Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

Does Kin Recognition and Sib-Mating Avoidance Limit the Risk of Genetic Incompatibility in a Parasitic Wasp?

Background: When some combinations of maternal and paternal alleles have a detrimental effect on offspring fitness, females should be able to choose mates on the basis of their genetic compatibility. In numerous Hymenoptera, the sex of an individual depends of the allelic combination at a specific locus (single-locus Complementary Sex Determination), and in most of these species individuals that are homozygous at this sexual locus develop into diploid males with zero fitness. Methods and Findings: In this paper, we tested the hypothesis of genetic incompatibility avoidance by investigating sibmating avoidance in the solitary wasp parasitoid, Venturia canescens. In the context of mate choice we show, for the first time in a non-social hymenopteran species, that females can avoid mating with their brothers through kin recognition. In ‘‘no-choice’ ’ tests, the probability a female will mate with an unrelated male is twice as high as the chance of her mating with her brothers. In contrast, in choice tests in small test arenas, no kin discrimination effect was observed. Further experiments with male extracts demonstrate that chemical cues emanating from related males influence the acceptance rate of unrelated males. Conclusions: Our results are compatible with the genetic incompatibility hypothesis. They suggest that the female wasps recognize sibs on the basis of a chemical signature carried or emitted by males possibly using a ‘‘self-referent phenotyp

Formation of Trans-Activation Competent HIV-1 Rev:RRE Complexes Requires the Recruitment of Multiple Protein Activation Domains

The HIV-1 Rev trans-activator is a nucleocytoplasmic shuttle protein that is essential for virus replication. Rev directly binds to unspliced and incompletely spliced viral RNA via the cis-acting Rev Response Element (RRE) sequence. Subsequently, Rev oligomerizes cooperatively and interacts with the cellular nuclear export receptor CRM1. In addition to mediating nuclear RNA export, Rev also affects the stability, translation and packaging of Rev-bound viral transcripts. Although it is established that Rev function requires the multimeric assembly of Rev molecules on the RRE, relatively little is known about how many Rev monomers are sufficient to form a trans-activation competent Rev:RRE complex, or which specific activity of Rev is affected by its oligomerization. We here analyzed by functional studies how homooligomer formation of Rev affects the trans-activation capacity of this essential HIV-1 regulatory protein. In a gain-of-function approach, we fused various heterologous dimerization domains to an otherwise oligomerization-defective Rev mutant and were able to demonstrate that oligomerization of Rev is not required per se for the nuclear export of this viral trans-activator. In contrast, however, the formation of Rev oligomers on the RRE is a precondition to trans-activation by directly affecting the nuclear export of Rev-regulated mRNA. Moreover, experimental evidence is provided showing that at least two protein activation domains are required for the formation of trans-activation competent Rev:RRE complexes. The presented data further refine the model of Rev trans-activation by directly demonstrating that Rev oligomerization on the RRE, thereby recruiting at least two protein activation domains, is required for nuclear export of unspliced and incompletely spliced viral RNA

Reverse transcriptase activity and Ty RNA are associated with virus-like particles in yeast.

The Ty element of yeast represents a class of eukaryotic transposons that show remarkable structural similarity to retroviral proviruses. Recently, these comparisons have been strengthened by a series of observations on the yeast Ty element: Ty transposes via an RNA intermediate; it contains a sequence (Fig. 1) which, when translated, is homologous to a conserved region found in all reverse transcriptases; a fusion protein encoded by Ty is produced by a frameshift event that is directly analogous to the production of Pr180gag-pol in a retrovirus such as Rous sarcoma virus. Here we identify the reverse transcriptase activity that, until now, has been presumed to mediate Ty transposition and show that it is sequestered in virus-like particles that also contain Ty RNA

Heteroplasmy due to chloroplast paternal leakage: another insight into Phragmites haplotypic diversity in North America

Chloroplasts contain several copies of their DNA, and intra-individual haplotypic variation (heteroplasmy) is common in plants, but unexplored in the cosmopolitan genus Phragmites. The aims of this study were to assess if heteroplasmy due to paternal leakage of the chloroplast occurs in Phragmites and which new insights into the evolutionary history of Phragmitesaustralis in North America can be identified from the heteroplasmic variation. Eight non-native P. australis haplotypes occur in North America and can interbreed with P. australis ssp. americanus and P. australis var. berlandieri, creating opportunities for biparental inheritance of distinctive haplotypes. The polymorphism in the trnT-trnL sequence length revealed seventeen cases of heteroplasmy worldwide, in contact zones of distantly related haplotypes and in known hybrid populations, nine of which occurred in North America. In America, the cloned sequences, combined with nuclear markers, identified recombined haplotypes between native P. australis ssp. americanus and invasive P. australis haplotype M, and between the species P. mauritianus and P. australis, due to chloroplast paternal leakage. The occurrence of heteroplasmy and recombined haplotypes suggest a local origin for some of the rare non-native haplotypes occurring in North America, and plastid leakage events in the evolutionary histories of P. australis ssp. americanus and P. australis var. berlandieri