Les oncogènes NUP98-PHF23 et NUP98-HOXD13 confèrent un potentiel aberrant d’auto-renouvellement aux progéniteurs thymiques

L’initiation de la leucémogénèse dans la leucémie aigue lymphoblastique (LAL)-T résulte de l’activation aberrante de facteurs de transcription de la lignée lymphocytaire T. Nous démontrons que les gènes de fusion NUP98-PHF23 (NP23) et NUP98-HOXD13 (NHD13) reprogramment les thymocytes normaux en cellules souches pré-leucémiques (CS-préL) possédant un potentiel aberrant d’auto-renouvellement. Basé sur des essais de clonalité performés sur des thymocytes transplantés en série, nous avons découvert que cette population est hiérarchisée similairement aux cellules souches hématopoïétiques normales. Ces CS-préL dévoilent un enrichissement du compartiment de précurseurs thymiques immatures KIT+ où les deux oncogènes, NP23 et NHD13, activent des gènes impliqués dans l’autorenouvellement, incluant Hoxa9, Hoxa10, Lyl1 et Hhex. De plus, l’activité d’autorenouvellement est abrogée par les ARN interférents contre Lyl1 et Hhex, indiquant leur implication fonctionnelle en aval de NP23 et NHD13. Puisque ces gènes sont aussi activés en aval de trois autres oncogènes dans la LAL-T, SCL/TAL1, LMO1 et LMO2, nous concluons que les niveaux d’activation de Lyl1 et Hhex fixent le seuil de reprogrammation des thymocytes normaux en CS-préL. Malgré l'efficacité des traitements de chimiothérapie actuels à diminuer la masse tumorale, les CS-préL sont épargnées, pouvant mener à des rechutes. Nos résultats répondent à ce besoin et proposent de nouvelles avenues permettant de cibler les CS-préL du compartiment de thymocytes immatures dans la LAL-T.

Aberrant protective force generation during neural provocation testing and the effect of treatment in patients with neurogenic cervicobrachial pain

Background: Observation of the occurrence of protective muscle activity is advocated in assessment of the peripheral nervous system by means of neural provocation tests. However, no studies have yet demonstrated abnormal force generation in a patient population. Objectives: To analyze whether aberrations in shoulder girdle-elevation force during neural tissue provocation testing for the median nerve (NTPTI) can be demonstrated, and whether possible aberrations can be normalized following cervical mobilization. Study Design: A single-blind randomized comparative controlled study. Setting: Laboratory setting annex in a manual therapy teaching practice. Participants: Twenty patients with unilateral or bilateral neurogenic cervicobrachial pain. Methods: During the NTPTI, we used a load cell and electrogoniometer to record continuously the shoulder-girdle elevation force in relation to the available range of elbow extension. Following randomization, we analyzed the immediate treatment effects of a cervical contralateral lateral glide mobilization technique (experimental group) and therapeutic ultrasound (control group). Results: On the involved side, the shoulder-girdle elevation force occur-red earlier, and the amount of force at the end of the test was substantially, though not significantly, greater than that on the uninvolved side at the corresponding range of motion. Together with a significant reduction in pain perception after cervical mobilization, a clear tendency toward normalization of the force curve could be observed, namely, a significant decrease in force generation and a delayed onset. The control group demonstrated no differences. Conclusions: Aberrations in force generation during neural, provocation testing are present in patients with neurogenic pain and can be normalized with appropriate treatment modalities.

Aberrant cervical thymus mimicking a cervical mass

A case of a 9-year-old female with suprasternal extension of the thymus mimicking thyroid gland enlargement is described. Ultrasonography successfully established the diagnosis. Aberrant cervical thymic tissue is an infrequently reported cause of paediatric neck masses. It is important to be aware of this entity to prevent anxiety and inappropriate investigation and/or intervention.

The tyrosine phosphatase DEP-1 induces cytoskeletal rearrangements, aberrant cell-substratum interactions and a reduction in cell proliferation

The receptor protein tyrosine phosphatase density-enhanced phosphatase-1 (DEP-1) has been implicated in aberrant cancer cell growth and immune cell function, however, its function within cells has yet to be properly elucidated. To investigate the cellular function of DEP-1, stable cell lines inducibly expressing DEP-1 were generated. Induction of DEP-1 expression was found to decrease PDGF-stimulated tyrosine phosphorylation of a number of cellular proteins including the PDGF receptor, and to inhibit growth factor-stimulated phosphorylation of components of the MAPK pathway, indicating that DEP-1 antagonised PDGF receptor signalling. This was supported by data showing that DEP-1 expression resulted in a reduction in cell proliferation. DEP-1-expressing cells had fewer actin-containing microfilament bundles, reduced vinculin and paxillin-containing adhesion plaques, and were defective in interactions with fibronectin. Defective cell-substratum adhesion correlated with lack of activation of FAK in DEP-1-expressing cells. Time-lapse interference reflection microscopy of live cells revealed that although small focal contacts at the leading edge were generated in DEP-1-expressing cells, they failed to mature into stable focal adhesions, as found in control cells. Further motility analysis revealed that DEP-1-expressing cells retained limited random motility, but showed no chemotaxis towards a gradient of PDGF. In addition, cell-cell contacts were disrupted, with a change in the localisation of cadherin from discrete areas of cell-cell contact to large areas of membrane interaction, and there was a parallel redistribution of beta-catenin. These results demonstrate that DEP-1 is a negative regulator of cell proliferation, cell-substratum contacts, motility and chemotaxis in fibroblasts.

Cue salience in multiple cue attentional capture

The predominant use of single element cues in visual attentional capture research motivated examination using dual capture cues. Participants in these studies viewed computer screens briefly displaying sequences of feature-defined positional cues and targets, with target identification response time recorded. Five initial experiments utilising the features of colour (purple) and intensity (bold font), and reported at EPC 2005, revealed contingent capture influences and suggested capture by colour cues may be more powerful than single cue literature has indicated. Three follow-up experiments manipulated displays and defining features to see if the conclusions remained. Experiments 6 and 7 investigated whether target identification in the initial series was based on a featural or singleton search. Experiment 8 then tested "onset' versus "purple" under the condition of specific attentional set, a featural change that appeared to remove purple colour dominance evidenced in the initial experimental series. Overall, outcomes of both experimental series suggest strong salience involvement with overtones of contingent capture for specific featural selections. The novel multi-cue approach revealed the significance of relative salience within these selections.

Aberrant reactive oxygen and nitrogen species generation in rheumatoid arthritis (RA):causes and consequences for immune function, cell survival, and therapeutic intervention

The infiltration and persistence of hematopoietic immune cells within the rheumatoid arthritis (RA) joint results in elevated levels of pro-inflammatory cytokines, increased reactive oxygen (ROS) and -nitrogen (RNS) species generation, that feeds a continuous self-perpetuating cycle of inflammation and destruction. Meanwhile, the controlled production of ROS is required for signaling within the normal physiological reaction to perceived "foreign matter" and for effective apoptosis. This review focuses on the signaling pathways responsible for the induction of the normal immune response and the contribution of ROS to this process. Evidence for defects in the ability of immune cells in RA to regulate the generation of ROS and the consequence for their immune function and for RA progression is considered. As the hypercellularity of the rheumatoid joint and the associated persistence of hematopoietic cells within the rheumatoid joint are symptomatic of unresponsiveness to apoptotic stimuli, the role of apoptotic signaling proteins (specifically Bcl-2 family members and the tumor suppressor p53) as regulators of ROS generation and apoptosis are considered, evaluating evidence for their aberrant expression and function in RA. We postulate that ROS generation is required for effective therapeutic intervention.

Group membership salience and task performance

Purpose – Social loafing is described in the literature as a frequent problem reducing individuals' performance when working in groups. This paper aims to utilize the social identity approach and proposes that under conditions of heightened group salience social loafing can be reduced and turned into social laboring (i.e. increased performance). Design/methodology/approach – Two experimental studies are conducted to examine the impact of participant's group membership salience on task performance. In Study 1, school teachers work either in coactive or in collective working conditions on brainstorming tasks. In Study 2, participants perform both a brainstorming task and a motor task. Findings – The results show social laboring effects. As predicted, participants in the high salient group conditions outperform participants in the low salient group conditions and the coactive individual condition. Practical implications – The results indicate that rather than individuating group members or tasks to overcome social loafing, managers can increase group performance by focusing on group members' perceptions of their groups as important and salient. Originality/value – The studies presented in this paper show that social identity theory and self categorization theory can fruitfully be applied to the field of group performance. The message of these studies for applied settings is that collective work in groups must not necessarily negatively impact performance, i.e. social loafing. By heightening the salience of group memberships groups can even outperform coactively working individuals.

Increased salience of gains versus decreased associative learning differentiate bipolar disorder from schizophrenia during incentive decision making

Background Abnormalities in incentive decision making, typically assessed using the Iowa Gambling Task (IGT), have been reported in both schizophrenia (SZ) and bipolar disorder (BD). We applied the Expectancy-Valence (E-V) model to determine whether motivational, cognitive and response selection component processes of IGT performance are differentially affected in SZ and BD. Method Performance on the IGT was assessed in 280 individuals comprising 70 remitted patients with SZ, 70 remitted patients with BD and 140 age-, sex-and IQ-matched healthy individuals. Based on the E-V model, we extracted three parameters, 'attention to gains or loses', 'expectancy learning' and 'response consistency', that respectively reflect motivational, cognitive and response selection influences on IGT performance. Results Both patient groups underperformed in the IGT compared to healthy individuals. However, the source of these deficits was diagnosis specific. Associative learning underlying the representation of expectancies was disrupted in SZ whereas BD was associated with increased incentive salience of gains. These findings were not attributable to non-specific effects of sex, IQ, psychopathology or medication. Conclusions Our results point to dissociable processes underlying abnormal incentive decision making in BD and SZ that could potentially be mapped to different neural circuits. © 2012 Cambridge University Press.

On the developmental continuity /discontinuity of early adolescent patterns of racial identity salience: Relations with later identities and psychosocial adjustment

Given the significant amount of attention placed upon race within our society, racial identity long has been nominated as a meaningful influence upon human development (Cross, 1971; Sellers et al., 1998). Scholars investigating aspects of racial identity have largely pursued one of two lines of research: (a) describing factors and processes that contribute to the development of racial identities, or (b) empirically documenting associations between particular racial identities and key adjustment outcomes. However, few studies have integrated these two approaches to simultaneously evaluate developmental and related adjustment aspects of racial identity among minority youth. Consequently, relations between early racial identity developmental processes and correlated adjustment outcomes remain ambiguous. Even less is known regarding the direction and function of these relationships during adolescence. To address this gap, the present study examined key multivariate associations between (a) distinct profiles of racial identity salience and (b) adjustment outcomes within a community sample of African-American youth. Specifically, a person-centered analytic approach (i.e., cluster analysis) was employed to conduct a secondary analysis of two archived databases containing longitudinal data measuring levels of racial identity salience and indices of psychosocial adjustment among youth at four different measurement occasions.^ Four separate groups of analyses were conducted to investigate (a) the existence of within-group differences in levels of racial identity salience, (b) shifts among distinct racial identity types between contiguous times of measurement, (c) adjustment correlates of racial identity types at each time of measurement, and (d) predictive relations between racial identity clusters and adjustment outcomes, respectively. Results indicated significant heterogeneity in patterns of racial identity salience among these African-American youth as well as significant discontinuity in the patterns of shifts among identity profiles between contiguous measurement occasions. In addition, within developmental stages, levels of racial identity salience were associated with several adjustment outcomes, suggesting the protective value of high levels of endorsement or internalization of racial identity among the sampled youth. Collectively, these results illustrated the significance of racial identity salience as a meaningful developmental construct in the lives of African-American adolescents, the implications of which are discussed for racial identity and practice-related research literatures. ^

Effects of emotional salience and semantic domain on cross-form priming

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Effects of emotional salience and semantic domain on cross-form priming

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

The effects of attractiveness and underlying components on the motivational salience and the memorability of face photographs

Facial attractiveness is a particularly salient social cue that influences many important social outcomes. Using a standard key-press task to measure motivational salience of faces and an old/new memory task to measure memory for face photographs, this thesis investigated both within-woman and between-women variations in response to facial attractiveness. The results indicated that within-woman variables, such as fluctuations in hormone levels, influenced the motivational salience of facial attractiveness. However, the between-women variable, romantic relationship status, did not appear to modulate women’s responses to facial attractiveness. In addition to attractiveness, dominance also contributed to both the motivational salience and memorability of faces. This latter result demonstrates that, although attractiveness is an important factor for the motivational salience of faces, other factors might also cause faces to hold motivational salience. In Chapter 2, I investigated the possible effects of women’s salivary hormone levels (estradiol, progesterone, testosterone, and estradiol-to-progesterone ratio) on the motivational salience of facial attractiveness. Physically attractive faces generally hold greater motivational salience, replicating results from previous studies. Importantly, however, the effect of attractiveness on the motivational salience of faces was greater in test sessions where women had high testosterone levels. Additionally, the motivational salience of attractive female faces was greater in test sessions where women had high estradiol-to-progesterone ratios. While results from Chapter 2 suggested that the motivational salience of faces was generally positively correlated with their physical attractiveness, Chapter 3 explored whether physical characteristics other than attractiveness contributed to the motivational salience of faces. To address this issue, I first had the faces rated on multiple traits. Principal component analysis of third-party ratings of faces for these traits revealed two orthogonal components that were highly correlated with trustworthiness and dominance ratings respectively. Both components were positively and independently related to the motivational salience of faces. While Chapter 2 and 3 did not examine the between-woman differences in response to facial attractiveness, Chapter 4 examined whether women’s responses to facial attractiveness differed as a function of their romantic partnership status. As several researchers have proposed that partnership status influences women’s perception of attractiveness, in Chapter 4 I compared the effects of men’s attractiveness on partnered and unpartnered women’s performance on two response measures: memory for face photographs and the motivational salience of faces. Consistent with previous research, women’s memory was poorer for face photographs of more attractive men and more attractive men’s faces held greater motivational salience. However, in neither study were the effects of attractiveness modulated by women’s partnership status or partnered women’s reported commitment to or happiness with their romantic relationship. A key result from Chapter 4 was that more attractive faces were harder to remember. Building on this result, Chapter 5 investigated the different characteristics that contributed to the memorability of face photographs. While some work emphasizes relationships with typicality, familiarity, and memorability ratings, more recent work suggests that ratings of social traits, such as attractiveness, intelligence, and responsibility, predict the memorability of face photographs independently of typicality, familiarity, and memorability ratings. However, what components underlie these traits remains unknown, as well as whether these components relate to the actual memorability of face photographs. Principal component analysis of all these face ratings produced three orthogonal components that were highly correlated with trustworthiness, dominance, and memorability ratings, respectively. Importantly, each of these components also predicted the actual memorability of face photographs.

Aberrant c-MET activation impairs perinuclear actin cap organization with YAP1 cytosolic relocation

Growing evidence indicates that cell and nuclear deformability plays a crucial role in the determination of cancer cells tumorigenic and metastatic potential. The perinuclear actin cap, by wrapping the nucleus with a functional network of actomyosin cables, can modulate nuclear architecture and consequently cell/nuclear elasticity. The hepatocyte growth factor receptor (MET) stands out among other membrane receptors as crucial player of the actin filaments organization, but no data are available on a specific role for MET in the actin cap assembly and the overall nuclear architecture organization. In a cell system characterized by MET hyperactivation, we observed a strong rearrangement of the cellular actin caps, with a complete dismantling of apical stress fibers and a strikingly enhanced nuclear height. CRISPR/Cas9 silencing of MET completely reverted the aberrant phenotype, resulting in flattened cells with perfectly aligned perinuclear actomyosin bundles, as well as decreased MAPK and PI3K/AKT signaling, cell proliferation rate and aggressiveness. Interestingly, MET ablated cells acquired a remarkably directed and polarized migratory phenotype, contrarily to cells with MET sustained activation showing meandering random walk. A pathway enrichment analysis comparing MET-activated and MET-KO cells RNAseq data, unveiled the contribution of multiple pathways associated with cytoskeleton remodeling, regulation of cell shape and response to mechanical stimuli. In line, the co-transcriptional activator YAP1, playing a major role in cell mechanosensing and focal adhesions/actin stabilization, appeared the culprit of the genetic reassembling of KO cells. Indeed, MET silencing was shown to induce YAP1 nuclear shuttling and increased co-transcriptional activity. Finally, we were able to induce in a normal epithelial model a phenotype closer to MET activated cancer cells only by introducing a constitutive fusion protein of MET. Taken together, our results demonstrate a new mechanism of MET-mediated actin remodeling responsible for a tumor-initiating capacity and meandering random migration, which requires YAP1 inactivation.