No description available.

No description available.

Les effets des émotions sur l’attention et la mémoire sont très documentés dans la littérature chez le sujet sain. Dans le trouble bipolaire, les données de la littérature suggérant la présence de schémas cognitifs dysfonctionnels, y compris durant l’euthymie, nous avons émis l’hypothèse que ces schémas pouvaient entraîner des biais mnésiques envers les stimuli émotionnels ainsi que des troubles de la régulation des émotions. Nous avons étudié l’effet implicite d’expressions faciales positives et négatives sur l’encodage de l’identité chez des patients à l’euthymie et chez des participants témoins. Nos résultats montrent un effet perturbateur de l’expression de joie sur l’encodage de l’identité chez les patients. Nous avons également étudié l’effet de la volition sur l’efficacité d’une stratégie de régulation émotionnelle, la réévaluation cognitive. En effet, en plus de trouble de la régulation émotionnelle, des perturbations des processus motivationnels ont également été documentées. Cette étude, conduite chez des participants témoins, a montré pour les valences émotionnelles positives et négatives, une augmentation de l’efficacité de cette stratégie lorsque les participants choisissent eux-mêmes de l’utiliser comparé à lorsqu’ils y sont contraints. Cette étude sera menée dans le trouble bipolaire afin de vérifier si un déficit de motivation est associé à une perte d’efficacité de cette stratégie de régulation des émotions. Ces données permettent de considérer les biais attentionnels et mnésiques pour les émotions positives comme un potentiel marqueur de trait du trouble ainsi que l’importance de la motivation dans l’efficacité de la stratégie de réévaluation cognitive. / The effects of emotions on attention and memory are widely documented in the literature in healthy subjects. On the basis of data from the literature suggesting the presence of dysfunctional cognitive patterns in bipolar disorder, including during euthymia, we hypothesized that these patterns could lead to memory biases towards emotional stimuli but also to impairments emotion regulation. We first studied the implicit effect of positive and negative facial expressions on identity encoding in euthymic bipolar patients and in healthy participants. Our results show a disruptive effect of expression of joy on identity encoding in bipolar patients, which distinguishes them from healthy participants. Second, we conducted a study to evaluate the effect of volition on the effectiveness of an emotional regulation strategy, cognitive reassessment. In addition to emotional regulation disorders, disturbances of motivational processes have also been documented in bipolar disorder. This study, which has so far been conducted only in healthy, showed for positive and negative emotional valences an increase in the effectiveness of the cognitive reappraisal strategy when participants choose to use it themselves compared to when forced to do so. The same study will soon be conducted on euthymic bipolar disorders patients, to see if a lack of motivation is associated with a loss of effectiveness of this strategy for regulating emotions. These data highlights the importance of considering attention and memory biases for positive emotions as a potential marker of bipolar disorder and the importance of motivation in the effectiveness of the cognitive reappraisal strategy.

No description available.

No description available.

A wide variety of cellular processes are regulated via the post-translation modification of substrate proteins by either ubiquitin or the small ubiquitin-like modifier, SUMO. In recent years, points of convergence between the once thought distinct and independent SUMO- and ubiquitin-conjugation pathways have been identified. The ubiquitin E3 ligase RNF4 catalyses the addition of ubiquitin modifications to previously SUMO modified proteins. This results in hybrid chains of SUMO and ubiquitin decorating target substrates. Do these SUMO-ubiquitin hybrid chains act as unique signals, distinct from the SUMO and ubiquitin chains that make them? Are there proteins that recognise them as such? The first part of this thesis details a protocol to identify and characterise the affinity of cellular proteins for ‘baits’ consisting of hybrid chains of SUMO and ubiquitin. This affinity chromatography based approach when coupled with high resolution mass spectrometry identified 30 proteins from HEK 293 cellular extracts that were putatively identified as showing affinity specifically for SUMO-ubiquitin hybrid chains. Validation of this approach comes from the identification of the recently postulated SUMO-ubiquitin hybrid chain interacting protein RAP80 amongst the proteins identified as putative SUMO-ubiquitin hybrid chain interacting proteins. SUMO-ubiquitin hybrid chains are then evaluated in an in vivo context. A proximity ligation assay was developed to probe the association between SUMO, ubiquitin and RAP80, suggesting a tight association between the three after DNA damage inducing stimuli. Interesting, the SUMO targeted ubiquitin E3 ligase RNF4 was shown not to be required for the recruitment of RAP80 to sites of DNA damage. The association between RAP80, SUMO, and ubiquitin was probed further by immunoprecipitaion of RAP80 from cell extracts after a SUMO specific proteases treatment. This SUMO specific protease treatment resulted in the loss of high molecular weight ubiquitin conjugates from RAP80 immunoprecipitated material suggesting that some RAP80 associated material is carrying SUMOylation dependent ubiquitin modifications. A SILAC based gel shift assay utilising both ubiquitin and SUMO-specific proteases was then developed to identify proteins that may anchor SUMO-ubiquitin hybrid chains. Although technically challenging, S100A8 was identified as a protein that after the action of ubiquitin and SUMO proteases shifts in a pattern consistent with that expected of a protein that may anchor a SUMO-ubiquitin hybrid chain.

Hypoxia is a relevant physiological stress associated with many processes such as adaptation to high altitudes or human diseases (e.g. cancer). An essential component responsible to regulate the molecular response to hypoxia in the cell is the transcription factor called Hypoxia Inducible Factor (HIF). HIF has recently been associated with a role in inflammation and immunity. Importantly, HIF-1alpha has shown to be regulated by the major inflammatory responsive transcription factor, NF-kappaB (nuclear factor kappaB). Here it is demonstrated that hypoxia also activates NF-kappaB in the context of a whole organism, Drosophila melanogaster, and that NF-kappaB is essential for the survival of these animals in hypoxia. The finding that NF-kappaB activation results in HIF stabilisation and activity, suggests a functional involvement of HIF transcription factor in processes where NF-kappaB is involved, in particular in response to infection and inflammation. In this work, HIF was shown to have a critical role in regulating the innate immune system by repressing NF-kappaB in a context of Drosophila, and also in human cancer cell lines. Importantly, HIF-1alpha depletion resulted in enhancement of CDK6-RelA association, and consequently increased inflammatory cytokines, such as IL-8. Functionally, this was relevant as it led to more angiogenesis in an in vitro model. A genome-wide analysis was also performed in order to understand the role of HIF in inflammation. This has revealed 2495 potential novel HIF-dependent target genes in inflammation, in which several of them were known hypoxia-induced HIF, or NF-kappaB target genes. Finally, it was also shown that HIF-1alpha and HIF-1beta physically interact with some NF-kappaB subunits. Additionally, HIF-1beta and HIF-2alpha were shown to be required for full activation of NF-kappaB following TNF-alpha. With this work, a new layer of complexity of the HIF-NF-kappaB crosstalk has been identified. These findings uncover a novel effect of HIF over the NF-kappaB pathway, with relevance for potential new therapies in inflammatory diseases and cancer.

La littérature sur les processus d’intégration multisensoriels (i.e., transformations sensorimotrice) avant et pendant des mouvements volontaires ont principalement utilisé des cibles visuelles. Considérant que la modalité d’une cible influence le cadre de référence utilisé pour contrôler un mouvement volontaire, l’objectif principal des trois expériences de la présente thèse était d’examiner ces processus de transformations sensorimotrices, et ce, spécifiquement pour des mouvements vers un cible somatosensorielle. Les deux premières expériences ont examiné les transformations sensorimotrices pendant la planification du mouvement. L’objectif de la troisième expérience était d’examiner les transformations sensorimotrices utilisée pour le contrôle du mouvement vers une cible somatosensorielle. Les résultats des deux premières expériences indiquent que des même des signaux auditifs peuvent faciliter l’utilisation d’un cadre de référence visuel du corps pour transformer la position de cibles somatosensorielles. Ces processus de transformation pourraient nécessiter des processus supplémentaires et engagent clairement des réseaux corticaux visuels et visuomoteurs. De plus, les résultats de la troisième expérience indique que des corrections apportées aux mouvements vers des cibles somatosensorielles perturbées prennent moins de temps pour être initiées en plus d’être plus efficaces et précises que des corrections apportées aux mouvement vers des cibles visuelles. De plus, cette troisième expérience indique que des cibles somatosensorielles ne sont pas nécessairement transformées dans un référentiel visuel avant de corriger un mouvement volontaire en cours d’exécution. / Research on multisensory integration for goal-directed movements has focused on targets external to the body. In this dissertation, three experiments were conducted to examine sensorimotor transformation processes for movements to body positions (i.e., somatosensory targets). The goal of the first experiment was to investigate if the modality of the cue used to indicate the location of a somatosensory target affects the body representation used to encode the target’s position during movement planning. The results showed that auditory cues prompted the use of an exteroceptive body representation for the encoding of movements to somatosensory targets in visual coordinates. The goal of the second experiment was expand on this finding and examine the neural processes associated with the visual remapping auditory-cued somatosensory targets. It was found that the sensorimotor transformation processes responsible for the conversion of somatosensory target positions to visual coordinates engages visuomotor cortical networks to a greater extent than movements to external visual targets. The goal of the third experiment was to examine the sensorimotor transformation processes employed for the online control of movements to somatosensory targets. These results provide evidence that the remapping of somatosensory targets into visual coordinates may not occur prior to online corrections. Altogether the findings of this thesis reveal that sensory cues can facilitate the remapping of somatosensory targets prior to goal directed actions. However, these remapping processes may be too costly to engage in during online control when there is no vision of the reaching limb.

El objetivo de esta investigación fue obtener un modelo matemático de calibración que permita estimar cuantitativamente el patrón ventilatorio (PV), en términos de volumen, en un grupo de voluntarios sanos y pacientes con enfermedad pulmonar obstructiva crónica (EPOC). Todo ello a partir de la información regional de la variación temporal de impedancia eléctrica obtenida con el equipo TIE4sys (sistema de tomografía por impedancia eléctrica), prescindiendo de la calibración individual con un neumotacómetro. Para lograr este objetivo la presente investigación se dividió en dos etapas. La primera etapa consistió en obtener y evaluar un grupo de ecuaciones de calibración utilizando 7 regiones de interés (ROI) en un grupo de voluntarios sanos (hombres y mujeres). La primera ROI incluyó todos los elementos de la imagen TIE. Dos ROI fueron definidas usando solamente los pixeles con variación superior al 70% y 30% de la máxima (método porcentajes). Dos fueron obtenidas definiendo el contorno de forma manual (método mouse) usando como referencia las ROI anteriores. Las dos últimas fueron máscaras elípticas con excentricidad 0,8 y eje mayor de 32 y 25 pixeles, respectivamente. En el caso de hombres, la media del coeficiente de determinación (R2) de las ecuaciones de calibración fue de 93 ± 5%. Los parámetros comunes en todas ellas fueron el pliegue subescapular y peso. Las menores dispersiones en la estimación de volumen se obtuvieron usando todos los elementos de la imagen, la ROI reducida al 70% con el método porcentajes y ambas máscaras elípticas. El valor medio de dichas dispersiones fue del 8%. En el caso de mujeres se analizaron 4 grupos: el grupo total y 3 que resultaron de estratificar la muestra en función al IMC. La media del R2 de todas las ecuaciones de calibración fue del 58 ± 12%. El parámetro más significativo en todas ellas fue la edad. En todos los grupos de mujeres se obtuvieron dispersiones en la estimación de volumen muy elevadas cuyo valor medio fue del 28 ± 5%. / The goal of this research is to obtain a mathematical calibration model to estimate, in a quantitative way and in terms of volume, the ventilatory pattern in a group of healthy volunteers and chronic obstructive pulmonary disease (COPD) patients. Several models were built from the changes on the regional electrical impedance obtained by TIE4sys (electrical impedance tomograph), without requiring an individual calibration with a pneumotachometer. In order to achieve this aim, the research was divided into 2 parts. The first part involved obtaining and assessing a set of calibration equations, using 7 regions of interest (ROI), in a group of healthy volunteers (males and females). The first ROI included all EIT image elements. Two ROI were defined by only including the pixels displaying changes larger than 70% and 30% of the maximum value of pixel change (percentage method). Two were determined by defining the region boundaries manually (mouse method), using as a reference the above ROI. The remaining two were elliptical masks with eccentricity of 0,8 and major axis of 32 and 25 pixels, respectively. In the case of healthy males, the mean value of the determination coefficients (R2) of all calibration equations was 93±5%. The parameters appearing in all of them were the subscapular skinfold and the weight. The smallest volume estimation dispersions obtained with TIE4sys were those using all elements of ROI, the reduced ROI by percentage method to 70% and both elliptical masks. The mean value of these volume estimation dispersions was of 8%. The group of female volunteers was further divided in 4 groups, one including all females and 3 groups obtained from the stratification of the sample according to BMI. The mean value of R2 of all calibration equations was of 58±12%. The most significant parameter involved in all of them was the age. The dispersion in the estimation of volume for all groups was of 28±3%.The second part involved the assessment of the previous healthy male calibration equations in a group of COPD patients. Preliminary results showed an underestimation of volume estimations obtained by TIE4sys. Due to this fact, a set of adjustment mathematical models were obtained in order to improve the estimation of volume. The mean value of R2 of all adjustment equations obtained in this group was 87±7%. The most significant parameters involved in these equations were subscapular skinfold and weight. The smallest volume estimation dispersions by TIE4sys were obtained by using the elliptical mask with major axis of 25 pixels. The mean value of these dispersions was 14±1%. Furthermore, a subgroup of patients for which all pulmonary function tests (PFT) were available, was analyzed. The mean value of R2 of all adjustment equations obtained in this sample was 88±6%. From all PFT parameters, only the pressure of carbon dioxide in arterial blood (PCO2) was involved in 4 of 7 adjustment equations obtained in this group. The mean value of volume dispersions obtained by TIE4sys, using this 4 equations, was of 19±6%. This value is higher than the one obtained for the whole group. Conclusion. The mathematical adjustment of the calibration equations for healthy males was better than the one obtained for females. This fact highlighted that the anthropometric parameters used in the male group were statistically significant, while they were not for females. For this reason, larger volume estimation dispersions were obtained in this latter group. In the case of COPD patients, all healthy male calibration equations were improved by a mathematical adjustment model. In this case, the smallest volume estimation dispersions were obtained by using the elliptical mask with major axis of 25 pixels. The results obtained in the group of healthy males and COPD patients have been encouraging and it leads us to think that EIT technique can become part of PFT. In the case of females additional efforts should be made to find a calibration equation

The rate of ribosome biogenesis regulates the growth rate of the cell and is believed to be linked to the cell’s proliferative potential. Moreover, ribosome production is down-regulated in terminally differentiated cells and up-regulated in the majority of cancers. rRNA transcription is regulated in these processes although much remains unclear about the regulation of rRNA processing. In eukaryotes, 18S ribosomal RNA (rRNA) processing is mediated by the small subunit (SSU) processome. This is composed of the U3 small nucleolar (sno)RNP, many sub-complexes and a range of putative rRNA binding and modifying proteins. It is not clear however, which proteins bind or cleave the pre-rRNA, with the exception of NOB1. Moreover, the majority of research to date has been conducted in the yeast Saccharomyces cerevisiae whereas the human SSU processome remains largely unstudied. Here we report that U3 snoRNP accumulation and function are regulated through the U3-specific hU3-55k protein. We demonstrate that U3 snoRNP levels are specifically down-regulated during human lung (CaLu-3) and colon (CaCo-2) epithelial cell differentiation and that this is likely mediated through regulating hU3- 55k levels. Moreover, CaCO-2 adenocarcinoma cells are believed to revert to their pre-cancerous phenotype during differentiation, suggesting that U3 snoRNP levels increase during tumourogenesis. We also show that phosphorylation of hU3-55k is likely to be essential for U3 snoRNP function; being required for the initial cleavage of the pre-rRNA. We therefore demonstrate two independent mechanisms that may regulate ribosome biogenesis through hU3-55k. We also demonstrate that the human and yeast SSU processomes contain many orthologous proteins. However, components responsible for 3’ pre-18S rRNA processing may function at temporally and spatially different points to their counterparts in yeast. Nonetheless, PNO1 and NOB1 are closely associated, with their nucleocytoplasmic shuttling affected by blocking pre-rRNA transcription, CRM1 mediated export and the mTOR pathway, likely preventing pre-40S export to the cytoplasm. This suggests yet another level of regulation to ribosome biogenesis through pre-rRNA processing