The duration of prograde garnet crystallization in the UHP eclogites at Lago di Cignana, Italy

The distinct core-to-rim zonation of different REEs in garnet in metamorphic rocks, specifically Sm relative to Lu, suggests that Sm-Nd and Lu-Hf isochron ages will record different times along a prograde garnet growth history. Therefore, REE zonations in garnet must be measured in order to correctly interpret the isochron ages in terms of the garnet growth interval, which could span several m.y. New REE profiles, garnet crystal size distributions, and garnet growth modeling, combined with previously published Sm-Nd and Lu-Hf geochronology on a UHP eclogite of the Zermatt-Saas Fee (ZSF) ophiolite, Lago di Cignana (Italy), demonstrate that prograde garnet growth of this sample occurred over a similar to 30 to 40 m.y. interval. Relative to peak metamorphism at 38 to 40 Ma, garnet growth is estimated to have begun at similar to 11 to 14 kbar pressure at similar to 70 to 80 Ma. Although such a protracted garnet growth interval is surprising, this is supported by plate tectonic reconstructions which suggest that subduction of the Liguro-Piemont ocean occurred through slow and oblique convergence. These results demonstrate that REE zonations in garnet, coupled to crystal size distributions, provide a powerful means for understanding prograde metamorphic paths when combined with Sm-Nd and Lu-Hf geochronology. (C) 2009 Elsevier B.V. All rights reserved.

Detailed 3D seismic imaging of a fault zone beneath Lake Geneva, Switzerland

An efficient high-resolution (HR) three-dimensional (3D) seismic reflection system for small-scale targets in lacustrine settings was developed. In Lake Geneva, near the city of Lausanne, Switzerland, the offshore extension of a complex fault zone well mapped on land was chosen for testing our system. A preliminary two-dimensional seismic survey indicated structures that include a thin (<40 m) layer of subhorizontal Quaternary sediments that unconformably overlie south-east-dipping Tertiary Molasse beds and a major fault zone (Paudeze Fault Zone) that separates Plateau and Subalpine Molasse (SM) units. A 3D survey was conducted over this test site using a newly developed three-streamer system. It provided high-quality data with a penetration to depths of 300 m below the water bottom of non-aliased signal for dips up to 30degrees and with a maximum vertical resolution of 1.1 m. The data were subjected to a conventional 3D processing sequence that included post-stack time migration. Tests with 3D pre-stack depth migration showed that such techniques can be applied to HR seismic surveys. Delineation of several horizons and fault surfaces reveals the potential for small-scale geologic and tectonic interpretation in three dimensions. Five major seismic facies and their detailed 3D geometries can be distinguished. Three fault surfaces and the top of a molasse surface were mapped in 3D. Analysis of the geometry of these surfaces and their relative orientation suggests that pre-existing structures within the Plateau Molasse (PM) unit influenced later faulting between the Plateau and SM. In particular, a change in strike of the PM bed dip may indicate a fold formed by a regional stress regime, the orientation of which was different from the one responsible for the creation of the Paudeze Fault Zone. This structure might have later influenced the local stress regime and caused the curved shape of the Paudeze Fault in our surveyed area.

Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.

BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

Cellular and molecular mechanisms underlying the effects of sleep loss on hippocampal synaptic plasticity

SUMMARY : The function of sleep for the organism is one of the most persistent and perplexing questions in biology. Current findings lead to the conclusion that sleep is primarily for the brain. In particular, a role for sleep in cognitive aspects of brain function is supported by behavioral evidence both in humans and animals. However, in spite of remarkable advancement in the understanding of the mechanisms underlying sleep generation and regulation, it has been proven difficult to determine the neurobiological mechanisms underlying the beneficial effect of sleep, and the detrimental impact of sleep loss, on learning and memory processes. In my thesis, I present results that lead to several critical steps forward in the link between sleep and cognitive function. My major result is the molecular identification and physiological analysis of a protein, the NR2A subunit of NMDA receptor (NMDAR), that confers sensitivity to sleep loss to the hippocampus, a brain structure classically involved in mnemonic processes. Specifically, I used a novel behavioral approach to achieve sleep deprivation in adult C57BL6/J mice, yet minimizing the impact of secondary factors associated with the procedure,.such as stress. By using in vitro electrophysiological analysis, I show, for the first time, that sleep loss dramatically affects bidirectional plasticity at CA3 to CA1 synapses in the hippocampus, a well established cellular model of learning and memory. 4-6 hours of sleep loss elevate the modification threshold for bidirectional synaptic plasticity (MT), thereby promoting long-term depression of CA3 to CA 1 synaptic strength after stimulation in the theta frequency range (5 Hz), and rendering long-term potentiation induction.more difficult. Remarkably, 3 hours of recovery sleep, after the deprivation, reset the MT at control values, thus re-establishing the normal proneness of synapses to undergo long-term plastic changes. At the molecular level, these functional changes are paralleled by a change in the NMDAR subunit composition. In particular, the expression of the NR2A subunit protein of NMDAR at CA3 to CA1 synapses is selectively and rapidly increased by sleep deprivation, whereas recovery sleep reset NR2A synaptic content to control levels. By using an array of genetic, pharmacological and computational approaches, I demonstrate here an obligatory role for NR2A-containing NMDARs in conveying the effect of sleep loss on CA3 to CAl MT. Moreover, I show that a genetic deletion of the NR2A subunit fully preserves hippocampal plasticity from the impact of sleep loss, whereas it does not alter sleepwake behavior and homeostatic response to sleep deprivation. As to the mechanism underlying the effects of the NR2A subunit on hippocampal synaptic plasticity, I show that the increased NR2A expression after sleep loss distinctly affects the contribution of synaptic and more slowly recruited NMDAR pools activated during plasticity-induction protocols. This study represents a major step forward in understanding the mechanistic basis underlying sleep's role for the brain. By showing that sleep and sleep loss affect neuronal plasticity by regulating the expression and function of a synaptic neurotransmitter receptor, I propose that an important aspect of sleep function could consist in maintaining and regulating protein redistribution and ion channel trafficking at central synapses. These findings provide a novel starting point for investigations into the connections between sleep and learning, and they may open novel ways for pharmacological control over hippocampal .function during periods of sleep restriction. RÉSUMÉ DU PROJET La fonction du sommeil pour l'organisme est une des questions les plus persistantes et difficiles dans la biologie. Les découvertes actuelles mènent à la conclusion que le sommeil est essentiel pour le cerveau. En particulier, le rôle du sommeil dans les aspects cognitifs est soutenu par des études comportementales tant chez les humains que chez les animaux. Cependant, malgré l'avancement remarquable dans la compréhension des mécanismes sous-tendant la génération et la régulation du sommeil, les mécanismes neurobiologiques qui pourraient expliquer l'effet favorable du sommeil sur l'apprentissage et la mémoire ne sont pas encore clairs. Dans ma thèse, je présente des résultats qui aident à clarifier le lien entre le sommeil et la fonction cognitive. Mon résultat le plus significatif est l'identification moléculaire et l'analyse physiologique d'une protéine, la sous-unité NR2A du récepteur NMDA, qui rend l'hippocampe sensible à la perte de sommeil. Dans cette étude, nous avons utilisé une nouvelle approche expérimentale qui nous a permis d'induire une privation de sommeil chez les souris C57BL6/J adultes, en minimisant l'impact de facteurs confondants comme, par exemple, le stress. En utilisant les techniques de l'électrophysiologie in vitro, j'ai démontré, pour la première fois, que la perte de sommeil est responsable d'affecter radicalement la plasticité bidirectionnelle au niveau des synapses CA3-CA1 de l'hippocampe. Cela correspond à un mécanisme cellulaire de l'apprentissage et de la mémoire bien établi. En particulier, 4-6 heures de privation de sommeil élèvent le seuil de modification pour la plasticité synaptique bidirectionnelle (SM). Comme conséquence, la dépression à long terme de la transmission synaptique est induite par la stimulation des fibres afférentes dans la bande de fréquences thêta (5 Hz), alors que la potentialisation à long terme devient plus difficile. D'autre part, 3 heures de sommeil de récupération sont suffisant pour rétablir le SM aux valeurs contrôles. Au niveau moléculaire, les changements de la plasticité synaptiques sont associés à une altération de la composition du récepteur NMDA. En particulier, l'expression synaptique de la protéine NR2A du récepteur NMDA est rapidement augmentée de manière sélective par la privation de sommeil, alors que le sommeil de récupération rétablit l'expression de la protéine au niveau contrôle. En utilisant des approches génétiques, pharmacologiques et computationnelles, j'ai démontré que les récepteurs NMDA qui expriment la sous-unité NR2A sont responsables de l'effet de la privation de sommeil sur le SM. De plus, nous avons prouvé qu'une délétion génétique de la sous-unité NR2A préserve complètement la plasticité synaptique hippocampale de l'impact de la perte de sommeil, alors que cette manipulation ne change pas les mécanismes de régulation homéostatique du sommeil. En ce qui concerne les mécanismes, j'ai .découvert que l'augmentation de l'expression de la sous-unité NR2A au niveau synaptique modifie les propriétés de la réponse du récepteur NMDA aux protocoles de stimulations utilisés pour induire la plasticité. Cette étude représente un pas en avant important dans la compréhension de la base mécaniste sous-tendant le rôle du sommeil pour le cerveau. En montrant que le sommeil et la perte de sommeil affectent la plasticité neuronale en régulant l'expression et la fonction d'un récepteur de la neurotransmission, je propose qu'un aspect important de la fonction du sommeil puisse être finalisé au règlement de la redistribution des protéines et du tracking des récepteurs aux synapses centraux. Ces découvertes fournissent un point de départ pour mieux comprendre les liens entre le sommeil et l'apprentissage, et d'ailleurs, ils peuvent ouvrir des voies pour des traitements pharmacologiques dans le .but de préserver la fonction hippocampale pendant les périodes de restriction de sommeil.

Functional chromatin features are associated with structural mutations in cancer.

BACKGROUND: Structural mutations (SMs) play a major role in cancer development. In some cancers, such as breast and ovarian, DNA double-strand breaks (DSBs) occur more frequently in transcribed regions, while in other cancer types such as prostate, there is a consistent depletion of breakpoints in transcribed regions. Despite such regularity, little is understood about the mechanisms driving these effects. A few works have suggested that protein binding may be relevant, e.g. in studies of androgen receptor binding and active chromatin in specific cell types. We hypothesized that this behavior might be general, i.e. that correlation between protein-DNA binding (and open chromatin) and breakpoint locations is common across divergent cancers. RESULTS: We investigated this hypothesis by comprehensively analyzing the relationship among 457 ENCODE protein binding ChIP-seq experiments, 125 DnaseI and 24 FAIRE experiments, and 14,600 SMs from 8 diverse cancer datasets covering 147 samples. In most cancers, including breast and ovarian, we found enrichment of protein binding and open chromatin in the vicinity of SM breakpoints at distances up to 200 kb. Furthermore, for all cancer types we observed an enhanced enrichment in regions distant from genes when compared to regions proximal to genes, suggesting that the SM-induction mechanism is independent from the bias of DSBs to occur near transcribed regions. We also observed a stronger effect for sites with more than one protein bound. CONCLUSIONS: Protein binding and open chromatin state are associated with nearby SM breakpoints in many cancer datasets. These observations suggest a consistent mechanism underlying SM locations across different cancers.

Structure et évolution thermique de la croûte supérieure des chaînes de subduction : approches thermologique et modélisation numérique, dans les North Cascades (U.S.A) et de la zone de faille Motagua (Guatemala)

Cette thèse cible l'étude de la structure thermique de la croûte supérieure (<10km) dans les arcs magmatiques continentaux, et son influence sur l'enregistrement thermochronologique de leur exhumation et de leur évolution topographique. Nous portons notre regard sur deux chaînes de montagne appartenant aux Cordillères Américaines : Les Cascades Nord (USA) et la zone de faille Motagua (Guatemala). L'approche utilisée est axée sur la thermochronologie (U-Th-Sm)/He sur apatite et zircon, couplée avec la modélisation numérique de la structure thermique de la croûte. Nous mettons en évidence la variabilité à la fois spatiale et temporelle du gradient géothermique, et attirons l'attention du lecteur sur l'importance de prendre en compte la multitude des processus géologiques perturbant la structure thermique dans les chaînes de type cordillère, c'est à dire formées lors de la subduction océanique sous un continent.Une nouvelle approche est ainsi développée pour étudier et contraindre la perturbation thermique autour des chambres magmatiques. Deux profiles âge-elevation (U-Th-Sm)/He sur apatite et zircon, ont été collectées 7 km au sud du batholithe de Chilliwack, Cascades Nord. Les résultats montrent une variabilité spatiale et temporelle du gradient géothermique lors de l'emplacement magmatique qui peut être contrainte et séparé de l'exhumation. Durant l'emplacement de l'intrusion, la perturbation thermique y atteint un état d'équilibre (-80-100 °C/km) qui est fonction du flux de magma et de ia distance à la source du magma, puis rejoint 40 °C/km à la fin du processus d'emplacement magmatique.Quelques nouvelles données (U-Th)/He, replacées dans une compilation des données existantes dans les Cascades Nord, indiquent une vitesse d'exhumation constante (-100 m/Ma) dans le temps et l'espace entre 35 Ma et 2 Ma, associée à un soulèvement uniforme de la chaîne contrôlé par l'emplacement de magma dans la croûte durant toute l'activité de l'arc. Par contre, après ~2 Ma, le versant humide de la chaîne est affecté par une accélération des taux d'exhumation, jusqu'à 3 km de croûte y sont érodés. Les glaciations ont un triple effet sur l'érosion de cette chaîne: (1) augmentation des vitesses d'érosion, d'exhumation et de soulèvement la où les précipitations sont suffisantes, (2) limitation de l'altitude contrôlé par la position de Γ Ε LA, (3) élargissement du versant humide et contraction du versant aride de la chaîne.Les modifications des réseaux de drainage sont des processus de surface souvent sous-estimés au profil d'événements climatiques ou tectoniques. Nous proposons une nouvelle approche couplant une analyse géomorphologique, des données thermochronologiques de basse température ((U-Th-Sm)/He sur apatite et zircon), et l'utilisation de modélisation numérique thermo-cinématique pour les mettre en évidence et les dater; nous testons cette approche sur la gorge de la Skagit river dans les North Cascades.De nouvelles données (U-Th)/He sur zircons, complétant les données existantes, montrent que le déplacement horizontal le long de la faille transformante continentale Motagua, la limite des plaques Caraïbe/Amérique du Nord, a juxtaposé un bloc froid, le bloc Maya (s.s.), contre un bloque chaud, le bloc Chortis (s.s.) originellement en position d'arc. En plus de donner des gammes d'âges thermochronologiques très différents des deux côtés de la faille, le déplacement horizontal rapide (~2 cm/a) a produit un fort échange thermique latéral, résultant en un réchauffement du côté froid et un refroidissement du côté chaud de la zone de faille de Motagua.Enfin des données (U-Th-Sm)/He sur apatite témoignent d'un refroidissement Oligocène enregistré uniquement dans la croûte supérieure de la bordure nord de la zone de faille Motagua. Nous tenterons ultérieurement de reproduire ce découplage vertical de la structure thermique par la modélisation de la formation d'un bassin transtensif et de circulation de fluides le long de la faille de Motagua. - This thesis focuses on the influence of the dynamic thermal structure of the upper crust (<10km) on the thermochronologic record of the exhumational and topographic history of magmatic continental arcs. Two mountain belts from the American Cordillera are studied: the North Cascades (USA) and the Motagua fault zone (Guatemala). I use a combined approach coupling apatite and zircon (U-Th-Sm}/He thermochronology and thermo- kinematic numerical modelling. This study highlights the temporal and spatial variability of the geothermal gradient and the importance to take into account the different geological processes that perturb the thermal structure of Cordilleran-type mountain belts (i.e. mountain belts related to oceanic subduction underneath a continent}.We integrate apatite and zircon (U-Th)/He data with numerical thermo-kinematic models to study the relative effects of magmatic and surface processes on the thermal evolution of the crust and cooling patterns in the Cenozoic North Cascades arc (Washington State, USA). Two age-elevation profiles that are located 7 km south of the well-studied Chiliiwack intrusions shows that spatial and temporal variability in geothermal gradients linked to magma emplacement can be contrained and separated from exhumation processes. During Chiliiwack batholith emplacement at -35-20 Ma, the geothermal gradient of the country rocks increased to a very high steady-state value (80-100°C/km), which is likely a function of magma flux and the distance from the magma source area. Including temporally varying geothermal gradients in the analysis allows quantifying the thermal perturbation around magmatic intrusions and retrieving a relatively simple denudation history from the data.The synthesis of new and previously published (U-Th)/He data reveals that denudation of the Northern Cascades is spatially and temporally constant at -100 m/Ma between ~32 and ~2 Ma, which likely reflects uplift due to magmatic crustal thickening since the initiation of the Cenozoic stage of the continental magmatic arc. In contrast, the humid flank of the North Cascades is affected by a ten-fold acceleration in exhumation rate at ~2 Ma, which we interpret as forced by the initiation of glaciations; around 3 km of crust have been eroded since that time. Glaciations have three distinct effects on the dynamics of this mountain range: (1) they increase erosion, exhumation and uplift rates where precipitation rates are sufficient to drive efficient glacial erosion; (2) they efficiently limit the elevation of the range; (3) they lead to widening of the humid flank and contraction of the arid flank of the belt.Drainage reorganizations constitute an important agent of landscape evolution that is often underestimated to the benefit of tectonic or climatic events. We propose a new method that integrates geomorphology, low-temperature thermochronometry (apatite and zircon {U-Th-Sm)/He), and 3D numerical thermal-kinematic modelling to detect and date drainage instability producing recent gorge incision, and apply this approach to the Skagit River Gorge, North Cascades.Two zircon (U-Th)/He age-elevation profiles sampled on both sides of the Motagua Fault Zone (MFZ), the boundary between the North American and the Caribbean plates, combined with published thermochronological data show that strike-slip displacement has juxtaposed the cold Maya block (s.s.) against the hot, arc derived, Chortis block (s.s ), producing different age patterns on both sides of the fault and short-wavelength lateral thermal exchange, resulting in recent heating of the cool side and cooling of the hot side of the MFZ.Finally, an apatite (U-Th-Sm)/He age-elevation profile records rapid cooling at -35 Ma localized only in the upper crust along the northern side of the Motagua fault zone. We will try to reproduce these data by modeling the thermal perturbation resulting from the formation of a transtensional basin and of fluid flow activity along a crustal- scale strike-slip fault.

Expression of neutral endopeptidase, endothelin-1, and nuclear factor kappa B in prostate cancer: interrelations and associations with prostate-specific antigen recurrence after radical prostatectomy.

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment. Results and Limitations. Membranous expression of NEP (P < 0.001), cytoplasmic ET-1 (P = 0.002), and cytoplasmic NFκB (P < 0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (P < 0.001) and NFκB (P < 0.001). ET-1 was also correlated with NFκB (P < 0.001). NEP expression (P = 0.017), pT stage (P = 0.013), and SMs (P = 0.036) were independent predictors of time to PSA recurrence. Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations.

Two-stage, extreme albitization of A-type granites from Rajasthan, NW India

Albitization is a common process during which hydrothermal fluids convert plagioclase and/or K-feldspar into nearly pure albite; however, its specific mechanism in granitoids is not well understood. The c. 1700 Ma A-type metaluminous ferroan granites in the Khetri complex of Rajasthan, NW India, have been albitized to a large extent by two metasomatic fronts, an initial transformation of oligoclase to nearly pure albite and a subsequent replacement of microcline by albite, with sharp contacts between the microcline-bearing and microcline-free zones. Albitization has bleached the original pinkish grey granite and turned it white. The mineralogical changes include transformation of oligoclase (similar to An(12)) and microcline (similar to Or(95)) to almost pure albite (similar to An(0 center dot 5-2)), amphibole from potassian ferropargasite (X-Fe 0 center dot 84-0 center dot 86) to potassic hastingsite (X-Fe 0 center dot 88-0 center dot 97) and actinolite (X-Fe 0 center dot 32-0 center dot 67), and biotite from annite (X-Fe 0 center dot 71-0 center dot 74) to annite (X-Fe 0 center dot 90-0 center dot 91). Whole-rock isocon diagrams show that, during albitization, the granites experienced major hydration, slight gain in Si and major gain in Na, whereas K, Mg, Fe and Ca were lost along with Rb, Ba, Sr, Zn, light rare earth elements and U. Whole-rock Sm-Nd isotope data plot on an apparent isochron of 1419 +/- 98 Ma and reveal significant disturbance and at least partial resetting of the intrusion age. Severe scatter in the whole-rock Rb-Sr isochron plot reflects the extreme Rb loss in the completely albitized samples, effectively freezing Sr-87/Sr-86 ratios in the albite granites at very high values (0 center dot 725-0 center dot 735). This indicates either infiltration of highly radiogenic Sr from the country rock or, more likely, radiogenic ingrowth during a considerable time lag (estimated to be at least 300 Myr) between original intrusion and albitization. The albitization took place at similar to 350-400 degrees C. It was caused by the infiltration of an ascending hydrothermal fluid that had acquired high Na/K and Na/Ca ratios during migration through metamorphic rocks at even lower temperatures in the periphery of the plutons. Oxygen isotope ratios increase from delta O-18 = 7 parts per thousand in the original granite to values of 9-10 parts per thousand in completely albitized samples, suggesting that the fluid had equilibrated with surrounding metamorphosed crust. A metasomatic model, using chromatographic theory of fluid infiltration, explains the process for generating the observed zonation in terms of a leading metasomatic front where oligoclase of the original granite is converted to albite, and a second, trailing front where microcline is also converted to albite. The temperature gradients driving the fluid infiltration may have been produced by the high heat production of the granites themselves. The confinement of the albitized granites along the NE-SW-trending Khetri lineament and the pervasive nature of the albitization suggest that the albitizing fluids possibly originated during reactivation of the lineament. More generally, steady-state temperature gradients induced by the high internal heat production of A-type granites may provide the driving force for similar metasomatic and ore-forming processes in other highly enriched granitoid bodies.

Syndrome métabolique et antipsychotiques atypiques : recommandations et prise en charge clinique

L'introduction des antipsychotiques atypiques (AA) avec leurs effets secondaires métaboliques a attiré une plus grande attention sur le risque iatrogène éventuel de maladies cardiovasculaires dans la population des patients atteints de schizophrénie ou de trouble bipolaire. À cet égard, l'analyse du rapport risque/bénéfice dans l'utilisation des ces médicaments se révèle souvent délicate, nécessitant la coordination de plusieurs savoirs et ressources des réseaux somatiques et psychiatriques. Dans cet article, les auteurs présentent une revue sur le syndrome métabolique (SM) et la maladie cardiovasculaire (MCV) dans la population psychiatrique. Sur la base des dernières recommandations internationales, ils proposent des directives de prise en charge des effets secondaires, notamment métaboliques, à l'introduction d'un AA.

Syndrome métabolique, une maladie mitochondriale? [Metabolic syndrome, a mitochondrial disease?]

Le syndrome métabolique (SM) associe dyslipidémie, hypertension, intolérance au glucose, état pro-inflammatoire/prothrombotique et surpoids, dont nous vous présentons une hypothèse physiopathologique émergente. Des recherches récentes ont montré que des dysfonctions mitochondriales induisent l'accumulation intracellulaire d'acylCoA et de diacylglycérol, inactivant la signalisation de l'insuline par un effet direct sur les transporteurs du glucose insulino-dépendants. Un défaut de la phosphorylation oxydative conduirait à l'insulino-résistance. Des atteintes de la fonction mitochondriale sont présentes dans le muscle, le foie, le pancréas et les vaisseaux sanguins et contribuent aux manifestations cliniques. Ces observations des atteintes mitochondriales nous montrent un lien entre la clinique et la physiopathologie du SM. The metabolic syndrome is a cluster of metabolic risk factors including: atherogenic dyslipidemia, elevated blood pressure, high plasma glucose and a prothrombotic and proinflammatory state, frequently associated to overweight. Impaired cell metabolism has been suggested as a relevant pathophysiological process. Indeed, the accumulation of intracellular fatty acylCoA and diacylglycerol, which then activate critical signal transduction pathways that ultimatly lead to suppression of insulin signalisation. Therefore a defect in mitochondrial function may be responsible for insulin resistance. Moreover, mitochondrial dysfunction has been found to take place in organs such as skeletal muscle, liver, pancreas and smoth vascular cells suggesting that mitochondrial defect could play a critical role in the occurence of cardiovascular diseases.

Vascular risk factors in the Swiss population.

BACKGROUND AND PURPOSE: Identification of the population at risk of stroke remains the best approach to assess the burden of cardiovascular morbidity and mortality. METHODS: The prevalence of hypertension (HT), hypercholesterolemia (HCh), diabetes mellitus (DM), overweight (OW), obesity (OB), tobacco use (SM), and their combinations was examined in 4,458 Swiss persons (1,741 men and 2,717 women, mean age 57.8 +/- 15 years), who volunteered for the present survey. RESULTS: OW was the most prevalent risk factor (50 %), followed by HT (47%), HCh (33%), SM (13 %) and DM (1.6 %). The proportion of persons without risk factors (RF) was 19.9%, with 1 RF 41.5%, 2 RF 33.8%, 3 RF 4%, and 4 RF 0.9%. OW was more prevalent in men than in women (53% vs. 41%, P=0.02). More men than women aged 41-50 years and 51-60 years had HT (49 % vs. 36%, P=0.01, and 52 % vs. 42%, P=0.02). The prevalence of HCh and DM did not show any sex-related differences. HT, OW and HCh were not only the most common single risk factors, but were also most likely to aggregate with each other. CONCLUSIONS: The majority of Swiss people have one or two vascular risk factors. OW and HT are by far most common and are likely to aggregate with each other. A small modification of these two factors would reduce the incidence of stroke and myocardial infarction significantly.

Unique spectrum of activity of prosimian TRIM5alpha against exogenous and endogenous retroviruses.

Lentiviruses, the genus of retrovirus that includes HIV-1, rarely endogenize. Some lemurs uniquely possess an endogenous lentivirus called PSIV ("prosimian immunodeficiency virus"). Thus, lemurs provide the opportunity to study the activity of host defense factors, such as TRIM5α, in the setting of germ line invasion. We characterized the activities of TRIM5α proteins from two distant lemurs against exogenous retroviruses and a chimeric PSIV. TRIM5α from gray mouse lemur, which carries PSIV in its genome, exhibited the narrowest restriction activity. One allelic variant of gray mouse lemur TRIM5α restricted only N-tropic murine leukemia virus (N-MLV), while a second variant restricted N-MLV and, uniquely, B-tropic MLV (B-MLV); both variants poorly blocked PSIV. In contrast, TRIM5α from ring-tailed lemur, which does not contain PSIV in its genome, revealed one of the broadest antiviral activities reported to date against lentiviruses, including PSIV. Investigation into the antiviral specificity of ring-tailed lemur TRIM5α demonstrated a major contribution of a 32-amino-acid expansion in variable region 2 (v2) of the B30.2/SPRY domain to the breadth of restriction. Data on lemur TRIM5α and the prediction of ancestral simian sequences hint at an evolutionary scenario where antiretroviral specificity is prominently defined by the lineage-specific expansion of the variable loops of B30.2/SPRY.

Analysis of potential transcriptomic biomarkers for Huntington's disease in peripheral blood.

Highly quantitative biomarkers of neurodegenerative disease remain an important need in the urgent quest for disease-modifying therapies. For Huntington's disease (HD), a genetic test is available (trait marker), but necessary state markers are still in development. In this report, we describe a large battery of transcriptomic tests explored as state biomarker candidates. In an attempt to exploit the known neuroinflammatory and transcriptional perturbations of disease, we measured relevant mRNAs in peripheral blood cells. The performance of these potential markers was weak overall, with only one mRNA, immediate early response 3 (IER3), showing a modest but significant increase of 32% in HD samples compared with controls. No statistically significant differences were found for any other mRNAs tested, including a panel of 12 RNA biomarkers identified in a previous report [Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, et al. (2005) Proc Natl Acad Sci USA 102:11023-11028]. The present results may nonetheless inform the future design and testing of HD biomarker strategies.

Munc18-1 mutations that strongly impair SNARE-complex binding support normal synaptic transmission.

Synaptic transmission depends critically on the Sec1p/Munc18 protein Munc18-1, but it is unclear whether Munc18-1 primarily operates as a integral part of the fusion machinery or has a more upstream role in fusion complex assembly. Here, we show that point mutations in Munc18-1 that interfere with binding to the free Syntaxin1a N-terminus and strongly impair binding to assembled SNARE complexes all support normal docking, priming and fusion of synaptic vesicles, and normal synaptic plasticity in munc18-1 null mutant neurons. These data support a prevailing role of Munc18-1 before/during SNARE-complex assembly, while its continued association to assembled SNARE complexes is dispensable for synaptic transmission.

β-Catenin Signaling Drives Differentiation and Proinflammatory Function of IRF8-Dependent Dendritic Cells.

β-Catenin signaling has recently been tied to the emergence of tolerogenic dendritic cells (DCs). In this article, we demonstrate a novel role for β-catenin in directing DC subset development through IFN regulatory factor 8 (IRF8) activation. We found that splenic DC precursors express β-catenin, and DCs from mice with CD11c-specific constitutive β-catenin activation upregulated IRF8 through targeting of the Irf8 promoter, leading to in vivo expansion of IRF8-dependent CD8α(+), plasmacytoid, and CD103(+)CD11b(-) DCs. β-Catenin-stabilized CD8α(+) DCs secreted elevated IL-12 upon in vitro microbial stimulation, and pharmacological β-catenin inhibition blocked this response in wild-type cells. Upon infections with Toxoplasma gondii and vaccinia virus, mice with stabilized DC β-catenin displayed abnormally high Th1 and CD8(+) T lymphocyte responses, respectively. Collectively, these results reveal a novel and unexpected function for β-catenin in programming DC differentiation toward subsets that orchestrate proinflammatory immunity to infection.