Some recent evidence has suggested abnormalities of the dorsal stream and possibly the mirror neuron system in autism, which may be responsible for impairments of joint attention, imitation, and secondarily for language delays. The current study investigates functional connectivity along the dorsal stream in autism, examining interregional blood oxygenation level dependent (BOLD) signal cross-correlation during visuomotor coordination. Eight high-functioning autistic men and 8 handedness and age-matched controls were included. Visually prompted button presses were performed with the preferred hand. For each subject, functional connectivity was computed in terms of BOLD signal correlation with the mean time series in bilateral visual area 17. Our hypothesis of reduced dorsal stream connectivity in autism was only in part confirmed. Functional connectivity with superior parietal areas was not significantly reduced. However, the autism group showed significantly reduced connectivity with bilateral inferior frontal area 44, which is compatible with the hypothesis of mirror neuron defects in autism. More generally, our findings suggest that dorsal stream connectivity in autism may not be fully functional.

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Plasmodium falciparum-derived cysteine protease falcipain-2 cleaves host erythrocyte hemoglobin at acidic pH and specific components of the membrane skeleton at neutral pH. Analysis of stage-specific expression of these 2 proteolytic activities of falcipain-2 shows that hemoglobinhydrolyzing activity is maximum in early trophozoites and declines rapidly at late stages, whereas the membrane skeletal protein hydrolyzing activity is markedly increased at the late trophozoite and schizont stages. Among the erythrocyte membrane skeletal proteins, ankyrin and protein 4.1 are cleaved by native and recombinant falcipain-2 near their C-termini. To identify the precise peptide sequence at the hydrolysis site of protein 4.1, we used a recombinant construct of protein 4.1 as substrate followed by MALDI-MS analysis of the cleaved product. We show that falcipain-2-mediated cleavage of protein 4.1 occurs immediately after lysine 437, which lies within a region of the spectrinactin-binding domain critical for erythrocyte membrane stability. A 16-mer peptide containing the cleavage site completely inhibited the enzyme activity and blocked falcipain-2-induced fragmentation of erythrocyte ghosts. Based on these results, we propose that falcipain-2 cleaves hemoglobin in the acidic food vacuole at the early trophozoite stage, whereas it cleaves specific components of the red cell skeleton at the late trophozoite and schizont stages. It is the proteolysis of skeletal proteins that causes membrane instability, which, in turn, facilitates parasite release in vivo. IntroductionPlasmodium falciparum causes the most severe form of human malaria and is becoming increasingly resistant to available antimalarial drugs. New chemotherapy-based approaches to fight the disease are therefore urgently needed. Parasite proteases that are involved in P falciparum development appear to be good targets. Mounting evidence suggests that cysteine proteases are involved in host cell rupture and release of merozoites. In the presence of such inhibitors, merozoites mature normally but are unable to escape from host erythrocytes. [1][2][3][4] The cluster of merozoites inside a red blood cell (RBC) is enclosed within 2 membranes: an inner parasitophorous vacuole membrane (PVM) and an outer RBC membrane. The rupture of these 2 membranes apparently releases the merozoites for another round of RBC invasion. In a recent study by Salmon et al,5 the authors propose a 2-step process for parasite release from the host erythrocyte: an initial exit of merozoites enclosed within the PVM followed by a rapid escape from the PVM by a proteolysisdependent mechanism. This study suggests that the RBC membrane is lost independently of the PVM. In another report, Winograd et al 6 used videomicroscopy to study the release of merozoites and concluded that an aperture is made through the PVM and RBC membranes to allow merozoites to exit in an orderly fashion. Merozoites were released together with the residual body containing hemozoin, leaving behind the red cell membrane and some...

Personal pronouns, such as 'I' and 'you', require a speaker/listener to continuously re-map their reciprocal relation to their referent, depending on who is saying the pronoun. This process, called 'deictic shifting', may underlie the incorrect production of these pronouns, or 'pronoun reversals', such as referring to oneself with the pronoun 'you', which has been reported in children with autism. The underlying neural basis of deictic shifting, however, is not understood, nor has the processing of pronouns been studied in adults with autism. The present study compared the brain activation pattern and functional connectivity (synchronization of activation across brain areas) of adults with high-functioning autism and control participants using functional magnetic resonance imaging in a linguistic perspective-taking task that required deictic shifting. The results revealed significantly diminished frontal (right anterior insula) to posterior (precuneus) functional connectivity during deictic shifting in the autism group, as well as reliably slower and less accurate behavioural responses. A comparison of two types of deictic shifting revealed that the functional connectivity between the right anterior insula and precuneus was lower in autism while answering a question that contained the pronoun 'you', querying something about the participant's view, but not when answering a query about someone else's view. In addition to the functional connectivity between the right anterior insula and precuneus being lower in autism, activation in each region was atypical, suggesting over reliance on individual regions as a potential compensation for the lower level of collaborative interregional processing. These findings indicate that deictic shifting constitutes a challenge for adults with high-functioning autism, particularly when reference to one's self is involved, and that the functional collaboration of two critical nodes, right anterior insula and precuneus, may play a critical role for deictic shifting by supporting an attention shift between oneself and others.

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We constructed a series of human immunodeficiency virus 1 (HIV-1)/simian immunodeficiency virus strain mac (SIVmac) chimeric viruses having vpr and/or nef genes of either HIV-1 or SIVmac based on a chimeric virus with LTRs, gag, pol, vif and vpx derived from SIVmac and tat, rev, vpu and env from HIV-1. All of the chimeric viruses replicated in human and macaque peripheral blood mononuclear cells (PBMCs) and in several CD4 + human cell lines, though their growth potentials were slightly different depending on whether vpr and nef were from HIV-1 or SIVmac, or were defective. The presence of nefaccelerated replication in all the cells used and the replication of each chimera appeared to reflect that of the parental virus from which nefwas derived. The presence of vpr had no clear effect in human and monkey PBMCs, but the replication of each chimera was influenced by the origin of vpr in H9 and A3.01 cells. NM-3rN, which carries HIV-1 vpr and SIVmac nef was inoculated intravenously into three rhesus monkeys, three cynomolgus monkeys and two pig-tailed monkeys. From 2 to 14 weeks after inoculation, viruses were consistently re-isolated from all the monkeys and virus loads were as high as that of SIVmac reported previously. The results indicate that infection with NM-3rN is more efficient than any of our previous chimeric viruses and suggest that NM-3rN, having HIV-1 Env, will be a useful challenge virus for evaluating AIDS vaccines based on HIV-1 Env in macaque monkeys instead of chimpanzees.

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