16q24.1 microdeletion in a premature newborn: Usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn.

OBJECTIVE:: Report of a 16q24.1 deletion in a premature newborn, demonstrating the usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn and multiple congenital malformations. DESIGN:: Descriptive case report. SETTING:: Genetic department and neonatal intensive care unit of a tertiary care children's hospital. INTERVENTIONS:: None. PATIENT:: We report the case of a preterm male infant, born at 26 wks of gestation. A cardiac malformation and bilateral hydronephrosis were diagnosed at 19 wks of gestation. Karyotype analysis was normal, and a 22q11.2 microdeletion was excluded by fluorescence in situ hybridization analysis. A cesarean section was performed due to fetal distress. The patient developed persistent pulmonary hypertension unresponsive to mechanical ventilation and nitric oxide treatment and expired at 16 hrs of life. MEASUREMENTS AND MAIN RESULTS:: An autopsy revealed partial atrioventricular canal malformation and showed bilateral dilation of the renal pelvocaliceal system with bilateral ureteral stenosis and annular pancreas. Array-based comparative genomic hybridization analysis (Agilent oligoNT 44K, Agilent Technologies, Santa Clara, CA) showed an interstitial microdeletion encompassing the forkhead box gene cluster in 16q24.1. Review of the pulmonary microscopic examination showed the characteristic features of alveolar capillary dysplasia with misalignment of pulmonary veins. Some features were less prominent due to the gestational age. CONCLUSIONS:: Our review of the literature shows that alveolar capillary dysplasia with misalignment of pulmonary veins is rare but probably underreported. Prematurity is not a usual presentation, and histologic features are difficult to interpret. In our case, array-based comparative genomic hybridization revealed a 16q24.1 deletion, leading to the final diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins. It emphasizes the usefulness of array-based comparative genomic hybridization analysis as a diagnostic tool with implications for both prognosis and management decisions in newborns with refractory persistent pulmonary hypertension and multiple congenital malformations.

Stereospecificity of the siderophore pyochelin outer membrane transporters in fluorescent pseudomonads.

Pyochelin (Pch) and enantio-pyochelin (EPch) are enantiomer siderophores that are produced by Pseudomonas aeruginosa and Pseudomonas fluorescens, respectively, under iron limitation. Pch promotes growth of P. aeruginosa when iron is scarce, and EPch carries out the same biological function in P. fluorescens. However, the two siderophores are unable to promote growth in the heterologous species, indicating that siderophore-mediated iron uptake is highly stereospecific. In the present work, using binding and iron uptake assays, we found that FptA, the Fe-Pch outer membrane transporter of P. aeruginosa, recognized (K(d) = 2.5 +/- 1.1 nm) and transported Fe-Pch but did not interact with Fe-EPch. Likewise, FetA, the Fe-EPch receptor of P. fluorescens, was specific for Fe-EPch (K(d) = 3.7 +/- 2.1 nm) but did not bind and transport Fe-Pch. Growth promotion experiments performed under iron-limiting conditions confirmed that FptA and FetA are highly specific for Pch and EPch, respectively. When fptA and fetA along with adjacent transport genes involved in siderophore uptake were swapped between the two bacterial species, P. aeruginosa became able to utilize Fe-EPch as an iron source, and P. fluorescens was able to grow with Fe-Pch. Docking experiments using the FptA structure and binding assays showed that the stereospecificity of Pch recognition by FptA was mostly due to the configuration of the siderophore chiral centers C4'' and C2'' and was only weakly dependent on the configuration of the C4' carbon atom. Together, these findings increase our understanding of the stereospecific interaction between Pch and its outer membrane receptor FptA.

Defining the RNA polymerase III transcriptome: Genome-wide localization of the RNA polymerase III transcription machinery in human cells.

Our view of the RNA polymerase III (Pol III) transcription machinery in mammalian cells arises mostly from studies of the RN5S (5S) gene, the Ad2 VAI gene, and the RNU6 (U6) gene, as paradigms for genes with type 1, 2, and 3 promoters. Recruitment of Pol III onto these genes requires prior binding of well-characterized transcription factors. Technical limitations in dealing with repeated genomic units, typically found at mammalian Pol III genes, have so far hampered genome-wide studies of the Pol III transcription machinery and transcriptome. We have localized, genome-wide, Pol III and some of its transcription factors. Our results reveal broad usage of the known Pol III transcription machinery and define a minimal Pol III transcriptome in dividing IMR90hTert fibroblasts. This transcriptome consists of some 500 actively transcribed genes including a few dozen candidate novel genes, of which we confirmed nine as Pol III transcription units by additional methods. It does not contain any of the microRNA genes previously described as transcribed by Pol III, but reveals two other microRNA genes, MIR886 (hsa-mir-886) and MIR1975 (RNY5, hY5, hsa-mir-1975), which are genuine Pol III transcription units.

The role of the inflammasome in nonmyeloid cells.

Inflammasomes are cytosolic multiprotein complexes that can proteolytically activate caspase-1. Activated caspase-1 is needed for the maturation and secretion of interleukin (IL)-1beta and IL-18. In the past decade, there has been tremendous progress in our knowledge of inflammasome function and IL-1 signaling, mainly in cells of the innate immune system, such as monocytes, macrophages, neutrophils, and dendritic cells. Because nonimmune cells, including keratinocytes, synovial cells, or astrocytes, can form an interface between the body and the environment or a defined compartment (brain, joint), they are important guardians for the detection of danger signals and the consecutive initiation of an inflammatory response. They are present in anatomical compartments that are less accessible to myeloid cells and thus can fulfill tasks usually performed by residential macrophages. This review focuses on recent progress in our understanding of the processing and functional role of IL-1 in epithelial, mesenchymal, and neuronal cells and in conditions such as tissue repair.

Multiscale assessment of plant diversity in wooded pastures of the Jura mountains

Résumé La diminution de la biodiversité, à toutes les échelles spatiales et sur l'ensemble de la planète, compte parmi les problèmes les plus préoccupants de notre époque. En terme de conservation, il est aujourd'hui primordial de mieux comprendre les mécanismes qui créent et maintiennent la biodiversité dans les écosystèmes naturels ou anthropiques. La présente étude a pour principal objectif d'améliorer notre compréhension des patrons de biodiversité végétale et des mécanismes sous jacents, dans un écosystème complexe, riche en espèces et à forte valeur patrimoniale, les pâturages boisés jurassiens. Structure et échelle spatiales sont progressivement reconnues comme des dimensions incontournables dans l'étude des patrons de biodiversité. De plus, ces deux éléments jouent un rôle central dans plusieurs théories écologiques. Toutefois, peu d'hypothèses issues de simulations ou d'études théoriques concernant le lien entre structure spatiale du paysage et biodiversité ont été testées de façon empirique. De même, l'influence des différentes composantes de l'échelle spatiale sur les patrons de biodiversité est méconnue. Cette étude vise donc à tester quelques-unes de ces hypothèses et à explorer les patrons spatiaux de biodiversité dans un contexte multi-échelle, pour différentes mesures de biodiversité (richesse et composition en espèces) à l'aide de données de terrain. Ces données ont été collectées selon un plan d'échantillonnage hiérarchique. Dans un premier temps, nous avons testé l'hypothèse élémentaire selon laquelle la richesse spécifique (le nombre d'espèces sur une surface donnée) est liée à l'hétérogénéité environnementale quelque soit l'échelle. Nous avons décomposé l'hétérogénéité environnementale en deux parties, la variabilité des conditions environnementales et sa configuration spatiale. Nous avons montré que, en général, la richesse spécifique augmentait avec l'hétérogénéité de l'environnement : elle augmentait avec le nombre de types d'habitats et diminuait avec l'agrégation spatiale de ces habitats. Ces effets ont été observés à toutes les échelles mais leur nature variait en fonction de l'échelle, suggérant une modification des mécanismes. Dans un deuxième temps, la structure spatiale de la composition en espèces a été décomposée en relation avec 20 variables environnementales et 11 traits d'espèces. Nous avons utilisé la technique de partition de la variation et un descripteur spatial, récemment développé, donnant accès à une large gamme d'échelles spatiales. Nos résultats ont montré que la structure spatiale de la composition en espèces végétales était principalement liée à la topographie, aux échelles les plus grossières, et à la disponibilité en lumière, aux échelles les plus fines. La fraction non-environnementale de la variation spatiale de la composition spécifique avait une relation complexe avec plusieurs traits d'espèces suggérant un lien avec des processus biologiques tels que la dispersion, dépendant de l'échelle spatiale. Dans un dernier temps, nous avons testé, à plusieurs échelles spatiales, les relations entre trois composantes de la biodiversité : la richesse spécifique totale d'un échantillon (diversité gamma), la richesse spécifique moyenne (diversité alpha), mesurée sur des sous-échantillons, et les différences de composition spécifique entre les sous-échantillons (diversité beta). Les relations deux à deux entre les diversités alpha, beta et gamma ne suivaient pas les relations attendues, tout du moins à certaines échelles spatiales. Plusieurs de ces relations étaient fortement dépendantes de l'échelle. Nos résultats ont mis en évidence l'importance du rapport d'échelle (rapport entre la taille de l'échantillon et du sous-échantillon) lors de l'étude des patrons spatiaux de biodiversité. Ainsi, cette étude offre un nouvel aperçu des patrons spatiaux de biodiversité végétale et des mécanismes potentiels permettant la coexistence des espèces. Nos résultats suggèrent que les patrons de biodiversité ne peuvent être expliqués par une seule théorie, mais plutôt par une combinaison de théories. Ils ont également mis en évidence le rôle essentiel joué par la structure spatiale dans la détermination de la biodiversité, quelque soit le composant de la biodiversité considéré. Enfin, cette étude souligne l'importance de prendre en compte plusieurs échelles spatiales et différents constituants de l'échelle spatiale pour toute étude relative à la diversité spécifique. Abstract The world-wide loss of biodiversity at all scales has become a matter of urgent concern, and improving our understanding of local drivers of biodiversity in natural and anthropogenic ecosystems is now crucial for conservation. The main objective of this study was to further our comprehension of the driving forces controlling biodiversity patterns in a complex and diverse ecosystem of high conservation value, wooded pastures. Spatial pattern and scale are central to several ecological theories, and it is increasingly recognized that they must be taken -into consideration when studying biodiversity patterns. However, few hypotheses developed from simulations or theoretical studies have been tested using field data, and the evolution of biodiversity patterns with different scale components remains largely unknown. We test several such hypotheses and explore spatial patterns of biodiversity in a multi-scale context and using different measures of biodiversity (species richness and composition), with field data. Data were collected using a hierarchical sampling design. We first tested the simple hypothesis that species richness, the number of species in a given area, is related to environmental heterogeneity at all scales. We decomposed environmental heterogeneity into two parts: the variability of environmental conditions and its spatial configuration. We showed that species richness generally increased with environmental heterogeneity: species richness increased with increasing number of habitat types and with decreasing spatial aggregation of those habitats. Effects occurred at all scales but the nature of the effect changed with scale, suggesting a change in underlying mechanisms. We then decomposed the spatial structure of species composition in relation to environmental variables and species traits using variation partitioning and a recently developed spatial descriptor, allowing us to capture a wide range of spatial scales. We showed that the spatial structure of plant species composition was related to topography at the coarsest scales and insolation at finer scales. The non-environmental fraction of the spatial variation in species composition had a complex relationship with several species traits, suggesting a scale-dependent link to biological processes, particularly dispersal. Finally, we tested, at different spatial scales, the relationships between different components of biodiversity: total sample species richness (gamma diversity), mean species .richness (alpha diversity), measured in nested subsamples, and differences in species composition between subsamples (beta diversity). The pairwise relationships between alpha, beta and gamma diversity did not follow the expected patterns, at least at certain scales. Our result indicated a strong scale-dependency of several relationships, and highlighted the importance of the scale ratio when studying biodiversity patterns. Thus, our results bring new insights on the spatial patterns of biodiversity and the possible mechanisms allowing species coexistence. They suggest that biodiversity patterns cannot be explained by any single theory proposed in the literature, but a combination of theories is sufficient. Spatial structure plays a crucial role for all components of biodiversity. Results emphasize the importance of considering multiple spatial scales and multiple scale components when studying species diversity.

Mutation screening of the urocortin gene: identification of new single nucleotide polymorphisms and association studies with obesity in French Caucasians.

A linkage between obesity-related phenotypes and the 2p21-23 locus has been reported previously. The urocortin (UCN) gene resides at this interval, and its protein decreases appetite behavior, suggesting that UCN may be a candidate gene for susceptibility to obesity. We localized the UCN gene by radiation hybrid mapping, and the surrounding markers were genotyped in a collection of French families. Evidence for linkage was shown between the marker D2S165 and leptin levels (LOD score, 1.34; P = 0.006) and between D2S2247 and the z-score of body mass index (LOD score, 1.829; P = 0.0019). The gene was screened for SNPs in 96 obese patients. Four new variants were established. Two single nucleotide polymorphisms were located in the promoter (-535 A-->G, -286 G-->A), one in intron 1 (+31 C-->G), and one in the 3'-untranslated region (+34 C-->T). Association studies in cohorts of 722 unrelated obese and 381 control subjects and transmission disequilibrium tests, performed for the two frequent promoter polymorphisms, in 120 families (894 individuals) showed that no association was present between these variants and obesity, obesity-related phenotypes, and diabetes. Thus, our analyses of the genetic variations of the UCN gene suggest that, at least in French Caucasians, they do not represent a major cause of obesity.

Insights into the biogeographical history of the Lower Guinea Forest Domain: evidence for the role of refugia in the intraspecific differentiation of Aucoumea klaineana.

Determining the biogeographical histories of rainforests is central to our understanding of the present distribution of tropical biodiversity. Ice age fragmentation of central African rainforests strongly influenced species distributions. Elevated areas characterized by higher species richness and endemism have been postulated to be Pleistocene forest refugia. However, it is often difficult to separate the effects of history and of present-day ecological conditions on diversity patterns at the interspecific level. Intraspecific genetic variation could yield new insights into history, because refugia hypotheses predict patterns not expected on the basis of contemporary environmental dynamics. Here, we test geographically explicit hypotheses of vicariance associated with the presence of putative refugia and provide clues about their location. We intensively sampled populations of Aucoumea klaineana, a forest tree sensitive to forest fragmentation, throughout its geographical range. Characterizing variation at 10 nuclear microsatellite loci, we were able to obtain phylogeographic data of unprecedented detail for this region. Using Bayesian clustering approaches, we demonstrated the presence of four differentiated genetic units. Their distribution matched that of forest refugia postulated from patterns of species richness and endemism. Our data also show differences in diversity dynamics at leading and trailing edges of the species' shifting distribution. Our results confirm predictions based on refugia hypotheses and cannot be explained on the basis of present-day ecological conditions.

Colloid cysts of the third ventricle: correlation of MR and CT findings with histology and chemical analysis.

Eight patients with colloid cysts of the third ventricle were examined with CT and MR. In six, surgical resection was performed and the material was subjected to histologic evaluation; the concentrations of trace elements were determined by particle-induced X-ray emission. Stereotaxic aspiration was performed in two. The investigation showed that colloid cysts are often iso- or hypodense relative to brain on CT (5/8), but sometimes have a center of increased density. Increased density did not correlate with increased concentration of calcium or other metals but did not correlate with high cholesterol content. Colloid cysts appear more heterogeneous on MR (6/8) than on CT (3/8), despite a homogeneous appearance at histology. High signal on short TR/TE sequences is correlated with a high cholesterol content. A marked shortening of the T2 relaxation time is often noticed in the central part of the cyst. Analysis of trace elements showed that this phenomenon is not related to the presence of metals with paramagnetic effects. Our analysis of the contents of colloid cysts does not support the theory that differing metallic concentrations are responsible for differences in MR signal intensity or CT density. We did find that increased CT density and high MR signal correlated with high cholesterol content.

On the multiwavelength spectrum of the microquasar 1E1740.7-2942

The microquasar 1E 1740.7-2942 is a source located in the direction of the Galactic Center. It has been detected at X-rays, soft gamma-rays, and in the radio band, showing an extended radio component in the form of a double-sided jet. Although no optical counterpart has been found so far for 1E 1740.7-2942, its X-ray activity strongly points to a galactic nature. Aims.We aim to improve our understanding of the hard X-ray and gamma-ray production in the system, exploring whether the jet can emit significantly at high energies under the light of the present knowledge. Methods.We have modeled the source emission, from radio to gamma-rays, with a cold-matter dominated jet model. INTEGRAL data combined with radio and RXTE data, as well as EGRET and HESS upper-limits, are used to compare the computed and the observed spectra. Results.From our modeling, we find out that jet emission cannot explain the high fluxes observed at hard X-rays without violating at the same time the constraints from the radio data, favoring the corona origin of the hard X-rays. Also, 1E 1740.7-2942 might be detected by GLAST or AGILE at GeV energies, and by HESS and HESS-II beyond 100 GeV, with the spectral shape likely affected by photon-photon absorption in the disk and corona photon fields.

Germination, senescence and pathogenic attack in soybean (Glycine max. L.): Identification of the cytosolic aconitase participating in the glyoxylate cycle

During our study of the glyoxylate cycle in soybean (Glycine max. L. var. Maple arrow), two mitochondrial and three cytosolic aconitase molecular species (EC 4.2.1.3) were detected, designated as M1, M2, C1, C2 and C3 isoforms, respectively, according to their intracellular locations and electrophoretic mobilities. Using the glyoxylate cycle marker enzymes isocitrate lyase (ICL, EC 4.1.3.1) and malate synthase (MS, EC 4.1.3.2), the activity of this pathway providing the essential link between P-oxidation and gluconeogenesis was confirmed during germination (cotyledons) and senescence (leaves). It was then established that, in both cases, the activity of the CI aconitase isoform developed concomitantly with the transcription and translation levels of the icl and ms genes. This strongly suggests that C1 aconitase is constitutive of the glyoxylate cycle. In addition, the same isoform was found to be active during pathogenic attack as well (hypocotyls). It might be assumed that in such a case the glyoxylate cycle is reinitiated as a part of a carbon reallocation system feeding on the diseased tissue cellular components.

The cognitive subscale of the "Alzheimer's Disease Assessment Scale" in a Brazilian sample

The cognitive subscale of the "Alzheimer's Disease Assessment Scale" (ADAS-Cog) is widely used for the evaluation of dementia and is very popular in dementia drug trials because of the characteristics of the scale. The objective of the present study was to adapt the ADAS-Cog for use for the Brazilian population. A major problem is that education is variable, a fact that may influence performance in cognitive evaluation. This study was conducted on a control group (CG) of 96 subjects (25 males and 71 females aged 68 ± 8.6 years) and on 44 Alzheimer's disease (AD) patients (19 males and 25 females aged 72 ± 6.4 years) with mild dementia (Clinical Dementia Rating score 1). For statistical analysis groups were divided into three educational levels: I, 0-4 years of schooling (65 CG/20 AD); II, 5-11 years of schooling (19 CG/7 AD), and III, 12 or more years of schooling (12 CG/17 AD). The battery was applied according to original instructions. Total mean score for CG and AD was 10.9 and 22.9 for level I, 7.8 and 22.4 for level II, and 6.2 and 15.4 for level III, respectively. These results indicate that our version of the ADAS-Cog is useful to identify mild dementia, though there may be an overlapping when comparing high education demented with low education non-demented subjects.

Unique and unifying themes in the mechanisms regulating the expression of the arabidopsis thaliana PR-1 and Solanum tuberosum PR-10a inducible defense genes

Arabidopsis is a model plant used to study disease resistance; Solanum tuberosum or potato is a crop species. Both plants possess inducible defense mechanisms that are deployed upon recognition of pathogen invasion. Transcriptional reprogramming is crucial to the activation of defense responses. The Pathogenesis-Related (PR) genes are activated in these defense programs. Expression of Arabidopsis PR-l and potato PR-10a serve as markers for the deployment of defense responses in these plants. PR-l expression indicates induction of systemic acquired resistance (SAR). Activation of SAR requires accumulation of salicylic acid (SA), in addition to the interaction of the non-expressor of pathogenesis-related genes I (NPRI), with the TGA transcription factors. The PR-10a is activated in response to pathogen invasion, wounding and elicitor treatment. PR-10a induction requires recruitment of the Whirly I (Whyl) activator to the promoter. This locus is also negatively regulated by the silencer element binding factor (SEBF). We established that both the PR-l and PR-10a are occupied by repressors under non-inducing conditions. TGA2 was found to be a constitutive resident and repressor of PR-l, which mediates repression by forming an oligomeric complex on the promoter. The DNA-binding activity of this oligomer required the TGA2 N-terminus (NT). Under resting conditions we determined that the PR-10a is bound by a repressosome containing SEBF and curiously the activator Pto interacting protein 4 (Pti4). In the context of this repressosome, SEBF is responsible for PR-10a binding, yet rWe also showed that PR-l and PR-10a are activated by different means. In PR-l activation the NPRI NT domain alleviates TGA2-mediated repression by interacting with the TGA2 NT. TGA2 remains at the PR-l but adopts a dimeric conformation and forms an enhanceosome with NPRl. In contrast, the PR-10a is activated by evicting the repressosome and recruiting Why! to the promoter. These results advance our understanding of the mechanisms regulating PR-l and PR-10a expression under resting and inducing conditions. This study also revealed that the means of regulation for related genes can differ greatly between model and crop s

Manufacturing 'authenticity' : a case study of the Niagara wine cluster

In this thesis, I use "Fabricating Authenticity," a model developed in the Production of Culture Perspective, to explore the evolving criteria for judging what constitute "real" and authentic Niagara wines, along with the naturalization of these criteria, as the Canadian Niagara wine cluster has come under increasing stress from globalization. Authenticity has been identified as a hallmark of contemporary marketing and important to cultural industries, which can use it for creating meaningful differentiation; making it a renewable resource for securing consumers, increasing market value; and for relationships with key brokers. This is important as free trade and international treaties are making traditional protective barriers, like trade tariffs and markups, obsolete and as governments increasingly allocate industry support via promotion and marketing policies that are directly linked to objectives of city and regional development, which in turn carry real implications for what gets to be judged authentic and inauthentic local culture. This research uses a mixed methods research strategy, drawing upon ethnographic observation, marketing materials, newspaper reports, and secondary data to provide insight into the processes and conflicts over efforts to fabricate authenticity, comparing the periods before and after the passage of NAFT A to the present period. The Niagara wine cluster is a good case in point because it has little natural advantage nor was there a tradition of quality table wine making to facilitate the naturalization of authenticity. Geographic industrial clusters have been found particularly competitive in the global economy and the exploratory case study contributes to our understanding of the dynamic of '1abricating authenticity," building on various theoretical propositions to attempt to derive explanations of how global processes affect strategies to create "authenticity," how these strategies affect cultural homogeneity and heterogeneity at the local level, and how the concept of "cluster" contributes to the process of managing authenticity.

Manipulation of the ubiquitin-proteasome system by HIV-1 : role of the accessory protein Vpr

Le virus de l’immunodéficience humaine de type 1 (VIH-1), l’agent étiologique du SIDA, est un rétrovirus complexe arborant plusieurs protéines accessoires : Nef, Vif, Vpr, et Vpu. Celles-ci sont impliquées dans la modulation de la réplication virale, dans l’évasion immunitaire et dans la progression de la pathogenèse du SIDA. Dans ce contexte, il a été démontré que la protéine virale R (Vpr) induit un arrêt de cycle cellulaire en phase G2. Le mécanisme par lequel Vpr exerce cette fonction est l’activation, ATR (Ataxia telangiectasia and Rad3 related)-dépendante, du point de contrôle de dommage à l’ADN, mais les facteurs et mécanismes moléculaires directement impliqués dans cette activité demeurent inconnus. Afin d’identifier de nouveaux facteurs cellulaires interagissant avec Vpr, nous avons utilisé une purification d’affinité en tandem (TAP) pour isoler des complexes protéiques natifs contenant Vpr. Nous avons découvert que Vpr s’associait avec CRL4A(VprBP), un complexe cellulaire d’E3 ubiquitine ligase, comprenant les protéines Cullin 4A, DDB1 (DNA damage-binding protein 1) et VprBP (Vpr-binding protein). Nos études ont mis en évidence que le recrutement de la E3 ligase par Vpr était nécessaire mais non suffisant pour l’induction de l’arrêt de cycle cellulaire en G2, suggérant ainsi que des événements additionnels seraient impliqués dans ce processus. À cet égard, nous apportons des preuves directes que Vpr détourne les fonctions de CRL4A(VprBP) pour induire la polyubiquitination de type K48 et la dégradation protéosomale de protéines cellulaires encore inconnues. Ces événements d’ubiquitination induits par Vpr ont été démontrés comme étant nécessaire à l’activation d’ATR. Finalement, nous montrons que Vpr forme des foyers ancrés à la chromatine co-localisant avec VprBP ainsi qu’avec des facteurs impliqués dans la réparation de l’ADN. La formation de ces foyers représente un événement essentiel et précoce dans l’induction de l’arrêt de cycle cellulaire en G2. Enfin, nous démontrons que Vpr est capable de recruter CRL4A(VprBP) au niveau de la chromatine et nous apportons des preuves indiquant que le substrat inconnu ciblé par Vpr est une protéine associée à la chromatine. Globalement, nos résultats révèlent certains des ménanismes par lesquels Vpr induit des perturbations du cycle cellulaire. En outre, cette étude contribue à notre compréhension de la modulation du système ubiquitine-protéasome par le VIH-1 et son implication fonctionnelle dans la manipulation de l’environnement cellulaire de l’hôte.

The roles of the somatosensory cortices in the perception of noxious and innocuous stimuli

Résumé Les premières études électrophysiologiques et anatomiques ont établi le rôle crucial du cortex somatosensoriel primaire et secondaire (SI et SII) dans le traitement de l'information somatosensorielle. Toutefois, les récentes avancées en techniques d’imagerie cérébrale ont mis en question leur rôle dans la perception somatosensorielle. La réorganisation du cortex somatosensoriel est un phénomène qui a été proposé comme cause de la douleur du membre fantôme chez les individus amputés. Comme la plupart des études se sont concentrées sur le rôle du SI, une étude plus approfondie est nécessaire. La présente série d'expériences implique une exploration du rôle des régions somatosensorielles dans la perception des stimuli douleureux et non-douleureux chez des volontaires sains et patients avec des douleurs de membre fantôme. La première étude expérimentale présentée dans le chapitre 3 est une méta-analyse des études de neuro-imagerie employant des stimuli nociceptifs chez des volontaires sains. En comparaison aux précédentes, la présente étude permet la génération de cartes quantitatives probabilistes permettant la localisation des régions activées en réponse à des stimuli nociceptifs. Le rôle du cortex somatosensoriel dans la perception consciente de stimuli chauds a été étudié dans le chapitre 4 grâce à une étude d'imagerie par résonance magnétique fonctionnelle, dans laquelle des stimuli thermiques douloureux et non-douloureux ont été administrés de manière contrebalancée. Grâce à cette procédure, la perception de la chaleur fut atténuée par les stimuli douloureux, ce qui permit la comparaison des stimuli consciemment perçus avec ceux qui ne le furent pas. Les résultats ont montrés que les stimulations chaudes perçues ont engendré l’activation de l’aire SI controlatérale, ainsi que de la région SII. Grâce à l’évaluation clinique de patients amputés présentant une altération de leurs perceptions somatosensorielles, il est également possible de dessiner un aperçu des régions corticales qui sous-tendent ces modifications perceptuelles. Dans le chapitre 5 nous avons émis l'hypothèse proposant que les sensations du membre fantôme représentent un corrélat perceptuel de la réorganisation somatotopique des représentations sensorielles corticales. En effet, la réorganisation des sensations peut donner des indices sur les régions impliquées dans la genèse des sensations référées. Ainsi, un protocole d’évaluation sensoriel a été administré à un groupe de patients affligés de douleur au niveau du membre fantôme. Les résultats ont montré que, contrairement aux études précédentes, les sensations diffèrent grandement selon le type et l'intensité des stimuli tactiles, sans évidence de la présence d’un modèle spatialement localisé. Toutefois, les résultats actuels suggèrent que les régions corticales à champs récepteurs bilatéraux présentent également des modifications en réponse à une déafférentation. Ces études présentent une nouvelle image des régions corticales impliquées dans la perception des stimuli somatosensoriels, lesquelles comprennent les aires SI et SII, ainsi que l'insula. Les résultats sont pertinents à notre compréhension des corrélats neurologiques de la perception somatosensorielle consciente.