The HIV-1 Nef protein is known to be secreted, and our group has shown that Nef is secreted from nef-transfected and HIV-1-infected cells in small exosome-like vesicles (d. 40-100 nm). The role of secreted Nef remains to be fully characterized. Thus, it is important to characterize the nature of and the mechanisms regulating Nef secretion. We hypothesized that specific structural domains on the Nef protein interact with components of the endosomal trafficking machinery, sorting Nef into multivesicular bodies (MVB) and packaging it in exosome-like vesicles. To identify those domains, a series of mutants spanning the entire nef sequence were made and cloned into the expression vector pQB1, which expresses the mutants as Nef-GFP fusion proteins. These constructs were used in transient transfection assays to identify sequences necessary for secretion of the Nef-GFP fusion protein. N-terminal domains were identified as critical for Nef-induced vesicle secretion: (1) a basic cluster of four arginine residues (aa 17, 19, 21, 22), (2) the phosphofurin acidic cluster sequence (PACS; Glu62-65), and (3) a previously uncharacterized domain spanning amino acid residues 66-70 (VGFPV), which we named the secretion modification region (SMR). Additional amino acids P25, 29GVG31, and T44 were identified in HIV-1 Nef as regulating its secretion. These residues have not been associated with other reported Nef functions. The myristoylation domain, ubiquitination lysine residues, and the C-terminal portion of Nef (aa 71-206) had no effect on secretion. A minimal HIV-1 Nef sequence, comprising the identified motifs, was sufficient for Nef-induced vesicle secretion.

The aim of this pilot study was to investigate whether children with a suspected auditory processing disorder (sAPD) in the presence of normal hearing, differ significantly from normal age-matched controls on particular parameters of auditory event-related potentials. We assessed nine children (mean age 9.5 years) in whom the clinical profile and the results in a screening test for auditory processing disorder (SCAN/SCAN-A) suggested the presence of an auditory processing disorder, and nine age-matched normal control subjects, using auditory event-related potentials (ERP) to phonemes/ba/(standard) and/da/(deviant). Analysis of the auditory ERP recordings revealed an enlarged P85 - 120 and attenuated N1 and P2 in all sAPD children compared to controls. We also found significantly increased N1 peak latency, and a larger peak to peak amplitude of the P85 - 120-N1 and P2-N2 and smaller peak to peak amplitude of the N1-P2 in the sAPD children. Subtraction of the standard auditory ERP from the deviant revealed a mismatch negativity with no significant differences in duration, peak or onset latency between the control subjects and sAPD. Our results indicate that neurophysiological measures may identify a group of children with specific problems suggestive of an auditory processing disorder in the absence of an obvious structural or functional lesion who warrant further study in order to assess whether these findings reflect delayed CNS myelination.

Sixty rats were trained in a runway with either small-or large-reward magnitude. Both small and large rewards were presented in single-or multiplepellet form. One training trial was given each day for 120 days. Early in training the large-reward animals ran faster than those receiving small reward and the effect was more pronounced in the multiple-pellet condition. Later in training the small-reward animals equaled the performance of the animals receiving large reward and even ran somewhat faster in the run section of the alley. The typical extinction effect of greater persistence for smallreward animals was observed, but only in the goal section.Both Black (1969) and McCain, Dyleski, and McElvain (1971) have published several experiments seriously questioning the long-held assumption that instrumental performance increases in strength with increases in reward magnitude. McCain et al. compared large (one 500-mg. pellet) and small (one 45-mg. pellet) reward in a runway after 24, 54, 60, 70, 78, 90, 116, or 135 training trials. They reported that large reward facilitated running speeds after limited training (24 trials) but that the effect was minimal or nonexistent after extended training (54-135 trials). The typical extinction finding of greater persistence after training with small reward than after large reward was observable somewhat longer. McCain et al. reported extinction differences to be reliable after 24-90 trials but not after 116 or 135 trials.Most of the experiments reviewed by

Four groups of rats were trained in a runway for 28 days on one of the following schedules: consistent reward (CRF), alternating partial reward (A), alternating partial reward followed by consistent reward (A-CRF), and an irregular partial reward schedule (I). Both Groups A and A-CRF learned to run faster on rewarded trials than on ronrewarded trials and Group A-CRF quickly learned to run rapidly on all trials after being shifted to consistent reward. Resistance to extinction was greatest for Groups A-CRF and I, with Groups A and CRF extinguishing much more rapidly. These results support a hypothesis which suggests that a sequence discrimination present at the outset of extinction will reduce resistance to extinction relative to schedules, with similar parameters, that do not result in or maintain a sequence discrimination.

3 experiments are reported on the reinstatement of a bar-press response by rats during free operant extinction. After extended training on a VR schedule of food reward, an extinction procedure in which reward was negatively correlated with the bar-press response was initiated, i.e., reward was presented after 4 min of no bar presses. Results indicated that pause-contingent reward served to increase the rate of responding beyond what could be explained by the eliciting properties of reward-correlated stimuli or the “novelty” of stimulus change.