Brain glucocorticoid receptors are necessary for the rhythmic expression of the clock protein, PERIOD2, in the central extended amygdala in mice

The adrenal glucocorticoid, corticosterone, induces changes in gene expression in both neural and non-neural tissues. The rhythmic release of corticosterone has been shown in rats to be necessary for the rhythmic expression of the clock protein PERIOD2 (PER2) in select regions of the limbic forebrain. The mechanisms mediating the effects of glucocorticoids on changes in gene expression have been linked to the transcriptional activity of the low affinity glucocorticoid receptor, GR. We examined the patterns of PER2 expression in the brains of mice containing an inactivation of GR gene restricted to neural tissues (GR(NesCre) mice). We found that central deletion of the GR gene blunts the daily pattern of PER2 expression in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and central nucleus of the amygdala (CEA) both of which make up the central extended amygdala, but not in the suprachiasmatic nucleus (SCN), basolateral amygdala (BLA) or dentate gyrus of the hippocampus (DG). These results implicate brain GR receptors in the regulation of PER2 expression in the BNSTov and CEA and are consistent with our previous findings that the rhythmic expression of PER2 in these areas is selectively sensitive to fluctuations in circulating corticosterone

Adaptively inferring human transcriptional subnetworks

Although the human genome has been sequenced, progress in understanding gene regulation in humans has been particularly slow. Many computational approaches developed for lower eukaryotes to identify cis-regulatory elements and their associated target genes often do not generalize to mammals, largely due to the degenerate and interactive nature of such elements. Motivated by the switch-like behavior of transcriptional responses, we present a systematic approach that allows adaptive determination of active transcriptional subnetworks (cis-motif combinations, the direct target genes and physiological processes regulated by the corresponding transcription factors) from microarray data in mammals, with accuracy similar to that achieved in lower eukaryotes. Our analysis uncovered several new subnetworks active in human liver and in cell-cycle regulation, with similar functional characteristics as the known ones. We present biochemical evidence for our predictions, and show that the recently discovered G2/M-specific E2F pathway is wider than previously thought; in particular, E2F directly activates certain mitotic genes involved in hepatocellular carcinomas. Additionally, we demonstrate that this method can predict subnetworks in a condition-specific manner, as well as regulatory crosstalk across multiple tissues. Our approach allows systematic understanding of how phenotypic complexity is regulated at the transcription level in mammals and offers marked advantage in systems where little or no prior knowledge of transcriptional regulation is available

Chronic stress and glucocorticoids: from neuronal plasticity to neurodegeneration

Stress and stress hormones, glucocorticoids (GCs), exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.The work was supported by Grants “PTDC/SAU-NMC/113934/2009,” funded by FCT, Portuguese Foundation for Science and Technology, and project DoIT, Desenvolvimento e Operacionalização da Investigação de Translação (N° do projeto 13853), funded by Fundo Europeu de Desenvolvimento Regional (FEDER) through the Programa Operacional Fatores de Competitividade (POFC). In addition, this work was also cofinanced by European Union FP7 Project SwitchBox (Nuno Sousa, Osborne F. X. Almeida) and the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER). Sheela Vyas acknowledges grant support from Foundation de France, Physiopathology of Parkinson, France Parkinson and ANR Grant “ParkStrim” N° 13-BSV1-0013-02. Work in FT research group was supported by Agence Nationale de la Recherche (TIMMS and StressPsyco) and Fondation pour la Recherche Médicale, Grant no. DEQ20140329552

Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone

The adrenal hormone corticosterone transcriptionally regulates responsive genes in the rodent hippocampus through nuclear mineralocorticoid and glucocorticoid receptors. Via this genomic pathway the hormone alters properties of hippocampal cells slowly and for a prolonged period. Here we report that corticosterone also rapidly and reversibly changes hippocampal signaling. Stress levels of the hormone enhance the frequency of miniature excitatory postsynaptic potentials in CA1 pyramidal neurons and reduce paired-pulse facilitation, pointing to a hormone-dependent enhancement of glutamate-release probability. The rapid effect by corticosterone is accomplished through a nongenomic pathway involving membrane-located receptors. Unexpectedly, the rapid effect critically depends on the classical mineralocorticoid receptor, as evidenced by the effectiveness of agonists, antagonists, and brain-specific inactivation of the mineralocorticoid but not the glucocorticoid receptor gene. Rapid actions by corticosterone would allow the brain to change its function within minutes after stress-induced elevations of corticosteroid levels, in addition to responding later through gene-mediated signaling pathways

Limited Increase of Particle Entrainment in the Off-Gas System of a Cold Crucible Induction Melter Compared with a Joule-Heated Metal Melter for HLLW Vitrification -11465

ABSTRACT Fission product solutions arising from reprocessing spent fuel from the nuclear reactors used for electrical production in France are immobilized in six vitrification lines at the AREVA La Hague plant. In 2010, the conventional Joule-heated metal melter was replaced in one of these six lines with a cold crucible melter. The cold crucible melter began vitrifying radioactive effluents produced by rinsing operations in legacy facilities in April 2010. The composition of these effluents requires a containment glass synthesis temperature that exceeds the operating temperatures limits of conventional ("hot") melters. The cold crucible melter technology has three main advantages: melt temperatures well above the current limit, increased glass production capacity, extended lifetime because of the lower wall temperatures. For these reasons the cold crucible melter can subsequently be used to vitrify a wide range of High-Level Liquid Waste (HLLW). This paper describes the assessment performed to characterize the entrainment of particles or chemicals and/or radioactive species to the off-gas treatment system from a Joule-heated metal melter (JHMM) and from a cold crucible induction melter (CCIM). Vitrification is performed in a two-step process. A calciner is used in each case to dry and calcine the high-level liquid waste, supplying only the dry residue to the melter together with glass frit. The off-gas treatment is identical for both melters. The paper first describes how the CEA uses its reconfigurable vitrification prototype, a full-scale mockup of a La Hague vitrification line, in support of AREVA to anticipate cold crucible melter operation under radioactive conditions. It describes the process equipment constituting the vitrification line from the melter (using a JHMM or a CCIM) to the off-gas treatment system. All the differences that contribute to the modification of radioactive particle entrainment from the calciner/melter to the off-gas treatment system are then described. The results obtained are then discussed concerning the volatility of species produced by vitrification during weekly tests implementing either the conventional melting pot or the cold crucible melter. The distribution of volatile species in the off-gas treatment devices is discussed. The paper concludes with a discussion of how using the CCIM vitrification process on one of the La Hague vitrification units can achieve an increased vitrification throughput at a higher temperature without any impact on the resulting waste release

Guidelines of the French Society of Otorhinolaryngology (SFORL), short version. Extension assessment and principles of resection in cutaneous head and neck tumors

AbstractCutaneous head and neck tumors mainly comprise malignant melanoma, squamous cell carcinoma, trichoblastic carcinoma, Merkel cell carcinoma, adnexal carcinoma, dermatofibrosarcoma protuberans, sclerodermiform basalioma and angiosarcoma. Adapted management requires an experienced team with good knowledge of the various parameters relating to health status, histology, location and extension: risk factors for aggression, extension assessment, resection margin requirements, indications for specific procedures, such as lateral temporal bone resection, orbital exenteration, resection of the calvarium and meningeal envelopes, neck dissection and muscle resection

The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib

The activation of glucocorticoid receptors (GR) by glucocorticoids increases stress-related memory through the activation of the MAPK signaling pathway and the downstream transcription factor Egr-1. Here, using converging in vitro and in vivo approaches, respectively, GR-expressing cell lines, culture of hippocampal neurons, and GR genetically modified mice (GRNesCre), we identified synapsin-Ia/Ib as one of the effectors of the glucocorticoid signaling cascade. Stress and glucocorticoid-induced activation of the GR modulate synapsin-Ia/Ib through two complementary mechanisms. First, glucocorticoids driving Egr-1 expression increase the expression of synapsin-Ia/Ib, and second, glucocorticoids driving MAPK activation increase its phosphorylation. Finally, we showed that blocking fucosylation of synapsin-Ia/Ib in the hippocampus inhibits its expression and prevents the glucocorticoid-mediated increase in stress-related memory. In conclusion, our data provide a complete molecular pathway (GR/Egr-1/MAPK/Syn-Ia/Ib) through which stress and glucocorticoids enhance the memory of stress-related events and highlight the function of synapsin-Ia/Ib as molecular effector of the behavioral effects of stress

Constitutive Notch2 signaling in neural stem cells promotes tumorigenic features and astroglial lineage entry

Recent studies identified a highly tumorigenic subpopulation of glioma stem cells (GSCs) within malignant gliomas. GSCs are proposed to originate from transformed neural stem cells (NSCs). Several pathways active in NSCs, including the Notch pathway, were shown to promote proliferation and tumorigenesis in GSCs. Notch2 is highly expressed in glioblastoma multiforme (GBM), a highly malignant astrocytoma. It is therefore conceivable that increased Notch2 signaling in NSCs contributes to the formation of GBM. Here, we demonstrate that mice constitutively expressing the activated intracellular domain of Notch2 in NSCs display a hyperplasia of the neurogenic niche and reduced neuronal lineage entry. Neurospheres derived from these mice show increased proliferation, survival and resistance to apoptosis. Moreover, they preferentially differentiate into astrocytes, which are the characteristic cellular population of astrocytoma. Likewise, we show that Notch2 signaling increases proliferation and resistance to apoptosis in human GBM cell lines. Gene expression profiling of GBM patient tumor samples reveals a positive correlation of Notch2 transcripts with gene transcripts controlling anti-apoptotic processes, stemness and astrocyte fate, and a negative correlation with gene transcripts controlling proapoptotic processes and oligodendrocyte fate. Our data show that Notch2 signaling in NSCs produces features of GSCs and induces astrocytic lineage entry, consistent with a possible role in astrocytoma formation

Enhanced neuronal Met signalling levels in ALS mice delay disease onset

Signalling by receptor tyrosine kinases (RTKs) coordinates basic cellular processes during development and in adulthood. Whereas aberrant RTK signalling can lead to cancer, reactivation of RTKs is often found following stress or cell damage. This has led to the common belief that RTKs can counteract degenerative processes and so strategies to exploit them for therapy have been extensively explored. An understanding of how RTK stimuli act at cellular levels is needed, however, to evaluate their mechanism of therapeutic action. In this study, we genetically explored the biological and functional significance of enhanced signalling by the Met RTK in neurons, in the context of a neurodegenerative disease. Conditional met-transgenic mice, namely Rosa26LacZ−stop−Met, have been engineered to trigger increased Met signalling in a temporal and tissue-specific regulated manner. Enhancing Met levels in neurons does not affect either motor neuron (MN) development or maintenance. In contrast, increased neuronal Met in amyotrophic lateral sclerosis (ALS) mice prolongs life span, retards MN loss, and ameliorates motor performance, by selectively delaying disease onset. Thus, our studies highlight the properties of RTKs to counteract toxic signals in a disease characterized by dysfunction of multiple cell types by acting in MNs. Moreover, they emphasize the relevance of genetically assessing the effectiveness of agents targeting neurons during ALS evolution