Disulfide-bound dimers of three-fingered toxins have been discovered in the Naja kaouthia cobra venom; that is, the homodimer of ␣-cobratoxin (a long-chain ␣-neurotoxin) and heterodimers formed by ␣-cobratoxin with different cytotoxins. According to circular dichroism measurements, toxins in dimers retain in general their three-fingered folding. The functionally important disulfide 26 -30 in polypeptide loop II of ␣-cobratoxin moiety remains intact in both types of dimers. Biological activity studies showed that cytotoxins within dimers completely lose their cytotoxicity. However, the dimers retain most of the ␣-cobratoxin capacity to compete with ␣-bungarotoxin for binding to Torpedo and ␣7 nicotinic acetylcholine receptors (nAChRs) as well as to Lymnea stagnalis acetylcholine-binding protein. Electrophysiological experiments on neuronal nAChRs expressed in Xenopus oocytes have shown that ␣-cobratoxin dimer not only interacts with ␣7 nAChR but, in contrast to ␣-cobratoxin monomer, also blocks ␣3␤2 nAChR. In the latter activity it resembles -bungarotoxin, a dimer with no disulfides between monomers. These results demonstrate that dimerization is essential for the interaction of three-fingered neurotoxins with heteromeric ␣3␤2 nAChRs. Three-fingered toxins (TFTs)2 are the main components of the Elapidae snake venoms. TFTs consist of one polypeptide chain, their spatial structure being characterized by a hydrophobic core stabilized by four disulfide bridges, which confine three polypeptide loops (fingers). In cobra venom TFTs are represented mainly by ␣-neurotoxins and cytotoxins. So-called short-chain ␣-neurotoxins (60 -62 amino acid residues, 4 intramolecular disulfides) effectively block nicotinic acetylcholine receptors (nAChRs) of muscle-type, and long-chain ␣-neurotoxins (65-75 residues with an additional disulfide in central loop II) block neuronal homopentameric ␣7 nAChR as well (1, 2). These toxins are widely used as tools in the nAChR studies. Cytotoxins, structurally related to short-chain ␣-neurotoxins, manifest another activity; they non-selectively disrupt cell membranes and, thus, kill the cells (3).Another example of TFT interacting with nAChR are -bungarotoxins (-Bgts), minor components of the krait (Elapidae) venom (4, 5). All -Bgts consist of 66 amino acid residues and, similar to long-chain ␣-neurotoxins, contain five disulfide bonds. However, in contrast to ␣-neurotoxins, -Bgts practically do not block muscle-type nAChRs and only weakly act on ␣7 nAChR but with high efficiency interact with ␣3␤2 neuronal receptors (6). Despite the vast array of data on structure-activity relationship for ␣-neurotoxins and -Bgts, it is not yet clear what are the main structural features determining the specificity of a toxin to the particular receptor type. Recently, based on the x-ray structure of ␣-cobratoxin (␣-CT) with acetylcholinebinding protein, Bourne et al. (7) suggested that Lys-29 is the main residue determining the difference in specificity between ␣-neurotoxins and -bungarotoxins. However, A29K mut...

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Objectives: An important subset of patients with schizophrenia present clinically significant persistent negative symptoms (PNS). Identifying the neural substrates of PNS could help improve our understanding and treatment of these symptoms. Methods: This study included 64 non-affective first-episode of psychosis (FEP) patients and 60 healthy controls; 16 patients displayed PNS (i.e., at least one primary negative symptom at moderate or worse severity sustained for at least six consecutive months). Using voxel-based morphometry (VBM), we explored for gray matter differences between PNS and non-PNS patients; patient groups were also compared to controls. All comparisons were performed at p < 0.05, corrected for multiple comparisons. Results: PNS patients had smaller gray matter in the right frontal medial–orbital gyrus (extending into the inferior frontal gyrus) and right parahippocampal gyrus (extending into the fusiform gyrus) compared to non-PNS patients. Compared to controls, PNS patients had smaller gray matter in the right parahippocampal gyrus (extending into the fusiform gyrus and superior temporal gyrus); non-PNS patients showed no significant differences to controls. Conclusion: Neural substrates of PNS are evident in FEP patients. A better understanding of the neural etiology of PNS may encourage the search for new medications and/or alternative treatments to better help those affected.

These results suggest that many of the brain regions involved in emotional face perception, including the amygdala, are equally recruited in both schizophrenia and controls, but flat affect can also moderate activity in some other brain regions, notably in the left amygdala and parahippocampal gyrus bilaterally. There were no significant group differences in the volume of the amygdala.