A new type of IRES within gag coding region recruits three initiation complexes on HIV-2 genomic RNA

Genomic RNA of primate lentiviruses serves both as an mRNA that encodes Gag and Gag-Pol polyproteins and as a propagated genome. Translation of this RNA is initiated by standard cap dependant mechanism or by internal entry of the ribosome. Two regions of the genomic RNA are able to attract initiation complexes, the 5′ untranslated region and the gag coding region itself. Relying on probing data and a phylogenetic study, we have modelled the secondary structure of HIV-1, HIV-2 and SIVMac coding region. This approach brings to light conserved secondary-structure elements that were shown by mutations to be required for internal entry of the ribosome. No structural homologies with other described viral or cellular IRES can be identified and lentiviral IRESes show many peculiar properties. Most notably, the IRES present in HIV-2 gag coding region is endowed with the unique ability to recruit up to three initiation complexes on a single RNA molecule. The structural and functional properties of gag coding sequence define a new type of IRES. Although its precise role is unknown, the conservation of the IRES among fast evolving lentiviruses suggests an important physiological role

Induction of lateralized spatial bias among normal subjects

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Multimodal virtual reality application for the study of unilateral spatial neglect

In the present paper, we describe a virtual reality application developed for the study of unilateral spatial neglect, a post-stroke neurological disorder that results in failure to respond to stimuli presented contralaterally to the damaged hemisphere. Recently, it has been proposed that patients with unilateral spatial neglect experience sensorimotor decorrelation in the affected space. Consequently, it is possible that since the sensorimotor experience in the affected space is perturbed, patients avoid this space, which results in neglect behavior. Here, we evaluate this hypothesis using a virtual reality application built on the base of the Stringed Haptic Workbench, a large-scale visuo-haptic system. The results provide support for the hypothesis and demonstrate that the proposed application is suitable for the envisioned goal

Uses of virtual reality for diagnosis, rehabilitation and study of unilateral spatial neglect: review and analysis

International audienceUnilateral spatial neglect is a disabling condition frequently occurring after stroke. People with neglect suffer from various spatial deficits in several modalities, which in many cases impair everyday functioning. A successful treatment is yet to be found. Several techniques have been proposed in the last decades, but only a few showed long-lasting effects and none could completely rehabilitate the condition. Diagnostic methods of neglect could be improved as well. The disorder is normally diagnosed with pen-and-paper methods, which generally do not assess patients in everyday tasks and do not address some forms of the disorder. Recently, promising new methods based on virtual reality have emerged. Virtual reality technologies hold great opportunities for the development of effective assessment and treatment techniques for neglect because they provide rich, multimodal, and highly controllable environments. In order to stimulate advancements in this domain, we present a review and an analysis of the current work. We describe past and ongoing research of virtual reality applications for unilateral neglect and discuss the existing problems and new directions for development

INT6 interacts with MIF4GD/SLIP1 and is necessary for efficient histone mRNA translation.

International audienceThe INT6/EIF3E protein has been implicated in mouse and human breast carcinogenesis. This subunit of the eIF3 translation initiation factor that includes a PCI domain exhibits specific features such as presence in the nucleus and ability to interact with other important cellular protein complexes like the 26S proteasome and the COP9 signalosome. It has been previously shown that INT6 was not essential for bulk translation, and this protein is considered to regulate expression of specific mRNAs. Based on the results of a two-hybrid screen performed with INT6 as bait, we characterize in this article the MIF4GD/SLIP1 protein as an interactor of this eIF3 subunit. MIF4GD was previously shown to associate with SLBP, which binds the stem-loop located at the 3' end of the histone mRNAs, and to be necessary for efficient translation of these cell cycle-regulated mRNAs that lack a poly(A) tail. In line with the interaction of both proteins, we show using the RNA interference approach that INT6 is also essential to S-phase histone mRNA translation. This was observed by analyzing expression of endogenous histones and by testing heterologous constructs placing the luciferase reporter gene under the control of the stem-loop element of various histone genes. With such a reporter plasmid, silencing and overexpression of INT6 exerted opposite effects. In agreement with these results, INT6 and MIF4GD were observed to colocalize in cytoplasmic foci. We conclude from these data that INT6, by establishing interactions with MIF4GD and SLBP, plays an important role in translation of poly(A) minus histone mRNAs

The proteolytic cleavage of eukarytic initiation factor (eIF0 4G is prevented by eIF4E binding protein (PHAS-I; 4E-BP1) in the reticulocyte lysate

A common feature of viral infection is the subversion of the host cell machinery towards the preferential translation of viral products. In some instances, this is partly mediated by the expression of virally encoded proteases which lead to the cleavage of initiation factor eIF4G. The foot-and-mouth disease virus encodes two forms of a cysteine proteinase (L protease) which bisects the eIF4G polypeptide into an N-terminal fragment containing the eIF4E binding site, and a C-terminal fragment which contains binding sites for eIF4A and eIF3 and which associates with the 40S ribosomal subunit. Previously, we have demonstrated that the cleavage of eIF4G by L protease stimulates the translation of uncapped transcripts encoding cellular proteins and supports internal initiation driven by picornavirus internal ribosome entry segment (IRES) elements. Use of reticulocyte lysates manipulated to deplete them of eIF4E and the N-terminal fragment suggests that the C-terminal fragment of eIF4G is responsible for these effects, and we have now confirmed this by purifying the C-terminal fragment and analysing its effects directly in the absence of L protease. Interestingly, we find that pre-incubation of reticulocyte lysates or ribosomal salt wash fractions with the specific eIF4E binding protein, PHAS-I (eIF4E-BP1), blocks the proteolytic cleavage of eIF4G by L protease. This effect can be reversed by addition of recombinant eIF4E. These data are consistent with a model whereby the L protease cleavage site in eIF4G is inaccessible until a change in conformation is induced by the binding of eIF4E. This may have implications for a role for eIF4E binding in triggering changes that expose other domains in the eIF4G molecule during initiation of translation

The Leader of Human Immunodeficiency Virus Type 1 Genomic RNA Harbors an Internal Ribosome Entry Segment That Is Active during the G(2)/M Phase of the Cell Cycle

The 5′ leader of the human immunodeficiency virus type 1 (HIV-1) genomic RNA contains highly structured domains involved in key steps of the viral life cycle. These RNA domains inhibit cap-dependent protein synthesis. Here we report that the HIV-1 5′ leader harbors an internal ribosome entry site (IRES) capable of driving protein synthesis during the G(2)/M cell cycle phase in which cap-dependent initiation is inhibited. The HIV-1 IRES was delineated with bicistronic mRNAs in in vitro and ex vivo assays. The HIV-1 leader IRES spans nucleotides 104 to 336 and partially overlaps the major determinants of genomic RNA packaging. These data strongly suggest that, as for HIV-1 transcription, IRES-mediated translation initiation could play an important role in virus replication during virus-induced G(2)/M cell cycle arrest