Regulation of microRNA function in rodent hippocampal neurons by an alternative Ube3a transcript

The activity-dependent regulation of neuronal maturation is important for the development of neural circuits and cognition. Defects in this process lead to severe neurodevelopmental disorders associated with intellectual disability and autism (Kuczewski et al., 2010). UBE3A has been previously demonstrated to control important aspects of neuronal maturation. UBE3A loss-of-function mutations cause Angelman syndrome (AS) (Kishino et al., 1997), whereas increased UBE3A gene dosage has been associated with autism-spectrum disorders (ASD) (Glessner et al., 2009). The UBE3A gene encodes an enzyme with ubiquitin ligase activity which is important for the degradation of neuronal proteins by the ubiquitin proteasome system. However, defects in UBE3A enzymatic activity unlikely account for the full spectrum of AS and ASD cases, since rare mutations outside the coding region have been identified (Bird, 2014). Recently, several alternative Ube3a transcripts have been described that include variable 5' and 3' ends, suggesting complex post-transcriptional regulation of Ube3a expression. In particular, the different 3’UTRs present in Ube3a 3' variants could be used for differential regulation of mRNA localization and translation. However, little was known concerning expression, localization and regulatory functions of the alternative Ube3a transcripts. In this work, I discovered that the rodent Ube3a1-RNA, which contains a truncated coding sequence and an alternative 3'UTR, has unique functions in neuronal maturation and a gene regulatory function that strongly differ from functions of the transcripts that code for the active Ube3a enzyme. Ube3a1-RNA is specifically increased by elevated neuronal activity and preferentially localizes to neuronal dendrites. Opposite to Ube3a enzyme-coding transcripts, Ubea1 is a negative regulator of dendrite outgrowth in rodent hippocampal neurons both in dissociated neuronal cultures and in vivo. In addition, Ube3a1 is necessary for dendritic spine maturation in cultured hippocampal neurons. Surprisingly, I found that the function of Ube3a1-RNA in the context of dendrite outgrowth was coding-independent and could be attributed to the presence of the alternative 3'UTR. Considering the molecular mechanisms underlying Ube3a1-RNA function, I found that the Ube3a1-RNA 3’UTR is a target of several microRNAs encoded by the miR-379/410 cluster, including miR-134 that was previously implicated in dendritogenesis and spine maturation. However, Ube3a1-RNA is not regulated by miRNAs in a canonical manner, but rather competes with other miR-379/410 target mRNAs for binding to common miRNAs. Therefore, Ube3a1-RNA can be considered as a competing endogenous RNA (ceRNA) following a hypothesis that was previously put forward in cancer cell lines. (Salmena et al., 2011) In conclusion, the results from my thesis describe a new gene regulatory mechanism operating in neuronal dendrites with important implications for neuronal maturation, circuit development and neurodevelopmental disorders

Quelles sont les origines du ministère de l’Identité nationale et de l’Immigration ?

Annoncée à la télévision le 8 mars 2007 par le candidat Nicolas Sarkozy, la création du ministère de l’Immigration, de l’Intégration, de l’Identité nationale et du Codéveloppement a d’abord été en France une promesse électorale, un sujet de campagne et aurait pu connaître le sort d’autres idées de ce genre : être oubliée ou reformulée une fois le candidat arrivé au pouvoir. On pouvait alors se demander s’il ne s’agissait que d’un simple gadget de campagne, destiné à ratisser les voix de l’ext..

Introduction : L’Europe des camps. La mise à l’écart des étrangers

L’Europe des années 1930 nous a appris à quel point des cultures politiques peuvent se transformer sans que les générations concernées en aient la moindre conscience. Ce risque d’ignorance s’aggrave probablement lorsqu’on croit, comme souvent aujourd’hui, être immunisé mieux qu’autrefois contre les phénomènes idéologiques et les dérives qu’ils entraînent. A cet égard les sciences sociales endossent une responsabilité particulière : celle de pouvoir aider à détecter précocement de telles mutat..

Du retournement de l’asile (1948-2008) à la xénophobie de gouvernement : construction d’un objet d’étude

En un demi-siècle, la politique du droit d’asile, référée aux articles 13 et 14 de la Déclaration universelle des droits de l’Homme (ONU, 1948), se retourne en son contraire, aboutissant aujourd’hui non seulement au rejet de la quasi-totalité des exilés demandant l’asile mais aussi à la disqualification sociale de cette population. Comme expliquer ce retournement ? Trois explications de sens commun sont souvent avancées : une augmentation massive des migrations économiques à la fin du XXe siècle ; le déclenchement d’une crise qui, à partir de 1973-1974, rendrait ces migrations économiquement insupportables ; l’émergence, du fait de tensions sur le marché du travail d’une xénophobie populaire. La mise en discussion de ces explications conduit à les abandonner pour envisager une autre hypothèse : celle d’une mutation culturelle des élites et des autorités publiques activant la construction de l’exilé comme un problème un risque ou une menace… ce que l’on peut nommer alors une « xénophobie de gouvernement ».In half a century, the policy and right of asylum, referenced in article 13 and 14 of the Universal Declaration of Human Rights (UN, 1948), have experienced a reversal, which has led to a situation where almost all the exiled persons who are applying for asylum are rejected, as well as socially disqualified. How can we account for this reversal? Three commonsensical explanations are generally put forward: a massive rise in economic migrations at the end of the 20th century; the triggering of a crisis which, from 1973-1974 onwards, has rendered these migrations economically unsustainable; the emergence, due to tensions on the labour market, of a working-class xenophobia. The examination of these explanations, however, compels us to set them aside in favour of another hypothesis, which focuses on a cultural mutation among elites and public authorities, which has activated the construction of exiled persons as a problem, a risk or a threat… what we then call a “governmental xenophobia”.  

Europa de los campos. La puesta a distancia de los extranjeros

Europa de los años 1930 nos ha enseñado hasta qué punto las culturas políticas pueden transformarse sin que las generaciones concernidas lo adviertan. El riesgo al que conduce esta ignorancia es posiblemente tanto más alto cuando se cree –como sucede a menudo hoy día– estar inmunizado contra los fenómenos ideológicos y sus derivados. Las ciencias sociales tienen una responsabilidad en este ámbito: la de poder detectar con antelación dichas mutaciones y darlas a conocer. Esta función de invest..

La nouvelle Europe politique des camps d’exilés : genèse d’une source élitaire de phobie et de répression des étrangers

L’Europe politique offre une figure spécifique au regard des efforts actuels pour multiplier en son sein et chez ses voisins les dispositifs de regroupement forcé et d’enfermement des exilés (demandeurs d’asile, réfugiés, sans-papiers, clandestins…). La nouveauté réside moins dans l’existence de ces dispositifs que dans la facilité avec laquelle ils sont affichés dans l’espace public, comme instruments ou finalité de politiques publiques. Ceci révèle une transformation profonde des cultures européennes et de la gouvernance à l’égard des exilés, autrefois victimes à aider, aujourd’hui coupables menaçants. Hors cette convergence européenne, souvent imputée aux opinions publiques, passe par trois processus dont on peut montrer l’origine élitaire : la spirale du rejet des demandes d’asile, le tournant national sécuritaire à l’égard des étrangers et l’harmonisation européenne de la lutte contre l’immigration sous couvert de « justice, liberté, sécurité » (JLS). Les cultures politiques européennes se transforment ainsi sous l’effet de la montée en puissance d’une xénophobie de gouvernement.The political Europe offers a specific figure if one considers the current efforts made to multiply within the Union and among its neighbours mechanisms of forced regrouping and confinement of exiles (asylum seekers, refugees, undocumented people, clandestine…). These systems are not new. What is new is the facility with which they are exposed in the public space as instruments and purpose to public policies. This reveals a profound transformation of the European cultures and of the governance in respect to exiles previously seen as victims in need of help and currently considered as threatening guilty people. But this European convergence, often imputed to the public opinion, goes through three processes having elite origins : the asylum rejection spiral, the national-security turn in respect to foreigners and to the European fight against immigration harmonization hidden by « justice, liberty, security » (JLS). The European political cultures thereby transform through the effect of the rise of government xenophobia

Sleep apnea syndrome in an elderly population admitted to a geriatric unit : prevalence and effect on cognitive function

International audienceBackground Sleep apnea leads to cognitive impairment in older patients, but its association with neurodegeneration remains controversial, and most studies do not distinguish between the more common obstructive form (OSAS) and the rarer central form (CSAS). Objective The purpose of this study was to assess the prevalence of the different forms of sleep apnea in a cohort of cognitively impaired elderly patients (>70 years) and to investigate their associations with cognitive deficit, weighted against known risk factors for neurodegeneration. Methods Overnight polygraphy was performed for 76 consecutive patients admitted to our geriatric unit. Their cognitive function was assessed using the Mini Mental-State Exam (MMSE), Mattis Dementia Rating Scale (MDRS) and Stroop test. Multivariable analyses were performed to determine associations between cognitive function and independent variables describing demographics, sleep apnea measures, and cardiovascular risk factors. Results The cohort comprised 58 women and 18 men aged a mean of 84 years (range, 73-96). Sleep apnea syndrome (SAS) was diagnosed in 48 patients (63%), of which 31 (41%) with OSAS and 17 (22%) with CSAS. Multivariable regression analysis revealed that MDRS was lower in patients with OSAS (beta = -10.03, p = 0.018), that Stroop Colors and Words delays increased with AHI (beta = 0.17, p = 0.030 and beta = 0.31, p = 0.047) and that that Stroop Interference delay was higher in patients with CSAS (beta = 24.45, p = 0.002). Conclusion Sleep apnea is thus highly prevalent in elderly patients with cognitive impairment. OSAS was associated with lower general cognitive function, while CSAS was only associated with increased Stroop Interference delays. Elderly patients with cognitive deficit could benefit from sleep apnea screening and treatment

Design of a Throttled Surge Tank for Refurbishment by Increase of Installed Capacity at a High-Head Power Plant

The Swiss confederation aims to phase out nuclear power production with its Energy Strategy 2050 program by increasing the renewable energy contribution to its overall energy generation. Hydroelectricity, which is the most important form of renewable energy in Switzerland, supplying almost 60% of the electricity in 2015, should increase its production capacity to achieve this goal. The case study presented in this paper focuses on the replacement of the third turbine in the Gondo high-head power plant with a turbine with a higher discharge capacity. The results of one-dimensional (1D) numerical simulations shown that throttling the surge tank is an efficient measure to adapt the existing hydraulic system for the increased discharge. Physical-scale modeling was performed to validate the design of the grid throttle placed at the bottom of the lower chamber of the existing surge tank. The grid throttle geometry and its head losses are compared with two existing similar throttles in Switzerland. Finally, prototype tests of the temporal evolution of water levels in the surge tank using the throttle coefficients obtained experimentally showed good agreement. Hybrid modeling using a combination of 1D numerical models, threedimensional (3D) physical models, and prototype tests are highly recommended for checking the transient performance of the waterway after a refurbishment of turbines with increased design discharge. Furthermore, placing a throttle at the bottom of an existing surge tank is often an effective and economical solution in the case of small increases in installed capacity

Decreased Cerebrospinal Fluid Flow Is Associated With Cognitive Deficit in Elderly Patients

Background: Disruptions in cerebrospinal fluid (CSF) flow during aging could compromise protein clearance from the brain and contribute to the etiology of Alzheimer’s Disease (AD).Objective: To determine whether CSF flow is associated with cognitive deficit in elderly patients (>70 years).Methods: We studied 92 patients admitted to our geriatric unit for non-acute reasons using phase-contrast magnetic resonance imaging (PC-MRI) to calculate their ventricular and spinal CSF flow, and assessed their global cognitive status, memory, executive functions, and praxis. Multivariable regressions with backward selection (criterion p < 0.15) were performed to determine associations between cognitive tests and ventricular and spinal CSF flow, adjusting for depression, anxiety, and cardiovascular risk factors.Results: The cohort comprised 71 women (77%) and 21 (33%) men, aged 84.1 ± 5.2 years (range, 73–96). Net ventricular CSF flow was 52 ± 40 μL/cc (range, 0–210), and net spinal CSF flow was 500 ± 295 μL/cc (range, 0–1420). Ventricular CSF flow was associated with the number of BEC96 figures recognized (β = 0.18, CI, 0.02–0.33; p = 0.025). Spinal CSF flow was associated with the WAIS Digit Span Backward test (β = 0.06, CI, 0.01–0.12; p = 0.034), and categoric verbal fluency (β = 0.53, CI, 0.07–0.98; p = 0.024) and semantic verbal fluency (β = 0.55, CI, 0.07–1.02; p = 0.024).Conclusion: Patients with lower CSF flow had significantly worse memory, visuo-constructive capacities, and verbal fluency. Alterations in CSF flow could contribute to some of the cognitive deficit observed in patients with AD. Diagnosis and treatment of CSF flow alterations in geriatric patients with neurocognitive disorders could contribute to the prevention of their cognitive decline