Biomedical subjects

P Jolicoeur

Publications and source records attributed to P Jolicoeur.

At least 91 records · Page 5Linked to original sources

PubMed1994

Expression of human immunodeficiency virus type 1 in the nervous system of transgenic mice leads to neurological disease.

Patients infected with the human immunodeficiency virus type 1 (HIV-1) frequently develop central and peripheral nervous system complications, some of which may reflect the effect of the virus itself. In order to elucidate the pathogenic mechanisms of HIV in neurological disease in a small animal model, we generated transgenic mice expressing the entire HIV genome under control of the promoter for the human neurofilament NF-L gene. The transgene was predominantly expressed in anterior thalamic and spinal motor neurons. Animals developed a neurological syndrome characterized by hypoactivity and weakness and by axonal degeneration in peripheral nerves. These results provide evidence for a role of HIV in affecting both the central and peripheral nervous systems. This animal model may also facilitate the development of therapeutic agents against the human disease.

Animals↗

PubMed1994

Murine AIDS is initiated in the lymph nodes draining the site of inoculation, and the infected B cells influence T cells located at distance, in noninfected organs.

The infection of cells which belong to the B-cell lineage is thought to be the primary event leading to the phenotypic and functional alterations seen in the murine AIDS (M. Huang, C. Simard, D. Kay, and P. Jolicoeur, J. Virol. 65:6562-6571, 1991). Using in situ hybridization, we studied the time course of the anatomic distribution of the murine AIDS-infected B cells in C57BL/6 mice inoculated intraperitoneally or in the foot pad with helper-free stocks of the defective murine AIDS virus. The local lymph nodes draining the injection site (the mediastinal or popliteal lymph nodes) were the primary organs in which infected B cells could be detected. From this initial site, the proliferating infected B cells were found to migrate progressively to most of the other lymph nodes and to the spleen. The bone marrow cells (containing the precursor B cells) were not found to be infected by the virus. These results suggest that the defective murine AIDS virus infects mature Ly-1- B cells present in lymph nodes. We compared the concanavalin A response of the T cells at an early time postinoculation, before all lymphoid organs are infiltrated with infected B cells. In lymphoid organs free of infected B cells, T cells were found to be hyperresponsive. In lymphoid organs in which infected B cells were present, T cells were hyporesponsive. These data suggest that infected B cells influence distant T cells, maybe by the release of a circulating factor or through another uninfected cell population activated by the infected B cells.

Animals↗

PubMed1994

Myristylation of Pr60gag of the murine AIDS-defective virus is required to induce disease and notably for the expansion of its target cells.

Murine AIDS (MAIDS) is characterized by severe lymphadenopathy and splenomegaly. The proliferation of the infected target B cells is also an important manifestation of the disease (M. Huang, C. Simard, D. G. Kay, and P. Jolicoeur, J. Virol. 65:6562-6571, 1991). The etiologic agent of MAIDS is a defective murine leukemia virus that is deleted of most of its pol and env genes and appears to encode a single protein, the Gag precursor Pr60gag protein. Pr60gag is myristylated and attached to the plasma membrane. To study the role myristylation on the function of Pr60gag, we have generated a myristylation-negative (Myr-) mutant of the MAIDS defective virus. We found that Myr- Pr60gag interacted less tightly with the plasma membrane. In addition, the Myr- MAIDS defective virus mutant was unable to induce expansion of infected cells and was nonpathogenic. These results emphasize the essential role of Pr60gag in the disease process. Our data also suggest that Pr60gag, once recruited to the cell membrane through its myristylation, interacts with other membrane-bound effectors to send signals to induce proliferation of the infected cells and to initiate immune dysfunctions.

Animals↗

PubMed1994

Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice.

The CD4 protein plays a critical role in the development and function of the immune system. To gain more insight into the mechanism of expression of the human CD4 gene, we cloned 42.2 kbp of genomic sequences comprising the CD4 gene and its surrounding sequences. Studies with transgenic mice revealed that a 12.6-kbp fragment of the human CD4 gene (comprising 2.6 kbp of 5' sequences upstream of the transcription initiation site, the first two exons and introns, and part of exon 3) contains the sequences required to support the appropriate expression in murine mature CD4+ CD8- T cells and macrophages but not in immature double-positive CD4+ CD8+ T cells. Expression in CD4+ CD8+ T cells was found to require additional regulatory elements present in a T-cell enhancer fragment recently identified for the murine CD4 gene (S. Sawada and D. R. Littman, Mol. Cell. Biol. 11:5506-5515, 1991). These results suggest that expression of CD4 in mature and immature T-cell subsets may be controlled by distinct and independent regulatory elements. Alternatively, specific regulatory elements may control the expression of CD4 at different levels in mature and immature T-cell subsets. Our data also indicate that mouse macrophages contain the regulatory factors necessary to transcribe the human CD4 gene.

Animals↗

PubMed1994

Low-virulent mouse hepatitis viruses exhibiting various tropisms in macrophages, T and B cell subpopulations, and thymic stromal cells.

Functional or cellular immunodeficiencies have been reported to result from various pathogenic mouse hepatitis virus (MHV) strains. Moreover, low-virulent MHV strains can reduce the ability of mice to seroconvert to other antigens or viruses. To determine the importance of low-virulent MHV strain tropism in immune cells, as a mechanism involved in the induction of immunodeficiencies, peritoneal exudate cells, T and B cell subpopulations, and thymic stromal cells were infected with low-virulent MHV-D, MHV-K, and MHV-N and pathogenic MHV-3 viral strains. Cell viability, percentages of viral protein-expressing cells, and virus titers have been analyzed. On the basis of our findings, low-virulent MHV viral strains exhibit various tropisms in macrophages, B lymphocyte subpopulations, or thymic stromal cells when compared with the more virulent MHV-3 serotype. All MHV strains tested have replicated in peritoneal exudate cells of C57BL/6 or A/J mice. Low-virulent MHV-N and pathogenic MHV-3 strains showed higher tropism for peritoneal exudate cells than low-virulent MHV-K and MHV-D strains. Likewise, MHV-N and -3 serotypes expressed higher tropism than MHV-D or -K serotypes for thymic stromal cells and B lymphoid cells. No tropism for T lymphocytes, however, was detected with MHV except when in contact with previously infected thymic stromal cells. These results raise the problem of immunologic disorders resulting from viral replication in immune cells in mouse colonies subclinically infected with low-virulent MHV strains.

Animals↗

PubMed1993

Neurological disease induced in transgenic mice expressing the env gene of the Cas-Br-E murine retrovirus.

The Cas-Br-E murine leukemia virus induces a spongiform myeloencephalopathy in susceptible mice. We constructed transgenic mice harboring either the viral genome (in a replication-defective form) or only its env gene. Low levels of expression of either transgene resulted in mild neuropathology and/or signs of neurological disease in more than half of these mice. These results indicate that the disease can occur in the absence of virus replication and strongly suggest that the env gp70/p15E complex is sufficient to induce disease.

Animals↗

PubMed1993

Top-bottom and front-behind decisions on rotated objects.

Human adults decided whether a dot was nearer the top or bottom of rotated drawings of objects in a top-bottom task, and whether a dot was at the front of or behind rotated objects in a front-behind task. These two tasks were performed with the head upright and with the head tilted clockwise and counterclockwise in separate blocks of trials in order to dissociate retinal from environmental perceptual frames of reference. Response times increased approximately linearly with increasing departure from the orientation of the perceptual reference frame in both tasks and the magnitude of the effect was similar across tasks. In the head tilted conditions, the perceptual frame of reference was located midway between the environmental and retinal upright for both tasks.

Adolescent↗

PubMed1993

An examination of the effects of axis foreshortening, monocular depth cues, and visual field on object identification.

Four experiments are reported on the identification of line drawings of common objects. In each experiment, performance on "unconventional" views of the objects, in which the major axis of the object was foreshortened, was compared to performance on more "conventional" views without appreciable foreshortening. In each experiment, except Experiment 2, where performance on the two views was experimentally equated, the foreshortened views were more difficult to identify than were the conventional views. Experiments 1 and 2 showed that if the foreshortened views were presented on a background with strong monocular depth cues, object identification was improved. This result suggests that part of the difficulty in identifying objects depicted from such a view stems from an improper depth interpretation of the object depictions. Experiments 3 and 4 examined visual field differences in the identification of the two types of object view. Results reported in the neuropsychological literature have shown that people with right-hemisphere damage have particular difficulty with the identification of unconventional views of objects that foreshorten major axes. Accordingly, it was expected that there would be a left visual field advantage for the foreshortened views. Neither experiment yielded any visual field effects consistent with this expectation. Possible reasons for the lack of a field effect are discussed.

Cues↗

PubMed1993

Long-range mapping of Mis-2, a common provirus integration site identified in murine leukemia virus-induced thymomas and located 160 kilobase pairs downstream of Myb.

The nondefective Moloney murine leukemia virus (MuLV) induces clonal or oligoclonal T-cell tumors in mice or rats. The proviruses of these nondefective MuLVs have been shown to act as insertion mutagens most frequently activating an adjacent cellular gene involved in cell growth control. Mutations by provirus insertions, recognized as common provirus integration sites, have been instrumental in identifying novel cellular genes involved in tumor formation. We have searched for new common provirus integration sites in Moloney MuLV-induced thymomas. Using cellular sequences flanking a provirus cloned from one of these tumors, we found one region, designated Mis-2, which was the target of provirus integration in a low (3%) percentage of these tumors. Mis-2 was mapped on mouse chromosome 10, approximately 160 kbp downstream of myb. The Mis-2 region may contain a novel gene involved in tumor development.

Animals↗

PubMed1993

Identification of the infected target cell type in spongiform myeloencephalopathy induced by the neurotropic Cas-Br-E murine leukemia virus.

The Cas-Br-E murine leukemia virus (MuLV) induces a progressive hindlimb paralysis accompanied by a spongiform myeloencephalopathy in susceptible mice. In order to better understand the pathological process leading to these neurodegenerative lesions, we have investigated the nature of the cell type(s) infected by the virus during the course of the disease in CFW/D and SWR/J mice. For this purpose, we used in situ hybridization with virus-specific probes in combination with cell-type-specific histochemical (lectin) and immunological markers as well as morphological assessment. In the early stage of infection, endothelial cells represented the main cell type expressing viral RNA in the central nervous system (CNS). With disease progression and the appearance of lesions, microglial cells became the major cell type infected, accounting for up to 65% of the total infected cell population in diseased areas. Morphologically, these cells appeared activated and were frequently found in clusters. Infection and activation of microglial cells were almost exclusively restricted to diseased regions of the CNS. Neurons in diseased regions were not discernibly infected with virus at either early or late times of disease progression. Similarly, the proportion of infected astrocytes was typically < 1%. Although some endothelial cells and oligodendrocytes were infected by the virus, their infection was not limited to diseased CNS regions. These results are consistent with a model of indirect motor neuron degeneration, subsequent to the infection of nonneuronal CNS cells and especially of microglial cells. Infected microglial cells may play a role in the disease process by releasing not only virions or viral env-gene-encoded gp70 proteins but also other factors which may be directly or indirectly toxic to neurons. Parallels between microglial cell infection by MuLV and by lentiviruses, and specifically by human immunodeficiency virus, are discussed.

Animals↗

PubMed1993

Orientation-invariant transfer of training in the identification of rotated natural objects.

The effects of stimulus orientation on naming were examined in two experiments in which subjects identified line drawings of natural objects following practice with the objects at the same or different orientations. Half the rotated objects were viewed in the orientation that matched the earlier presentations, and half were viewed at an orientation that mismatched the earlier presentations. Systematic effects of orientation on naming time were found during the early presentations. These effects were reduced during later presentations, and the size of this reduction did not depend on the orientation in which the object had been seen originally. The results are consistent with a dual-systems model of object identification in which initially large effects of disorientation are the result of a normalization process such as mental rotation, and in which attenuation of the effects is due to a shift from the normalization system to a feature/part-based system.

Adult↗

PubMed1993

Perceptual versus postperceptual mediation of visual context effects: evidence from the letter-superiority effect.

Two experiments demonstrated letter-context effects that cannot easily be accounted for by postperceptual theories based on structural redundancy, figural goodness, or memory advantage. In Experiment 1, subjects identified the color of a letter fragment more accurately in letter than in nonletter contexts. In Experiment 2, subjects identified the feature presented in a precued color more accurately in letters than in nonletters. We argue that these effects result from top-down perceptual processing.

Adult↗

PubMed1993

The Vin-1 gene, identified by provirus insertional mutagenesis, is the cyclin D2.

The Vin-1 gene was initially identified as a gene whose expression is altered by the integration of proviruses in the Vin-1 common site of integration in retrovirus-induced rodent T-cell leukemias. We have now isolated the Vin-1 cDNA. Sequencing of the Vin-1 cDNA and Vin-1 exons revealed that the proviruses are integrated at the 5' end of the Vin-1 gene in an inverse transcriptional orientation. The sequence of the Vin-1 gene is identical to that of the recently identified G1-phase cyclin D2 gene. The human homolog of the Vin-1/cyclin D2 gene (CCND2) was mapped to chromosome 12, band p13.3, by in situ hybridization, confirming previous mapping data. Our results strongly support a role of the cyclin D2 gene in oncogenesis and thereby implicate altered cell cycle regulation in transformation.

Amino Acid Sequence↗

PubMed1992

Mental rotation, physical rotation, and surface media.

Subjects made mirror-normal discriminations on alphanumeric characters shown in different orientations in the picture plane. Either the characters or the background rotated during stimulus presentation in Experiments 1-3. Character rotation in the direction of mental rotation facilitated mental rotation, whereas rotation in the opposite direction inhibited it. In Experiment 4, characters were presented in different surface media so as to stimulate only one representation at a time. Mental rotation performance was similar whether the stimuli were defined by luminance, color, texture, relative motion, or binocular disparity, suggesting that mental rotation occurs at a level beyond that of the independent analyses of these different media. These results support those of Experiments 1-3 in excluding the participation of low-level motion analysis centers in the mental rotation processes.

Adult↗

PubMed1992

Reference frame and effects of orientation on finding the tops of rotated objects.

Effects of stimulus orientation across trial blocks and the spatial reference frame were investigated with a task in which Ss, with their head upright or tilted, judged a dot to be near the top or the bottom of rotated line drawings of objects. Objects used in this task were also named. Response times from the first block of trials increased linearly for objects rotated from 0 degrees to 120 degrees from the upright. Across blocks, orientation effects diminished for naming but remained the same for top-bottom discriminations. Practice with top-bottom discriminations diminished orientation effects when the same objects were subsequently named. The spatial reference frame for top-bottom discriminations was midway between retinal and environmental coordinates. Specifying the location of object features is of greater importance for top-bottom discriminations than for naming and underlies orientation effects in these tasks.

Adult↗

PubMed1992

Orientation congruency effects in visual search.

Subjects searched for the letter E in a background of Ls and Fs in displays that had 1, 2, 4, 8, or 12 letters. The letters could be shown at one of six orientations (upright or rotated clockwise in 60 degrees increments). The displays were either congruent for orientation (all letters had the same orientation) or incongruent (letters in haphazard orientations except for the target on E-present trials). Search time increased linearly with the number of letters in the display, and more so for E-absent trials than for E-present trials. Letter orientation, in general, increased search time and produced an M-shaped function. Furthermore, orientation effects were attenuated in congruent displays relative to those produced by incongruent displays. The results demonstrated systematic orientation effects on the time to search for a simple pattern embedded in simple backgrounds, and provided converging evidence for the orientation-congruency effect found by Jolicoeur (1990b, Journal of Experimental Psychology: Human Perception and Performance, 16, 351-364).

Adult↗

PubMed1992

U3 long terminal repeat-mediated induction of intracellular immunity by a murine retrovirus: a novel model of latency for retroviruses.

BL/VL3 radiation leukemia virus (RadLV) is a thymotropic, highly leukemogenic murine leukemia virus (MuLV) which is unable to replicate in vitro in mouse fibroblasts. We have previously reported that the U3 long terminal repeat region of its genome is responsible for this block (E. Rassart, Y. Paquette, and P. Jolicoeur, J. Virol. 62:3840-3848, 1988). By using hybrids of permissive and resistant cells infected with BL/VL3 RadLV or fibrotropic MuLV, we found that the resistant phenotype was dominant. Investigation to determine at which step of the virus cycle the block operates revealed that integration, transcription, and translation of the BL/VL3 viral genome occurred at normal levels in nonpermissive cells. The BL/VL3 RadLV Pr65gag proteins made in nonpermissive cells were also myristylated and located at the membrane, and the levels of their cleaved products were similar to those of fibrotropic MuLV. However, processing of BL/VL3 RadLV Pr85env was impaired in nonpermissive cells. Virions were not released into the culture medium of nonpermissive cells, as measured by reverse transcriptase activity and by content in p30 or gp70 protein and as documented by lower levels of budding particles seen by electron microscopy. These results indicate that BL/VL3 RadLV replication is blocked at a late stage of the virus cycle, i.e., at virion assembly. Interestingly, these BL/VL3 RadLV-infected nonpermissive fibroblasts were resistant to superinfection by fibrotropic Moloney MuLV, and this resistance also occurred at a late step of the Moloney virus cycle. Since this block is dominant, it appears that the U3 long terminal repeat region of the BL/VL3 viral genome has the ability to induce a cellular suppressor factor(s), thus bringing intracellular immunity against itself and against other ecotropic MuLVs.

Animals↗

PubMed1992

Identification of a novel gene, Vin-1, in murine leukemia virus-induced T-cell leukemias by provirus insertional mutagenesis.

The BL/VL3 radiation leukemia virus is a nondefective retrovirus which induces clonal or oligoclonal T-cell leukemia in mice. To study the role of provirus insertional mutagenesis in the development of these neoplasias, we searched for common provirus integration sites in BL/VL3 radiation leukemia virus-induced tumors. Using cellular sequences flanking a provirus cloned from one of these thymomas, we found that the viral genome was integrated into a common region, designated Vin-1, in a low percentage (5%) of these tumors. The proviruses found in this locus were integrated in the same orientation, close to a CpG-rich island, at proximity of a transcriptional unit encoding a 6-kb RNA. Vin-1 RNA was detected in several organs of the adult mouse. Vin-1 RNA levels were high in tumors having a provirus inserted within the Vin-1 region but were also high in some other tumors whose Vin-1 region was not found to be rearranged. Vin-1 was found to be well conserved among mammalian species and was mapped to mouse chromosome 6, between raf and K-ras-2. Vin-1 appears to be a novel gene which may be involved in tumor development.

Animals↗