Le stress, l'hyperactivation et l'insomnie

La présente thèse vise à améliorer la compréhension du rôle du stress et de l’hyperactivation dans le trouble d’insomnie. Dans un premier temps, 22 individus souffrant d’insomnie, 23 bons dormeurs ayant une vulnérabilité élevée à l’insomnie et 24 bons dormeurs ayant une faible vulnérabilité à l’insomnie, appariés selon l’âge et le sexe, ont été comparés dans le cadre d’une étude observationnelle. Ces participants ont porté un actigraphe enregistrant le sommeil, pris des prélèvements de salive pour l’analyse du cortisol, et complété des questionnaires évaluant le stress, l’activation et le sommeil à chaque jour pendant une semaine. Les résultats suggèrent que les individus souffrant d’insomnie perçoivent les événements quotidiens comme plus stressants, rapportent une activation cognitive et somatique plus élevée à l’heure du coucher et ont un taux de cortisol plus élevé à l’heure du coucher que les bons dormeurs ayant une faible vulnérabilité à l’insomnie. Des analyses suggèrent par ailleurs que l’activation cognitive à l’heure du coucher joue un rôle de médiateur important dans la relation entre le stress et le sommeil, particulièrement chez les bons dormeurs ayant une vulnérabilité élevée à l’insomnie et ceux souffrant déjà d’insomnie. Dans un deuxième temps, un sous-échantillon de la première étude, incluant 10 individus souffrant d’insomnie, 10 bons dormeurs ayant une vulnérabilité élevée à l’insomnie et 10 bons dormeurs ayant une faible vulnérabilité à l’insomnie, ont dormi deux nuits consécutives en laboratoire. Ces participants ont été soumis à un stresseur expérimental standardisé, durant lequel des mesures évaluant l’activation psychologique et physiologique ont été recueillies. Les résultats suggèrent que les individus souffrant d’insomnie ont une réponse et une sécrétion du cortisol à l’heure du coucher plus élevées, ainsi qu’une activation cognitive plus élevée à l’heure du coucher, comparativement aux bons dormeurs ayant une faible vulnérabilité à l’insomnie. Les bons dormeurs ayant une vulnérabilité élevée à l’insomnie ne diffèrent pas de ceux ayant une faible vulnérabilité à l’insomnie ou de ceux souffrant déjà d’insomnie sur toutes les variables mesurant l’activation. Enfin, une activation élevée induite par le stresseur expérimental est associée à un sommeil plus perturbé. L’ensemble des résultats de la thèse soutient la conceptualisation d’hyperactivation dans l’insomnie et souligne l’existence probable d’un continuum du trouble d’insomnie. Une réactivité élevée du sommeil au stress et une hyperactivation à l’heure du coucher représenteraient un trait de vulnérabilité chez certains bons dormeurs. L’adoption des interventions préventives portant sur la gestion du stress et des stratégies visant à réduire l’activation aurait le potentiel à prévenir les individus à haut risque de développer du trouble d’insomnie. Des études supplémentaires sont requises afin de confirmer et prolonger les résultats de la thèse.This thesis aimed to improve the understanding of the role of stress and hyperarousal in insomnia. First, an observational study was conducted. Participants included 22 individuals with insomnia, 23 good sleepers with high vulnerability to insomnia, and 24 good sleepers with low vulnerability to insomnia, who were matched for age and sex. Over one week, they wore wrist actigraph, collected saliva samples for cortisol, and completed daily self-monitoring questionnaires assessing stress, bedtime arousal, and sleep. Results suggested that individuals with insomnia perceived daily events as more stressful, reported higher pre-sleep cognitive and somatic arousal, and had greater bedtime cortisol secretion than good sleepers with low vulnerability to insomnia. Analyses also revealed that pre-sleep cognitive arousal but not physiological arousal (cortisol) plays an important mediating role in the relation between stress and sleep disturbances, particularly among individuals with heightened sleep reactivity, including good sleepers with high vulnerability to insomnia and those with insomnia disorder. In the second study, a subsample composed of 10 individuals with insomnia, 10 good sleepers with high vulnerability to insomnia, and 10 good sleepers with low vulnerability to insomnia underwent two consecutive nights of polysomnography in the sleep laboratory. A standardized experimental stressor was administered, and various psychological and physiological arousal indices were assessed. Individuals with insomnia showed greater acute cortisol response, higher cortisol secretion at bedtime, as well as higher pre-sleep cognitive arousal than good sleepers with low vulnerability to insomnia. Good sleepers with high vulnerability to insomnia did not differ from those with low vulnerability to insomnia or those who already had insomnia on any arousal variable. Further, stress-induced hyperarousal was associated with more disturbed sleep. Overall results of the thesis support the hyperarousal conceptualization of insomnia and highlight the potential existence of a continuum of insomnia disorder. Heightened stress-related sleep reactivity and bedtime hyperarousal might represent a trait-like vulnerability in certain good sleepers. Adopting preventive interventions targeting stress management and strategies to reduce bedtime hyperarousal might protect at-risk individuals from developing chronic insomnia problems. More research is warranted to validate and expand the findings of the present thesis

Sex differences in the effect of stress on response to food reward cues

OBJECTIVE: The overlap in literature on stress and human reward processing is relatively small but growing as its significance becomes increasingly implicated in the obesity epidemic. The greater prevalence of obesity, especially severe obesity, among females than males suggests that there may be sex differences in hormones driving eating behaviors and in food reward processing. There is an important gap in the literature – a paucity of studies employing robust psychosocial stressors in combination with a food-related reward neuroimaging task to examine sex differences in the effect of psychosocial stress on hormones and food reward processing in humans. We hypothesized that male and female healthy subjects exposed to stressful situations during the Maastricht Acute Stress Test (MAST) will show sex differences in physiological, subjective self-report, and neural measures. The physiological variables measured ghrelin and cortisol reactivity. Subjective self-report variables measured perceived threat (pre-/post-task appraisals), state anxiety (pre-/post-scan state anxiety), and visual analogue scale ratings of appetite and mood (hunger/sadness/tension). The neural variables utilized a food incentive delay (FID) task that measured hedonic value (valence ratings of reward vs. neutral cue, success, or fail), incentive motivation (reaction time to reward vs. neutral success), and reward sensitivity (blood-oxygen-level-dependent activation during functional magnetic resonance imaging in response to food reward vs. neutral anticipation and receipt) in predefined brain regions of interest (ROIs): the caudate, nucleus accumbens, putamen, amygdala, and hypothalamus. METHODS: A total of 42 healthy subjects between the ages of 21 and 45 with body mass index between 18 and 35 were enrolled. Each participant completed a stress visit, during which the stress version of the MAST was administered, and a no-stress visit, during which the no-stress version of the MAST was administered. The order of visits for each subject was randomly assigned. Demographic data as well as physiological, subjective self-report, and neural measures were obtained at each visit. RESULTS: Subjects experienced greater percent increase in cortisol from pre-MAST to post-MAST at the stress visit than the no-stress visit. At the stress visit, post-MAST raw cortisol levels were significantly higher in males than in females and pre-FID raw ghrelin levels were significantly higher in females than males. Subjects endorsed higher perceived threat, lower pre-scan state anxiety, and more negative post-MAST mood at the stress visit compared to the no-stress visit. During the stress visit, no significant sex differences were found in perceived threat, state anxiety, or mood. Lastly, there were no main effects of visit or sex on appetite, valence ratings, and functional response in the ROIs. Across visits, females reacted significantly slower than males to food reward and neutral cues. There was a significant effect of phase on functional response in the amygdala, but not in any other ROIs, with subjects across visits showing significantly greater amygdala activation in response to food reward (vs. neutral) receipt than anticipation. DISCUSSION: Our study revealed, as predicted, that there was a significant effect of stress on cortisol and ghrelin, and on subjective self-reported perceived threat, pre-scan state anxiety, and post-MAST mood. At the stress visit, compared to the no-stress visit, subjects showed greater increase in cortisol and reported higher perceived threat, lower pre-scan state anxiety, and more negative post-MAST mood, indicating that the stressful impact of the MAST induced the intended physiological consequences. Sex differences were observed in the effect of stress on cortisol at post-MAST time point (T20) and on ghrelin at pre-FID time point (T80). Our findings support sex differences in ghrelin and cortisol response to stress in agreement with previous studies’ findings. We failed to reject the null hypothesis that there is no effect of stress on appetite, valence ratings, reaction times, and functional response in the ROIs in response to food reward (vs. neutral) anticipation and receipt. We also did not find significant sex differences, or interactions involving sex, in perceived threat, state anxiety, appetite, mood, or valence ratings. Notably, we did not detect statistically significant sex differences in blood-oxygen-level-dependent signal activation in the caudate, nucleus accumbens, putamen, amygdala, or hypothalamus in response to reward (vs. neutral) anticipation and receipt. Future research can extend our findings by examining individual and potential sex differences in pervasive trait-level qualities to better understand the role of emotional eating tendencies on ghrelin, and reward anticipation and receipt

Charge Characteristics of Agouti-Related Protein Implicate Potent Involvement of Heparan Sulfate Proteoglycans in Metabolic Function.

The endogenous melanocortin peptide agouti-related protein (AgRP) plays a well-known role in foraging, but its contribution to metabolic regulation is less understood. Mature AgRP(83-132) has distinct residues for melanocortin receptor binding and heparan sulfate interactions. Here, we show that AgRP increases ad libitum feeding and operant responding for food in mice, decreases oxygen consumption, and lowers body temperature and activity, indicating lower energy expenditure. AgRP increased the respiratory exchange ratio, indicating a reduction of fat oxidation and a shift toward carbohydrates as the primary fuel source. The duration and intensity of AgRP's effects depended on the density of its positively charged amino acids, suggesting that its orexigenic and metabolic effects depend on its affinity for heparan sulfate. These findings may have major clinical implications by unveiling the critical involvement of interactions between AgRP and heparan sulfate to the central regulation of energy expenditure, fat utilization, and possibly their contribution to metabolic disease

The Role of Thermodynamic Phase Shifts in the Extratropical Cloud Optical Depth Feedback

No abstract availabl

Multi-GPU Acceleration of the iPIC3D Implicit Particle-in-Cell Code

iPIC3D is a widely used massively parallel Particle-in-Cell code for the simulation of space plasmas. However, its current implementation does not support execution on multiple GPUs. In this paper, we describe the porting of iPIC3D particle mover to GPUs and the optimization steps to increase the performance and parallel scaling on multiple GPUs. We analyze the strong scaling of the mover on two GPU clusters and evaluate its performance and acceleration. The optimized GPU version which uses pinned memory and asynchronous data prefetching outperform their corresponding CPU versions by 5-10x on two different systems equipped with NVIDIA K80 and V100 GPUs.Comment: Accepted for publication in ICCS 201

CRISPR-Cas9 mediated cell line engineering of apoptosis pathways increases antibody expression with site-specific modifications for antibody drug conjugation

New generation of antibody drug conjugates (ADCs) have expanded the repertoire of antibody drugs in the clinic and the market for cancer and inflammation indications by using highly stable linkers to attach potent small-molecule drug to various targeting antibodies. The drug and site of drug linkage to the antibody can have profound impact on the physiochemical properties and pharmacological profile of the ADC. Ambrx has developed a technology, Eukaryotic Chemical Orthogonal Directed Engineering (EuCODE), which allows non-natural amino acids with diverse physicochemical and biological properties to be genetically encoded and site-specifically incorporated into proteins/antibodies in mammalian cells. The non-natural amino acid provides a handle for the attachment of a small-molecule drug to generate homogenous ADC with a defined Drug-to-Antibody Ratio (DAR). To establish a CHO expression system for high production of monoclonal antibodies (mAbs) containing non-natural amino acids, we successfully generated a EuCODE platform cell line stably expressing engineered amber suppressor tRNA and its cognate tRNA synthetase specific for non-natural amino acid para-acetyl phenylalanine (pAF). When transfected with antibody of interest engineered with amber nonsense codon (TAG) at selected sites suitable for drug conjugation, this EuCODE platform cell line generates stable cell lines producing pAF containing mAbs for site-specifically conjugated ADC. In order to improve production titers of pAF containing antibody and achieve a robust platform, the platform cell line and stable cell lines were further evolved using CRISPR/Cas9 genome editing technology to sequentially knock out selected genes in glutamine synthesis and apoptosis pathways to improve selection efficiency and prevent loss of viable cell mass in production cultures, respectively. Inhibition of apoptosis pathway leads to dramatic increase in viable cell mass and results in extended production time and increased productivity. Phenotypic and genetic properties of these CRISPR engineered cell lines and product quality of the antibody will be discussed in the context of using the platform to develop a commercial manufacturing cell line

ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects.

BackgroundDolutegravir (DTG), a once-daily, human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF).MethodsING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy-naive, HIV-1-infected adults. Subjects received DTG (50 mg) plus abacavir/lamivudine (600/300 mg) once daily. The CSF and plasma (total and unbound) DTG concentrations were measured at weeks 2 and 16. The HIV-1 RNA levels were measured in CSF at baseline and weeks 2 and 16 and in plasma at baseline and weeks 2, 4, 8, 12, and 16.ResultsThirteen white men enrolled in the study; 2 withdrew prematurely, 1 because of a non-drug-related serious adverse event (pharyngitis) and 1 because of lack of treatment efficacy. The median DTG concentrations in CSF were 18 ng/mL (range, 4-23 ng/mL) at week 2 and 13 ng/mL (4-18 ng/mL) at week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from baseline in CSF (n = 11) and plasma (n = 12) HIV-1 RNA were -3.42 and -3.04 log10 copies/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA levels <50 copies/mL and 10 of 11 (91%) had CSF HIV-1 RNA levels <2 copies/mL at week 16.ConclusionsThe DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma. Clinical Trials Registration. NCT01499199