Neuroactive Steroids Reverse Tonic Inhibitory Deficits in Fragile X Syndrome Mouse Model

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. A reduction in neuronal inhibition mediated by γ-aminobutyric acid type A receptors (GABAARs) has been implicated in the pathophysiology of FXS. Neuroactive steroids (NASs) are known allosteric modulators of GABAAR channel function, but recent studies from our laboratory have revealed that NASs also exert persistent metabotropic effects on the efficacy of tonic inhibition by increasing the protein kinase C (PKC)-mediated phosphorylation of the α4 and β3 subunits which increase the membrane expression and boosts tonic inhibition. We have assessed the GABAergic signaling in the hippocampus of fragile X mental retardation protein (FMRP) knock-out (Fmr1 KO) mouse. The GABAergic tonic current in dentate gyrus granule cells (DGGCs) from 3- to 5-week-old (p21–35) Fmr1 KO mice was significantly reduced compared to WT mice. Additionally, spontaneous inhibitory post synaptic inhibitory current (sIPSC) amplitudes were increased in DGGCs from Fmr1 KO mice. While sIPSCs decay in both genotypes was prolonged by the prototypic benzodiazepine diazepam, those in Frm1-KO mice were selectively potentiated by RO15-4513. Consistent with this altered pharmacology, modifications in the expression levels and phosphorylation of receptor GABAAR subtypes that mediate tonic inhibition were seen in Fmr1 KO mice. Significantly, exposure to NASs induced a sustained elevation in tonic current in Fmr1 KO mice which was prevented with PKC inhibition. Likewise, exposure reduced elevated membrane excitability seen in the mutant mice. Collectively, our results suggest that NAS act to reverse the deficits of tonic inhibition seen in FXS, and thereby reduce aberrant neuronal hyperexcitability seen in this disorder

Rotating Brane World Black Holes

A five dimensional rotating black string in a Randall-Sundrum brane world is considered. The black string intercepts the three brane in a four dimensional rotating black hole. The geodesic equations and the asymptotics in this background are discussed.Comment: 10 pages, minor changes, typos corrected and references adde

Search for Global Metric Anisotropy in Type Ia Supernova Data

We examine the Type 1a supernova data in order to determine if it shows any signal of large scale anisotropy. The anisotropy is modelled by an extended G\"{o}del metric, which incorporates expansion along with rotation. The model is smoothly connected to the usual FRW type, while expressing anisotropic metric effects depending on certain parameters. We find no significant signal of anisotropy in the data. We obtain bounds on an anisotropic redshift versus magnitude relationship, and accompanying parameters of the G\"{o}del-Obukhov metric.Comment: 16 pages, 2 figures, minor changes, to be published in Modern Physics Letters

Genetic Deletion of the Clathrin Adaptor GGA3 Reduces Anxiety and Alters GABAergic Transmission

Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) is a monomeric clathrin adaptor that has been shown to regulate the trafficking of the Beta-site APP-cleaving enzyme (BACE1), which is required for production of the Alzheimer’s disease (AD)-associated amyloid βpeptide. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that depletion of GGA3 results in increased BACE1 levels and activity owing to impaired lysosomal trafficking and degradation. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. We report here that GGA3 deletion results in novelty-induced hyperactivity and decreased anxiety-like behaviors. Given the pivotal role of GABAergic transmission in the regulation of anxiety-like behaviors, we performed electrophysiological recordings in hippocampal slices and found increased phasic and decreased tonic inhibition in the dentate gyrus granule cells (DGGC). Moreover, we found that the number of inhibitory synapses is increased in the dentate gyrus of GGA3 null mice in further support of the electrophysiological data. Thus, the increased GABAergic transmission is a leading candidate mechanism underlying the reduced anxiety-like behaviors observed in GGA3 null mice. All together these findings suggest that GGA3 plays a key role in GABAergic transmission. Since BACE1 levels are elevated in the brain of GGA3 null mice, it is possible that at least some of these phenotypes are a consequence of increased processing of BACE1 substrates

Metric for Security Activities assisted by Argumentative Logic

International audienceRecent security concerns related to future embedded systems make enforcement of security requirements one of the most critical phases when designing such systems. This paper introduces an approach for efficient enforcement of security requirements based on argumentative logic, especially reasoning about activation or deactivation of different security mechanisms under certain functional and non-functional requirements. In this paper, the argumentative logic is used to reason about the rationale behind dynamic enforcement of security policies

Brick Walls on the Brane

The so-called ``brick-wall model'' is a semi-classical approach that has been used to explain black hole entropy in terms of thermal matter fields. Here, we apply the brick-wall formalism to thermal bulk fields in a Randall-Sundrum brane world scenario. In this case, the black hole entity is really a string-like object in the anti-de Sitter bulk, while appearing as a Schwarzchild black hole to observers living on the brane. In spite of these exotic circumstances, we establish that the Bekenstein-Hawking entropy law is preserved. Although a similar calculation was recently considered in the literature, this prior work invoked a simplifying assumption (which we avoid) that can not be adequately justified.Comment: 18 pages, Latex; references and discussion added but conclusions unchanged; references missing in V4 have been restore

Introducing Preference-Based Argumentation to Inconsistent Ontological Knowledge Bases

International audienceHandling inconsistency is an inherent part of decision making in traditional agri-food chains – due to the various concerns involved. In order to explain the source of inconsistency and represent the existing conflicts in the ontological knowledge base, argumentation theory can be used. However, the current state of art methodology does not allow to take into account the level of significance of the knowledge expressed by the various ontological knowledge sources. We propose to use preferences in order to model those differences between formulas and evaluate our proposal practically by implementing it within the INRA platform and showing a use case using this formalism in a bread making decision support system

Artificial intelligence and cloud-based collaborative platforms for managing disaster, extreme weather and emergency operations

YesNatural disasters are often unpredictable and therefore there is a need for quick and effective response to save lives and infrastructure. Hence, this study is aimed at achieving timely, anticipated and effective response throughout the cycle of a disaster, extreme weather and emergency operations management with the help of advanced technologies. This study proposes a novel, evidence-based framework (4-AIDE) that highlights the role of artificial intelligence (AI) and cloud-based collaborative platforms in disaster, extreme weather and emergency situations. A qualitative approach underpinned by organizational information processing theory (OIPT) is employed to design, develop and conduct semi-structured interviews with 33 respondents having experience in AI and cloud computing industries during emergency and extreme weather situations. For analysing the collected data, axial, open and selective coding is used that further develop themes, propositions and an evidence-based framework. The study findings indicate that AI and cloud-based collaborative platforms offer a structured and logical approach to enable two-way, algorithm-based communication to collect, analyse and design effective management strategies for disaster and extreme weather situations. Managers of public systems or businesses can collect and analyse data to predict possible outcomes and take necessary actions in an extreme weather situation. Communities and societies can be more resilient by transmitting and receiving data to AI and cloud-based collaborative platforms. These actions can also help policymakers identify critical pockets and guide administration for their necessary preparation for unexpected, extreme weather, and emergency events.This study has been supported by the Area of Excellence AI, Data Science & Business at NEOMA Business School, France under the fund number 416005

Developmental seizures and mortality result from reducing GABAᴀ receptor α2-subunit interaction with collybistin

Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain unclear. Using isothermal titration calorimetry and complementary methods we demonstrate an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents. Gabra2–1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development