The paracaspase MALT1: biological function and potential for therapeutic inhibition.

The paracaspase MALT1 has a central role in the activation of lymphocytes and other immune cells including myeloid cells, mast cells and NK cells. MALT1 activity is required not only for the immune response, but also for the development of natural Treg cells that keep the immune response in check. Exaggerated MALT1 activity has been associated with the development of lymphoid malignancies, and recently developed MALT1 inhibitors show promising anti-tumor effects in xenograft models of diffuse large B cell lymphoma. In this review, we provide an overview of the present understanding of MALT1's function, and discuss possibilities for its therapeutic targeting based on recently developed inhibitors and animal models.

Does Gamma-aminobutyric acid function as a plant resistance mechanism against phytophagous insect activity? /

Gamma-aminobutyric acid (GAB A) is a ubiquitous non-protein amino acid synthesized via the decarboxylation of L-glutamate in a reaction catalyzed by the cytosolic enzyme L-glutamate decarboxylase (GAD). In animals it functions as an inhibitory neurotransmitter. In plants it accumulates rapidly in response to various stresses, but its function remains unclear. The hypothesis that GABA accumulation in leaf tissue may function as a plant resistance mechanism against phytophagous insect activity was investigated. GABA accumulation in response to mechanical stimulation, mechanical damage and insect activity was demonstrated. In wt tobacco (Nicotiana tabacum cv Samsun), mechanical stimulation or damage caused GABA to accumulate within 2 min from mean levels of 14 to 37 and 1~9 nmol g-l fresh weight (FW), respectively. In the transgenic tobacco strain CaMVGAD27c overexpressing Petunia GAD, the same treatments caused GABA to accumulate from 12 to 59 and 279 nmol g-l FW, respectively. In the transgenic tobacco strain CaMVGADilC 11 overexpressing Petunia GAD lacking an autoinhibitory domain, mechanical stimulation or damage caused GABA to accumulate from 180 to 309 and 630 nmol g-l FW, respectively. Ambulatory activity by tobacco budworm (TBW) larvae (Heliothis virescens) on leaves of CaMVGAD27c tobacco caused GABA to accumulate from 28 to 80 nmol g-l FW within 5 min. Ambulatory and leaf-rolling activity by oblique banded leaf roller (OBLR) larvae (Choristoneura rosaceana cv Harris) on wt soybean leaves (Glycine max cv Harovinton) caused GABA to accumulate from 60 to 1123 nmol g-l FW within 20 min. Increased GABA levels in leaf tissue were shown to affect phytophagous preference in TBW larvae presented with wt and transgenic tobacco leaves. When presented with leaves of Samsun wt and CaMVGAD27c plants, TBW larvae consumed more wt leaf tissue (640 ± 501 S.D. mm2 ) than transgenic leaf tissue (278 ± 338 S.D. mm2 ) nine times out of ten. When presented with leaves of Samsun wt and CaMVGAD~C11 plants, TBW larvae consumed more transgenic leaf tissue (1219 ± 1009 S.D. mm2 ) than wt leaf tissue (28 ± 31 S.D. mm2 ) ten times out of ten. These results indicate that: (1) ambulatory activity of insect larvae on leaves results in increased GABA levels, (2) transgenic tobacco leaves with increased capacity for GABA synthesis deter feeding, and (3) transgenic tobacco leaves with constitutively higher GABA levels stimulate feeding.

Expression and function of endothelin and its receptors in vascular adventitial fibroblasts

Objective: The adventitia has been recognized to play important roles in vascular oxidative stress, remodelling and contraction. We recently demonstrated that adventitial fibroblasts are able to express endothelin-1 (ET-1) in response to angiotensin II (ANG II). However, the mechanisms by which ANG II induces ET-1 expression are unknown. It is also unclear whether the ET-1 receptors are expressed in the adventitia. We therefore examined the role of oxidative stress in the regulation of ET-1. We also investigated the expression of both the ETA and ETB receptors and the roles of these two types of receptors in collagen synthesis and ET-1 clearance in adventitial fibroblasts. Methods and Results: Adventitial fibroblasts were isolated and cultured from the thoracic mouse aorta. Cells were treated with ANG II (lOOnM), ET-1 (lOpM), NADPH oxidase inhibitor apocynin (lOOfiM), the superoxide anion scavenger tempol (lOOfiM), the ANG II receptor antagonists (100[aM), losartan (AT| receptor) and PD 1233 19 (AT2 receptor), the ET-1 receptor antagonists (lOOuM), BQ123 (ETA receptor) and BQ788 (ETB receptor), and the ETB receptor agonist (lOOnM) Sarafotoxin 6C. ET-1 peptide levels were determined by ELISA, while ETA ,ETB and collagen levels were determined by Western blot. ANG II increased ET-1 peptide levels in a time-dependent manner reaching significance when incubated for 24 hours. NAD(P)H oxidase inhibitor, apocynin, as well as the superoxide scanverger, tempol, significantly reduced ANG Il-induced ET-1 peptide levels while over-expression of SOD1 (endogenous antioxidant enzyme) significantly decreased ANG Il-induced collagen I expression, therefore implicating reactive oxygen species in the mediation of ET-1. ANG II increased ETA receptor protein as well as collagen in a similar fashion, reaching significance after 4, 6, and 24 hours treatment. ANG II induced collagen was reduced while in the presence of the ETA receptor antagonist suggesting the role of the ETa receptor in the regulation of the extracellular matrix. ANG II treatment also increased ETB receptor protein levels in a time-dependent manner. ANG II treatment in the presence of the ETB receptor antagonist significantly increased ET-1 peptide levels. On another hand, the ETB receptor agonist, Sarafotoxin 6C, significantly decreased ET-1 peptide levels. These data implicate the role of the ETb receptor in the clearance of the ET-1 peptide. Conclusion: ANG II-induced increases of ET-1 peptide appears to be mediated by reactive oxygen species derived from NAD(P)H oxidase. Both the ETA and ETB receptors are expressed in adventitial fibroblasts. The ETA receptor subtype mediates collagen I expression, while the ETB receptor may play a protective role through increasing the clearance of the ET- 1 peptide.

Effect of diurnal cycling temperatures on cardiovascular- ventilatory function in statically-acclimated rainbow trout, Salmo gairdneri

Four groups of rainbow trout, Salmo gairdneri, were acclimated to 2°, 10°, and 18°e, and to a diurnal temperature cycle (100 ± 4°C). To evaluate the influence of cycling temperatures in terms of an immediate as opposed to acclimatory response various ventilatory-cardiovascular rate functions were observed for trout, either acclimated to cycling temperatures or acclimated to constant temperatures and exposed to a diurnal temperature cycle for the first time (10° ± 4°C for trout acclimated to 10°C; 18°+ 4°C for trout acclimated to l8°e). Gill resistance and the cardiac to ventilatory rate ratio were then calculated. Following a post preparatory recovery period of 36 hr, measurements were made over a 48 hour period with the first 24 hours being at constant temperature in the case of statically-acclimated fish followed by 24 hours under cyclic temperature conditions. Trout exhibited marked changes in oxygen consumption (Vo ) with temp- 2 erature both between acclimation groups, and in response to the diurnal temperature cycle. This increase in oxygen uptake appears to have been achieved by adjustment of ventilatory and, to some extent, cardiovascular activity. Trout exhibited significant changes in ventilatory rate (VR), stroke volume (Vsv), and flow (VG) in response to temperature. Marked changes in cardiac rate were also observed. These findings are discussed in relation to their importance in convective oxygen transport via water and blood at the gills and tissues. Trout also exhibited marked changes in pressure waveforms associated with the action of the resp; ratory pumps with temperature. Mean differenti a 1 pressure increased with temperature as did gill resistance and utilization. This data is discussed in relation to its importance in diffusive oxygen transport and the conditions for gas exchange at the gills. With one exception, rainbow trout were able to respond to changes in oxygen demand and availability associated with changes in temperature by means of adjustments in ventilation, and possibly pafusion, and the conditions for gas exchange at the gills. Trout acclimated to 18°C, however, and exposed to high cyclic temperatures, showed signs of the ventilatory and cardiovascular distress problems commonly associated with low circulating levels of oxygen in the blood. It appears these trout were unable to fully meet the oxygen requirements associated with c~ling temperatures above 18°C. These findings were discussed in relation to possible limitations in the cardiovascular-ventilatory response at high temperatures. The response of trout acclimated to cycling temperatures was generally similar to that for trout acclimated to constant temperatures and exposed to cycling temperatures for the first time. This result suggested that both groups of fish may have been acclimated to a similar thermal range, regardless of the acclimation regime employed. Such a phenomenon would allow trout of either acclimation group to respond equally well to the imposed temperature cycle. Rainbow trout showed no evidence of significant diurnal rhythm in any parameters observed at constant temperatures (2°, 10°, and 18° C), and under a 12/12 light-dark photoperiod regime. This was not taken to indicate an absence of circadian rhythms in these trout, but rather a deficiency in the recording methods used in the study.

The role of daytime napping in sleepiness and cognitive function in 24-70 year olds /

Daytime napping improves well-being and performance for young adults. The benefits of napping in older adults should be investigated because they have fragmented nocturnal sleep, cognitive declines, and more opportunity to nap. In addition, experience with napping might influence the benefits of napping. Study 1 examined the role of experience with napping in young adults. Habitual (n = 23) and non-habitual nappers (n = 16) were randomly assigned to a 20-minute nap or a 20- minute reading condition. Both groups slept the same according to macro architecture. However, microarchitecture showed greater theta, alpha, and beta power during Stage 1, and greater delta, alpha, and sigma power during Stage 2 for habitual nappers, for the most part indicating better sleep. Both groups felt less sleepy after the nap. P2 latency, reflecting information processing, decreased after the nap for habitual nappers, and after the control condition for non-habitual nappers. In sum, both groups who slept felt better, but only the habitual nappers who napped gained a benefit in terms of information processing. Based on this outcome, experience with napping was investigated in Study 2. Study 2 examined the extent to which daytime napping enhanced cognition in older adults, especially frontal lobe function. Cognitive deficits in older adults may be due to sleep loss and age-related decline in brain functioning. Longer naps were expected to provide greater improvement, particularly for older adults, by reducing sleep pressure. Thirty-two adults, aged 24-70 years, participated in a repeated measures dose-response manipulation of sleep pressure. Twenty- and sixty-minute naps were compared to a no-nap condition in three age groups. Mood, subjective sleepiness, reaction time, working memory, 11 novelty detection, and waking electro physiological measures were taken before and after each condition. EEG was also recorded during each nap or rest condition. Napping reduced subjective sleepiness, improved working memory (serial addition / subtraction task), and improved attention (reduced P2 amplitude). Physiological sleepiness (i.e., waking theta power) increased following the control condition, and decreased after the longer nap. Increased beta power after the short nap, and seen with older adults overall, may have reflected increased mental effort. Older adults had longer latencies and smaller amplitudes for several event-related potential components, and higher beta and gamma power. Following the longer nap, gamma power decreased for older adults, but increased for young adults. Beta and gamma power may represent enhanced alertness or mental effort. In addition, Nl amplitude showed that benefits depend on the preceding nap length as well as age. Since the middle group had smaller Nl amplitudes following the short nap and rest condition, it is possible that they needed a longer nap to maintain alertness. Older adults did not show improvements to Nl amplitude following any condition; they may have needed a nap longer than 60 minutes to gain benefits to attention or early information processing. Sleep characteristics were not related to benefits of napping. Experience with napping was also investigated. Subjective data confirmed habitual nappers were happier to nap, while non-habitual nappers were happier to stay awake, reflecting self-identified napping habits. Non-habitual nappers were sleepier after a nap, and had faster brain activity (i.e., heightened vigilance) at sleep onset. These reasons may explain why non-habitual nappers choose not to nap.

Behavioural and neural correlates of emotion recognition as a function of psychopathic personality traits

Psychopathy is associated with well-known characteristics such as a lack of empathy and impulsive behaviour, but it has also been associated with impaired recognition of emotional facial expressions. The use of event-related potentials (ERPs) to examine this phenomenon could shed light on the specific time course and neural activation associated with emotion recognition processes as they relate to psychopathic traits. In the current study we examined the PI , N170, and vertex positive potential (VPP) ERP components and behavioural performance with respect to scores on the Self-Report Psychopathy (SRP-III) questionnaire. Thirty undergraduates completed two tasks, the first of which required the recognition and categorization of affective face stimuli under varying presentation conditions. Happy, angry or fearful faces were presented under with attention directed to the mouth, nose or eye region and varied stimulus exposure duration (30, 75, or 150 ms). We found that behavioural performance to be unrelated to psychopathic personality traits in all conditions, but there was a trend for the Nl70 to peak later in response to fearful and happy facial expressions for individuals high in psychopathic traits. However, the amplitude of the VPP was significantly negatively associated with psychopathic traits, but only in response to stimuli presented under a nose-level fixation. Finally, psychopathic traits were found to be associated with longer N170 latencies in response to stimuli presented under the 30 ms exposure duration. In the second task, participants were required to inhibit processing of irrelevant affective and scrambled face distractors while categorizing unrelated word stimuli as living or nonliving. Psychopathic traits were hypothesized to be positively associated with behavioural performance, as it was proposed that individuals high in psychopathic traits would be less likely to automatically attend to task-irrelevant affective distractors, facilitating word categorization. Thus, decreased interference would be reflected in smaller N170 components, indicating less neural activity associated with processing of distractor faces. We found that overall performance decreased in the presence of angry and fearful distractor faces as psychopathic traits increased. In addition, the amplitude of the N170 decreased and the latency increased in response to affective distractor faces for individuals with higher levels of psychopathic traits. Although we failed to find the predicted behavioural deficit in emotion recognition in Task 1 and facilitation effect in Task 2, the findings of increased N170 and VPP latencies in response to emotional faces are consistent wi th the proposition that abnormal emotion recognition processes may in fact be inherent to psychopathy as a continuous personality trait.

Response curves of deterministic and probabilistic cellular automata in one and two dimensions

One of the most important problems in the theory of cellular automata (CA) is determining the proportion of cells in a specific state after a given number of time iterations. We approach this problem using patterns in preimage sets - that is, the set of blocks which iterate to the desired output. This allows us to construct a response curve - a relationship between the proportion of cells in state 1 after niterations as a function of the initial proportion. We derive response curve formulae for many two-dimensional deterministic CA rules with L-neighbourhood. For all remaining rules, we find experimental response curves. We also use preimage sets to classify surjective rules. In the last part of the thesis, we consider a special class of one-dimensional probabilistic CA rules. We find response surface formula for these rules and experimental response surfaces for all remaining rules.

The form and function of aggressive subtypes: Relations with the goodness of fit between adolescent temperament and parent personality

The current research investigated whether the interaction between adolescent temperament and parent personality, consistent with the goodness of fit perspective, differentially predicted overt (e.g., kicking, punching, insulting) and relational (e.g., gossiping, rumour spreading, ostracising) forms of reactive (e.g., provoked, a response to goal blocking, unplanned and emotional) and proactive (e.g., unprovoked, goal-directed, deliberate and relatively unemotional) aggression. Mothers, fathers and their adolescent child (N = 448, age 10-17) from southern Ontario, Canada filled out questionnaires on adolescent temperament (i.e., frustration, fear, and effortful control) and aggression. Parents reported on their own personality traits (i.e., agreeableness, conscientiousness, and emotional stability). The form and function of aggression not encompassed by the subtype under investigation were controlled in each regression analysis. Consistent with the hypothesis, results indicated that a poor fit between adolescent temperament vulnerabilities and lower parent personality traits, including agreeableness, conscientiousness and emotional stability, was predictive of greater levels of differentiated aggression. For instance, lower father conscientiousness strengthened the relation between higher frustration and reactive overt aggression. Unexpectedly in some cases, temperament risk factors were more strongly associated with aggression subtypes when personality scores were at higher levels, particularly agreeableness and conscientiousness, traits normally considered to be at the optimal end of the dimension. For example, higher father agreeableness strengthened the relation between higher frustration and reactive relational aggression. At the main effects level, low fearfulness was significantly associated with only the overt subtypes of aggression, and unexpectedly, higher frustration and lower effortful control were related to both proactive and reactive subtypes of aggression. A temperamentally vulnerable adolescent was also at greater risk of displaying aggressive behaviour when the father lacked emotional stability, but not the mother. These results are broadly consistent with the prediction that temperament risk factors are more strongly associated with aggression subtypes when an adolescent predisposition does not fit well with parent personality traits. Mechanisms pertaining to stress in the family environment and the fostering of self-regulation abilities are discussed with respect to why a poor fit between temperament and parent personality is predictive of adolescent differentiated aggression.

I Believe in me, not OCB: Evaluation of Group Function-Based CBT as a Treatment for Obsessive Compulsive Behaviour in Four Children with HFA

Researchers have conceptualized repetitive behaviours in individuals with Autism Spectrum Disorder (ASD) on a continuum oflower-Ievel, motoric, repetitive behaviours and higher-order, repetitive behaviours that include symptoms ofOCD (Hollander, Wang, Braun, & Marsh, 2009). Although obsessional, ritualistic, and stereotyped behaviours are a core feature of ASD, individuals with ASD frequently experience obsessions and compulsions that meet DSM-IV-TR (American Psychiatric Association, 2000) criteria for Obsessive-Compulsive Disorder (OCD). Given the acknowledged difficulty in differentiating between OCD and Autism-related obsessive-compulsive phenomena, the present study uses the term Obsessive Compulsive Behaviour (OCB) to represent both phenomena. This study used a multiple baseline design across behaviours and ABC designs (Cooper, Heron, & Heward, 2007) to investigate if a 9-week Group Function-Based Cognitive Behavioural Therapy (CBT) decreased OCB in four children (ages 7 - 11 years) with High Functioning Autism (HFA). Key treatment components included traditional CBT components (awareness training, cognitive-behavioural skills training, exposure and response prevention) as well as function-based assessment and intervention. Time series data indicated significant decreases in OCBs. Standardized assessments showed decreases in symptom severity, and increases in quality of life for the participants and their families. Issues regarding symptom presentation, assessment, and treatment of a dually diagnosed child are discussed.

Frontal Lobe Function and Performance Monitoring following Total Sleep Deprivation

Imaging studies have shown reduced frontal lobe resources following total sleep deprivation (TSD). The anterior cingulate cortex (ACC) in the frontal region plays a role in performance monitoring and cognitive control; both error detection and response inhibition are impaired following sleep loss. Event-related potentials (ERPs) are an electrophysiological tool used to index the brain's response to stimuli and information processing. In the Flanker task, the error-related negativity (ERN) and error positivity (Pe) ERPs are elicited after erroneous button presses. In a Go/NoGo task, NoGo-N2 and NoGo-P3 ERPs are elicited during high conflict stimulus processing. Research investigating the impact of sleep loss on ERPs during performance monitoring is equivocal, possibly due to task differences, sample size differences and varying degrees of sleep loss. Based on the effects of sleep loss on frontal function and prior research, it was expected that the sleep deprivation group would have lower accuracy, slower reaction time and impaired remediation on performance monitoring tasks, along with attenuated and delayed stimulus- and response-locked ERPs. In the current study, 49 young adults (24 male) were screened to be healthy good sleepers and then randomly assigned to a sleep deprived (n = 24) or rested control (n = 25) group. Participants slept in the laboratory on a baseline night, followed by a second night of sleep or wake. Flanker and Go/NoGo tasks were administered in a battery at 1O:30am (i.e., 27 hours awake for the sleep deprivation group) to measure performance monitoring. On the Flanker task, the sleep deprivation group was significantly slower than controls (p's <.05), but groups did not differ on accuracy. No group differences were observed in post-error slowing, but a trend was observed for less remedial accuracy in the sleep deprived group compared to controls (p = .09), suggesting impairment in the ability to take remedial action following TSD. Delayed P300s were observed in the sleep deprived group on congruent and incongruent Flanker trials combined (p = .001). On the Go/NoGo task, the hit rate (i.e., Go accuracy) was significantly lower in the sleep deprived group compared to controls (p <.001), but no differences were found on false alarm rates (i.e., NoGo Accuracy). For the sleep deprived group, the Go-P3 was significantly smaller (p = .045) and there was a trend for a smaller NoGo-N2 compared to controls (p = .08). The ERN amplitude was reduced in the TSD group compared to controls in both the Flanker and Go/NoGo tasks. Error rate was significantly correlated with the amplitude of response-locked ERNs in control (r = -.55, p=.005) and sleep deprived groups (r = -.46, p = .021); error rate was also correlated with Pe amplitude in controls (r = .46, p=.022) and a trend was found in the sleep deprived participants (r = .39, p =. 052). An exploratory analysis showed significantly larger Pe mean amplitudes (p = .025) in the sleep deprived group compared to controls for participants who made more than 40+ errors on the Flanker task. Altered stimulus processing as indexed by delayed P3 latency during the Flanker task and smaller amplitude Go-P3s during the Go/NoGo task indicate impairment in stimulus evaluation and / or context updating during frontal lobe tasks. ERN and NoGoN2 reductions in the sleep deprived group confirm impairments in the monitoring system. These data add to a body of evidence showing that the frontal brain region is particularly vulnerable to sleep loss. Understanding the neural basis of these deficits in performance monitoring abilities is particularly important for our increasingly sleep deprived society and for safety and productivity in situations like driving and sustained operations.

Investigating Changes in Parent Knowledge about Obsessive Compulsive Behaviour Following Group Function-Based Cognitive Behavioural Therapy for Children with High Functioning Autism

This study investigated improvements in parent knowledge of effective intervention strategies following participation in a group function-based CBT treatment (GFbCBT) package for children with comorbid OCD and ASD. Nineteen parents of children ages 7-12 years with High Functioning Autism (HFA) participated in the 9-week treatment program. Key components of treatment included psychoeducation and mapping, cognitive-behavioural skills training, function-based interventions and exposure and response prevention (ERP). Treatment sessions also included direct parent education, which followed a behavioural skills training model (Miltenberger, 2008). Parent knowledge (N = 19) was measured pre and post treatment using a vignette about a child demonstrating obsessive-compulsive behaviour. Results of a one-tailed pairwise t-test indicated statistically significant changes (p=.036) in overall parent knowledge following participation in treatment. Statistically significant changes were also found in parents’ ability to generate ERP and function-based intervention strategies. These results provide preliminary evidence that parents benefit from active involvement in the GFbCBT treatment package.

Untangling the Organizational Ambiguities in Supply Chain Risk Recognition, Assessment, and Response: The Role of Network Embeddedness

In this thesis, I focus on supply chain risk related ambiguity, which represents the ambiguities firms exhibit in recognizing, assessing, and responding to supply chain disruptions. I, primarily, argue that ambiguities associated with recognizing and responding to supply chain risk are information gathering and processing problems. Guided by the theoretical perspective of bounded rationality, I propose a typology of supply chain risk related ambiguity with four distinct dimensions. I, also, argue that the major contributor to risk related ambiguity is often the environment, specifically the web of suppliers. Hence, I focus on the characteristics of these supplier networks to examine the sources of ambiguity. I define three distinct elements of network embeddedness – relational, structural, and positional embeddedness – and argue that the ambiguity faced by a firm in appropriately identifying the nature or impacts of major disruptions is a function of these network properties. Based on a survey of large North American manufacturing firms, I found that the extent of the relational ties a firm has and its position in the network are significantly related to supply chain risk related ambiguity. However, this study did not provide any significant support for the hypothesized relationship between structural embeddedness and ambiguity. My research contributes towards the study of supply chain disruptions by using the idea of bounded rationality to understand supply chain risk related ambiguity and by providing evidence that the structure of supply chain networks influences the organizational understanding of and responses to supply chain disruptions.

Effects of Cerebral Blood Flow and PETCO2 on Cognitive Function During Passive Heat Stress

This thesis tested whether cognitive performance during passive heat stress may be affected by changes in cerebrovascular variables as opposed to strictly thermally-induced changes. A pharmacological reduction in cerebral blood flow (CBF) using indomethacin along with a hypocapnia-induced CBF reduction during passive heat stress (Tre ~1.5°C above baseline) were used to investigate any cerebrovascular-mediated changes in cognitive performance. Repeated measures analysis of variance indicated that One-Touch Stockings of Cambridge (OTS) performance was not affected by a significant reduction in CBF during passive heat stress. More specifically, OTS accuracy measures did not change as a result of either a reduction in CBF or increasing passive heat stress. However, it was found that OTS response time indices improved with increasing passive heat stress independent of CBF changes. In conclusion, a significant reduction in CBF does not cause additional changes in performance of an executive functioning task during severe passive heat stress.

Reactive Hyperemia as endothelial function determinant using plethysmography methods

L’atteinte de la fonction endothéliale représente une phase précoce de l’athérosclérose, un stade où les patients sont généralement asymptomatiques. Il existe donc un intérêt certain à détecter la dysfonction endothéliale. Nous avons développé une technique de mesure des variations de flot artériel au niveau des membres supérieurs, basée sur la spectroscopie proche infrarouge (NIRS). Cette approche permettrait d’étudier le niveau d’atteinte vasculaire et probablement de quantifier le degré de dysfonction endothéliale périphérique lors d’une hyperémie réactive. L'expérience a été exécutée sur deux cohortes de 13 et de 15 patients et a été comparée à la pléthysmographie par jauge de contrainte (SGP) qui est considérée comme une méthode de référence. Par la suite, nous avons caractérisé la réponse endothéliale par modélisation de la courbe hyperémique du flot artériel. Des études préliminaires avaient démontré que la réponse hyperémique adoptait majoritairement une forme bi-modale. Nous avons tenté de séparer les composantes endothéliales-dépendantes et endothéliales-indépendantes de l’hyperémie. La quantification des deux composantes de la réaction hyperémique permet de calculer un indice de la ‘santé’ du système endothélial local. Cet indice est nommé le ηfactor. Les résultats montrent une forte corrélation des mesures de flots entre la technique développée et la méthode de référence (r=0.91). Nous avons conclu que NIRS est une approche précise pour la mesure non-invasive du flot artériel. Nous avons obtenu une bonne répétabilité (ICC = 0.9313) pour le ηfactor indiquant sa robustesse. Cependant des études supplémentaires sont nécessaires pour valider la valeur de diagnostic du facteur défini. Mots clés: hyperémie réactive, réponse myogénique, oxyde nitrique, athérosclérose, spectroscopie proche infrarouge

The role of DcR3 in systemic lupus erythematosus and islet β-Cell viability and function

Le récepteur DcR3 (Decoy receptor 3) est un membre de la famille des récepteurs aux facteurs de nécrose tumorale (TNF). Il est fortement exprimé dans les tissus humains normaux ainsi que les tumeurs malignes. DcR3 est un récepteur pour trois ligands de la famille du TNF tels que FasL, LIGHT et TL1A. Étant une protéine soluble donc dépourvue de la portion transmembranaire et intracytoplasmique, le récepteur DcR3 est incapable d’effectuer une transduction de signal intracellulaire à la suite de son interaction avec ses ligands. De ce fait, DcR3 joue un rôle de compétiteur pour ces derniers, afin d’inhiber la signalisation via leurs récepteurs fonctionnels tels que Fas, HVEM/LTbetaR et DR3. Lors de nos précédentes études, nous avons pu démontrer, que DcR3 pouvaist moduler la fonction des cellules immunitaires, et aussi protéger la viabilité des îlots de Langerhans. À la suite de ces résultats, nous avons généré des souris DcR3 transgéniques (Tg) en utilisant le promoteur du gène β-actine humaine afin d’étudier plus amplement la fonction de ce récepteur. Les souris Tg DcR3 ont finalement développé le syndrome lupus-like (SLE) seulement après l’âge de 6 mois. Ces souris présentent une variété d'auto-anticorps comprenant des anticorps anti-noyaux et anti-ADN. Elles ont également manifesté des lésions rénales, cutanées, hépatiques et hématopoïétiques. Contrairement aux modèles de lupus murin lpr et gld, les souris DcR3 sont plus proche du SLE humain en terme de réponse immunitaire de type Th2 et de production d'anticorps d'anti-Sm. En péus, nous avons constaté que les cellules hématopoïétiques produisant DcR3 sont suffisantes pour causer ces pathologies. DcR3 peut agir en perturbant l’homéostasie des cellules T pour interférer avec la tolérance périphérique, et ainsi induire l'autoimmunité. Chez l'humain, nous avons détecté dans le sérum de patients SLE des niveaux élevés de la protéine DcR3. Chez certains patients, comme chez la souris, ces niveaux sont liés directement aux titres élevés d’IgE. Par conséquent, DcR3 peut représenter un facteur pathogénique important du SLE humain. L’étude des souris Tg DcR3, nous a permis aussi d’élucider le mécanisme de protection des îlots de Langerhans. Le blocage de la signalisation des ligands LIGHT et TL1A par DcR3 est impliqué dans une telle protection. D'ailleurs, nous avons identifié par ARN microarray quelques molécules en aval de cette interaction, qui peuvent jouer un rôle dans le mécanisme d’action. Nous avons par la suite confirmé que Adcyap1 et Bank1 joue un rôle critique dans la protection des îlots de Langerhans médiée par DcR3. Notre étude a ainsi élucidé le lien qui existe entre la signalisation apoptotique médiée par Fas/FasL et la pathogénèse du SLE humain. Donc, malgré l’absence de mutations génétiques sur Fas et FasL dans le cas de cette pathologie, DcR3 est capable de beoquer cette signalisation et provoquer le SLE chez l’humain. Ainsi, DcR3 peut simultanément interférer avec la signalisation des ligands LIGHT et TL1A et causer un phénotype plus complexe que les phénotypes résultant de la mutation de Fas ou de FasL chez certains patients. DcR3 peut également être utilisé comme paramètre diagnostique potentiel pour le SLE. Les découvertes du mécanisme de protection des îlots de Langerhans par DcR3 ouvrent la porte vers de nouveaux horizons afin d'explorer de nouvelles cibles thérapeutiques pour protéger la greffe d'îlots.