Biomedical subjects

P Jolicoeur

Publications and source records attributed to P Jolicoeur.

At least 19 recordsLinked to original sources

PubMed2006

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice.

Dysregulated expression of the homeobox gene, HOX11 is a frequent etiologic event in T-cell acute lymphoblastic leukemias. HOX11-transgenic mice (IgHmu-HOX11Tg)-expressing HOX11 in the B-cell compartment develop B-cell lymphomas with extended latency. The latency suggests that additional genetic events are required prior to the onset of malignant lymphoma. We report the identification of 17 HOX11 collaborating genes, revealed through their propensity to be targeted in a proviral insertional mutagenesis screen. Seven integrations disrupted genes in mitotic spindle checkpoint control, suggesting that cells with elevated HOX11 expression are especially sensitive to dysregulation of chromosome segregation during mitosis. IgHmu-HOX11Tg primary B-lymphocyte cultures exposed to the aneugenic agents, colchicine and colcemid, exhibited increased incidences of chromosome missegregation as assessed by cytokinesis-block micronucleus assays. Additionally, IgHmu-HOX11Tg cultures were shown to exhibit aberrant bypass of spindle checkpoint arrest, as assessed by the increased presence of cycling cells determined by assessment of DNA content and by BrdU immunolabelling. Western immunoblotting revealed elevated expression of the mitotic effector molecules, cyclin A, cyclin B1 and cdc20 in IgHmu-HOX11Tg cultures. Moreover, spontaneously arising lymphoid neoplasms in IgHmu-HOX11Tg mice frequently exhibit aberrant expression of mitotic regulators, concomitant with increased development of micronuclei, abnormal mitotic checkpoint control and increased incidences of abnormal karyotypes when expanded in culture. Collectively, these findings indicate that abnormal regulation of spindle checkpoint control as a result of HOX11 overexpression leads to a heightened predisposition for development of aneuploidy, contributing to oncogenesis.

Animals↗

PubMed2006

Spatial attention freezes during the attention blink.

A variant of the rapid serial visual presentation paradigm was used to display sequentially two lateral sequences of stimuli, one to the left and one to the right of fixation, embedding two pairs of target stimuli, T1 and T2. T1 was composed of a pair of alphanumeric characters, and subjects had either to ignore T1 or to encode T1 for a delayed response. T2 was a lateral square of a prespecified color. The square had a small gap in one side, and the task for this stimulus was to report which side had the gap. When subjects were required to ignore T1, the T2-locked ERP produced a clear N2pc, that is, a greater negativity at electrode sites contralateral to the position occupied by T2. This N2pc was followed by a sustained posterior contralateral negativity (SPCN). When subjects were required to monitor T1 in addition to T2, both the N2pc and the SPCN components amplitude depended on the difficulty of the task associated with T1. If T1 was composed of digits that had to be encoded for a delayed same/different judgment, both the N2pc and the SPCN components were entirely suppressed. Although attenuated, such components were present when T1 was composed of a pair of symbols that subjects could disregard. The results suggest that a set of mechanisms subserving the allocation of attention in the spatial domain, resulting in the N2pc, suffer significant interference from concurrent cognitive operations required to encode information into visual short-term memory.

Adult↗

PubMed2005

Central processing overlap modulates P3 latency.

Two experiments examined the issue of the functional mechanisms exerting a modulatory effect on the latency of the P3. In experiment 1, using a psychological refractory period (PRP) paradigm, two sequential stimuli (T(1) and T(2)) were presented in each trial at varying stimulus onset asynchronies (SOAs), each requiring a speeded choice response. Substantial lengthening of the reaction time to T(2) was observed as SOA decreased (i.e., PRP effect). A systematic investigation of the T(2)-locked P3 component amplitude and latency was undertaken to discover whether either of these P3 parameters was correlated with the PRP effect. The results showed lengthening of the T(2)-locked P3 component latency as SOA was decreased, and, across subjects, a positive correlation between the PRP effect and P3 latency lengthening. No SOA-dependent P3 amplitude variation was observed. In experiment 2, the P3 component was measured under single-task conditions. P3 amplitude was higher under single-task than under dual-task conditions, but no SOA-dependent latency variations were observed in this experiment. Overall, the results of both experiments support the notion that part of the processing reflected in P3 activity occurs at or after the locus of the PRP effect, thus suggesting strongly that central mechanisms are involved in P3 latency variations.

Adult↗

PubMed2004

Expression and analysis of the Epstein-Barr virus BARF1-encoded protein from a tetracycline-regulatable adenovirus system.

Epstein-Barr virus (EBV) has been associated with human cancers of lymphocytic or epithelial origin. Potential functions of the BARF1 early gene in EBV oncogenesis emerged from our observations showing expression of BARF1-encoded protein in nasopharyngeal carcinoma biopsies, and induction of either malignant transformation (in rodent fibroblast and human B cell lines) or immortalization (in monkey primary epithelial cells) following BARF1 transfection. We previously reported expression of the BARF1 product as a cytoplasm/membrane-associated protein from 293-tTA cells infected with a BARF1-recombinant adenovirus. Since constitutive expression of BARF1 from this heterologous system became inefficient, we developed a tetracycline-regulatable recombinant vector expressing BARF1 and green fluorescent protein from a dicistronic message. As here reported, stable and efficient expression of BARF1 from this vector in either permissive or non-permissive cell lines, allowed the first sequencing identification and further molecular characterization of BARF1-encoded protein.

Adenoviridae↗

PubMed2003

Four-dot masking produces the attentional blink.

When two target stimuli (T1 and T2) are presented sequentially within half a second of each other, identification accuracy is often poor for T2. This phenomenon, known as attentional blink (AB), can be observed generally only if the stimulus terminating the presentation of T2 acts as an interruption mask. Recent evidence suggests that even four small dots surrounding a target item can exert masking effects, provided the target onset occurs at an unattended spatial location. In order to test whether an AB could be observed under conditions of four-dot masking of T2, five rapid serial visual presentation streams of letters were synchronously displayed on each trial of the present experiment. T1 and T2 were digits presented at unpredictable locations and unpredictable temporal intervals. T2 was followed by either a blank field, a letter, or four-dots. No AB was observed when T2 was not masked, but robust and equally sized ABs were observed when T2 was followed by both the letter mask and the four-dots.

Adult↗

PubMed2003

Electrophysiological evidence of visual encoding deficits in a cross-modal attentional blink paradigm.

Two experiments are reported in which two target stimuli, T1 and T2, were presented at variable stimulus onset asynchronies (SOAs). In Experiment 1, T1 and T2 were visual stimuli embedded in a rapid serial visual presentation (RSVP) stream of distractors. Participants were asked to report T1 and T2 at the end of the stream. In Experiment 2, T1 was an auditory stimulus, and T2 a visual stimulus embedded in an RSVP stream. Participants made a speeded discriminative response to T1, and reported T2 at the end of the stream. An attentional blink (AB) effect was observed in both experiments: T2 report suffered at short SOA compared to long SOA. During the AB, the amplitude of the P300 component of the event-related potential (ERP) locked to T2 onset was sensibly reduced in both experiments. Behavioral and ERP results were very similar across the two experiments. Implications for models of the AB effect are discussed.

Attention↗

PubMed2002

Assessing the emetic potential of PDE4 inhibitors in rats.

1. Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha(2)-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors. 2. Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg(-1), i.m.) and ketamine (10 mg kg(-1), i.m.). PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) - PDE4 inhibitor: 0.01 - 3 mg kg(-1)), like MK-912 (alpha(2)-adrenoceptor antagonist: 0.01 - 3 mg kg(-1)), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1 - 10 mg kg(-1)). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors. 3. Neither MK-912 (3 mg kg(-1)) nor PMNPQ (0.1 - 1 mg kg(-1)) altered the duration of anaesthesia induced via a non-alpha(2)-adrenoceptor pathway (sodium pentobarbitone 50 mg kg(-1), i.p.). 4. Central NK(1) receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar(9), Met(O(2))(11)]-substance P (NK(1) receptor agonist, 6 microg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5. In summary, this model is functionally coupled to PDE4, specific to alpha(2)-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2001

Distinct regulatory elements are required for faithful expression of human CD4 in T cells, macrophages, and dendritic cells of transgenic mice.

To identify the regulatory elements controlling expression of the human CD4 (hCD4) gene in different cell types of the immune system, deletion and chimeric (human/murine) reporter genes were constructed and tested in transgenic (Tg) mice. Regulatory elements required for the proper hCD4 expression in the immature double-positive thymic T cells were identified in the enhancer and in the 3' end of intron 1. Expression of hCD4 in macrophages is controlled by at least 2 sets of regulatory elements: one present in front of exon 1 and the second at the 5' end of intron 1. The hCD4 elements required for expression on both myeloid and lymphoid CD8alpha(+) dendritic cells (DCs) from lymph node and thymus were found to be different from those required for macrophage expression. The results indicate that expression of hCD4 in T cells, macrophages, and DCs is controlled by distinct regulatory elements.

Animals↗

PubMed2001

The AIDS disease of CD4C/HIV transgenic mice shows impaired germinal centers and autoantibodies and develops in the absence of IFN-gamma and IL-6.

The mechanisms responsible for degeneration of germinal centers (GC) and follicular dendritic cell (FDC) networks during progression to AIDS remain elusive. Here, we show that CD4(+) T cells from CD4C/HIV-1 Tg mice, which develop a severe AIDS-like disease, express low levels of CD40 ligand. Accordingly, GC formation, FDC networks, and immunoglobulin isotype switching are impaired in these animals. However, Tg B cells respond to in vitro CD40 stimulation. Total serum IgG levels are reduced in Tg mice, whereas total IgM levels are increased with a significant amount showing DNA specificity. IFN-gamma- and IL-6-deficient CD4C/HIV Tg mice also develop the AIDS-like disease and produce auto-Ab. Thus, CD4C/HIV Tg mice have immune dysfunction accompanied by autoimmune responses.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Interactions between search mechanisms in conjunction search.

We report the results of a technique designed to measure interactions between different visual search processes. We interrupted pop-out search before it produced a detection response, by adding extra distractors to the display so that a target initially defined by a single feature difference (e.g., a yellow horizontal line among yellow vertical lines) could then only be found on the basis of the conjunction of two features (a yellow horizontal line among yellow vertical lines and pink horizontal lines; difficult search). This technique has been used to measure the duration of the perceptual components of pop-out search, independent of over-all response time, for targets presented among different sets of distractors. In addition, when pop-out failed because it was interrupted, past work has shown that it nevertheless provided useful information to the processes responsible for difficult search. That is, partial pop-out assisted difficult search, when extra distractors made search difficult because the target was between the two types of distractors in the relevant feature space (Olds, Cowan, & Jolicoeur, 2000a,b,c). The present results demonstrate that partial pop-out also assists difficult search when difficult search is a conjunction search, and therefore these interactions may occur at a stage where information from different feature dimensions is combined.

Adult↗

PubMed2001

The pathogenicity of human immunodeficiency virus (HIV) type 1 Nef in CD4C/HIV transgenic mice is abolished by mutation of its SH3-binding domain, and disease development is delayed in the absence of Hck.

The human immunodeficiency virus type 1 (HIV-1) Nef protein is an important determinant of AIDS pathogenesis. We have previously reported that HIV-1 Nef is responsible for the induction of a severe AIDS-like disease in CD4C/HIV transgenic (Tg) mice. To understand the molecular mechanisms of this Nef-induced disease, we generated Tg mice expressing a mutated Nef protein in which the SH3 ligand-binding domain (P(72)XXP(75)XXP(78)) was mutated to A(72)XXA(75)XXQ(78). This mutation completely abolished the pathogenic potential of Nef, although a partial downregulation of the CD4 cell surface expression was still observed in these Tg mice. We also studied whether Hck, one of the effectors previously found to bind to this PXXP motif of Nef, was involved in disease development. Breeding of Tg mice expressing wild-type Nef on an hck(-/-) (knockout) background did not abolish any of the pathological phenotypes. However, the latency of disease development was prolonged. These data indicate that an intact PXXP domain is essential for inducing an AIDS-like disease in CD4C/HIV Tg mice and suggest that interaction of a cellular effector(s) with this domain is required for the induction of this multiorgan disease. Our findings indicate that Hck is an important, but not an essential, effector of Nef and suggest that another factor(s), yet to be identified, may be more critical for disease development.

Animals↗

PubMed2001

Cross-modal attentional deficits in processing tactile stimulation.

In order to substantiate recent theorization on the possible links between the causes of the attentional blink and the psychological refractory period phenomena (e.g., Jolicoeur, 1999a), four experiments are reported in which two target stimuli, T1 and T2, were presented in different modalities at varying stimulus onset asynchronies (SOAs), with each stimulus being associated with a distinct task, Task1 and Task2. In Experiment 1, T1 was a tone, and Task1 was a speeded vocal response based on pitch. T2 was a brief press applied to either of two distal fingerpads, and Task2 was a speeded manual response based on tactile stimulus location. In Experiment 2, the same T1 as that used in Experiment 1 was presented, and in Task1 the subject either made a speeded vocal response based on pitch or ignored T1. T2 was a masked tactile stimulation, and Task2 was an unspeeded manual discrimination of the tactile stimulation location. This Task2 was maintained in Experiments 3 and 4. The auditory T1 was replaced with a white digit embedded in a rapid serial visualization presentation of a stream of black letters, and in Task1 the subject either made an unspeeded decision based on T1 identity or ignored T1. In all the experiments, the results showed an SOA-locked impairment in Task2. As SOA was decreased, reaction times in the speeded Task2 of Experiment 1 increased, and accuracy in the unspeeded Task2 of Experiments 2-4 decreased. The SOA-locked impairment was almost eliminated when T1 could be ignored or was absent. The results are discussed in terms of central processing limitations as the cause of such effects.

Adult↗

PubMed2001

Pathogenesis of defective retroviruses.

Concerns about the presence of contaminating defective retroviruses in cells used for vaccine preparations have been raised. These concerns mainly reflect the fact that (i) most species harbour several copies of endogenous defective and/or non-defective retroviral sequences in their genome; (ii) these sequences have frequently been found to participate in recombination events giving rise to novel viral entities; and (iii) several strains of defective retroviruses have been shown to be pathogenic. Here, a brief description of the main features of defective retroviruses is provided. In addition, the characteristics and plasticity of defective retroviruses are illustrated with a defective retrovirus inducing a mouse disease, murine AIDS (MAIDS).

Defective Viruses↗

PubMed2000

The time-course of pop-out search.

Olds, Cowan and Jolicoeur [2000. Tracking visual search over space and time. Psychonomic Bulletin & Review (in press)] interrupted pop-out search by adding distractors to a display after a delay. They analyzed the response time distributions from conditions with different delays for interruption and showed that when pop-out search fails, its partially completed computations can be used to assist other, slower search processes. This paper demonstrates that expectancies, numbers of items and colors in the display, and color onsets do not explain those results. Finally, an experiment in which the target was moved mid-trial demonstrates that partial pop-out assists difficult search by indicating something about where the target is, or where the target is not.

Adult↗

PubMed2000

The combined effects of plane disorientation and foreshortening on picture naming: one manipulation or two?

Objects disoriented in plane away from the upright and objects rotated in depth producing foreshortening are harder to identify than canonical views. In Experiments 1 and 2, participants named pictures of familiar objects. There was no interaction between plane and depth rotation effects on initial presentation or after practice. Experiment 3 was a dual-task psychological refractory period study. Participants classified a high-low tone with a speeded keypress and then named a canonical, plane-rotated, or foreshortened view of an object. Naming was slower when the picture was presented 50 ms after the tone compared with 800 ms after the tone. Plane rotation effects were reduced (but not eliminated) at the short tone-picture stimulus onset asynchrony, but foreshortening effects were not reduced. The results implicate an early, prebottleneck locus for some processes compensating for plane rotation and a subsequent bottleneck or postbottleneck locus for compensation for foreshortening.

Adult↗

PubMed2000

Two distinct Notch1 mutant alleles are involved in the induction of T-cell leukemia in c-myc transgenic mice.

We have previously characterized a large panel of provirus insertion Notch1 mutant alleles and their products arising in thymomas of MMTV(D)/myc transgenic mice. Here, we show that these Notch1 mutations represent two clearly distinct classes. In the first class (type I), proviral integrations were clustered just upstream of sequences encoding the transmembrane domain. Type I Notch1 alleles produced two types of mutant Notch1 RNA, one of which encoded the entire Notch1 cytoplasmic domain [N(IC)] and the other of which encoded a soluble ectodomain [N(EC)(Mut)] which, in contrast to the processed wild-type ectodomain [N(EC)(WT)], did not reside at the cell surface and became secreted in a temperature-dependent manner. A second, novel class of mutant Notch1 allele (type II) encoded a Notch1 receptor with the C-terminal PEST motif deleted (DeltaCT). The type II Notch1(DeltaCT) protein was expressed as a normally processed receptor [N(EC)(WT) and N(IC)(DeltaCT)] at the cell surface, and its ectodomain was found to be shed into the extracellular medium in a temperature- and calcium-dependent manner. These data suggest that both type I and type II mutations generate two structurally distinct Notch1 N(EC) and N(IC) proteins that may participate in tumor formation, in collaboration with the c-myc oncogene, through distinct mechanisms. Constitutive type I N(IC) and type II N(IC)(DeltaCT) expression may enhance Notch1 intracellular signaling, while secreted or shed type I N(EC)(Mut) and type II N(EC) proteins may differentially interact in an autocrine or paracrine fashion with ligands of Notch1 and affect their signaling.

Alleles↗

PubMed2000

Partial orientation pop-out helps difficult search for orientation.

We interrupted pop-out search before it produced a detection response by adding extra distractors to the search display. We show that when pop-out for an orientation target fails because of this interruption, it nevertheless provides useful information to the processes responsible for difficult search. That is, partial pop-out assists difficult search. This interaction has also been found for color stimuli (Olds, Cowan, & Jolicoeur, 2000a, 2000b). These results indicate that interactions and/or overlap between the mechanisms responsible for pop-out and the mechanisms responsible for difficult search may be quite general in early visual selection.

Adult↗

PubMed2000

Tracking visual search over space and time.

Visual perception consists of early preattentive processing and subsequent attention-demanding processing. Most researchers implicitly treat preattentive processing as a domain-dependent, indivisible stage. We show, however, by interrupting preattentive visual processing of color before its completion, that it can be dissected both temporally and spatially. The experiment depends on changing easy (preattentive) selection into difficult (attention-demanding) selection. We show that although the mechanism subserving preattentive selection completes processing as early as 200 msec after stimulus onset, partial selection information is available well before completion. Furthermore, partial selection occurs first at locations near fixation, spreading radially outward as processing proceeds.

Adult↗