acetylcholine receptor transmembrane region has been constructed which may represent the channel in its open-state. The positions of helices flanking the ion channel match those observed by electron microscopy and previously reported by others. Residues labelled, mutated or by other means known to have a strong influence on ion flux are each accessible from the lumen of the modelled channel. The model provides new insights into our current understanding of the ion channel structure, and suggests some novel explanations for the results of labelling and mutation studies such as those involving ion channel blockers and residue-dependent changes in ion selectivity.      

Homologies and disparities of glutamate receptors: a critical analysis

Based on analysis of aligned amino acid sequences the following statements are made: (i) There is evolutionary homology between the N-terminal extracellular region of ionotropic Glutamate receptors/Kainate Binding Proteins and a family of procaryote amino acid binding proteins. (ii) Homology of the N-terminal extracellular domain of the metabotropic glutamate receptors with a family of receptors with a guanylate cyclase intracellular domain appears to be valid. (iii) There is no evidence for homology between the N-terminal extracellular domain of the nicotinic Acetylcholine, GABA, Glycine and 5HT3 receptors and that of the ionotropic Glutamate receptors/Kainate Binding proteins. (iv) The proposal of homology for the N-terminal extracellular domain of metabotropic Glutamate receptors and that of ionotropic Glutamate receptors does not appear to hold.